CN111440105A - Alfacalcidol carbamate derivative and preparation method and application thereof - Google Patents
Alfacalcidol carbamate derivative and preparation method and application thereof Download PDFInfo
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- CN111440105A CN111440105A CN202010249534.3A CN202010249534A CN111440105A CN 111440105 A CN111440105 A CN 111440105A CN 202010249534 A CN202010249534 A CN 202010249534A CN 111440105 A CN111440105 A CN 111440105A
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- 229960002535 alfacalcidol Drugs 0.000 title claims abstract description 52
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 title claims abstract description 41
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 7
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 7
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 4
- 201000005202 lung cancer Diseases 0.000 claims abstract description 4
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- -1 nitro, amino, hydroxy Chemical group 0.000 claims description 9
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 10
- 229960005084 calcitriol Drugs 0.000 abstract description 9
- 235000020964 calcitriol Nutrition 0.000 abstract description 9
- 239000011612 calcitriol Substances 0.000 abstract description 9
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 6
- 230000004663 cell proliferation Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 4
- 239000013641 positive control Substances 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 3
- 230000004614 tumor growth Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 230000001472 cytotoxic effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 201000005249 lung adenocarcinoma Diseases 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 201000006035 X-linked dominant hypophosphatemic rickets Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000037180 bone health Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 208000022458 calcium metabolism disease Diseases 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 description 1
- 229960000413 doxercalciferol Drugs 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 208000011111 hypophosphatemic rickets Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000008410 smoothened signaling pathway Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000032349 type 2B vitamin D-dependent rickets Diseases 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to an alfacalcidol carbamate derivative and a method for preparing the compound. The derivative prepared by the invention has stronger activity of inhibiting the growth of tumor cells, and can be expected to be used as an anti-tumor medicament. According to the alfacalcidol carbamate derivative provided by the invention, an aryl carbamate structure is introduced into the compound structure, and the compound is found to have stronger tumor cell proliferation inhibition activity through an in vitro tumor cell proliferation inhibition experiment, is equivalent to or superior to a positive control drug calcitriol, and can be applied to preparation of medicines for preventing and treating breast cancer, colon cancer, lung cancer and liver cancer.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to an alfacalcidol carbamate derivative and a preparation method and application 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 (BoneCare 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.
Disclosure of Invention
The purpose of the invention is as follows: in view of the above, the present invention aims to provide alfacalcidol carbamate derivatives, which have activity of inhibiting tumor cell proliferation equivalent to or better than that of calcitriol, and can be used for preparing antitumor drugs.
The technical scheme is as follows: the invention provides an alfacalcidol carbamate derivative, which has a structure shown in a formula (I):
wherein the R substituents are: H. c1-C6Alkyl of (C)3-C7Cycloalkyl of, C1-C6Alkoxy, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl;
further, the alfacalcidol carbamate derivative has a structure shown in any one of formulas 2a to f:
wherein,
when R is hydrogen, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 a; compound 2 a: 3-O- (phenylcarbamoyl) -alfacalcidol;
when R is 4-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 b; compound 2 b: 3-O- (4' -fluorophenylcarbamoyl) -alfacalcidol;
when R is 4-chlorphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 c; compound 2 c: 3-O- (4' -chlorophenylcarbamoyl) -alfacalcidol;
when R is 4-methoxyphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 d; compound 2 d: 3-O- (4' -methoxyphenylcarbamoyl) -alfacalcidol;
when R is 3-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 e; compound 2 e: 3-O- (3' -fluorophenylcarbamoyl) -alfacalcidol;
when R is 4-nitrophenyl, the alfacalcidol carbamate derivative is a compound having a structure shown by formula 2 f; compound 2 f: 3-O- (4' -nitrophenylcarbamoyl) -alfacalcidol.
The invention also provides a preparation method of the alfacalcidol carbamate derivative, which comprises the following steps:
is prepared by reacting alfacalcidol with N, N-Carbonyldiimidazole (CDI) in toluene to obtain 3-O-imidazolecarboxylatol, then reacting with substituted aniline and 1, 8-diazabicycloundecen-7-ene (DBU) in N, N-dimethylformamide, and then reacting in methanol at 55 ℃,
wherein the reaction has the formula:
the invention also provides application of the alfacalcidol carbamate derivative in preparing medicines for preventing and treating breast cancer, colon cancer, lung cancer and liver cancer.
Has the advantages that: compared with the prior art, the alfacalcidol carbamate derivative provided by the invention has the advantages that an aryl carbamate structure is introduced into the compound structure, and the compound is found to have stronger tumor cell proliferation inhibition activity through an in vitro tumor cell proliferation inhibition experiment, is equivalent to or superior to calcitriol serving as a positive control drug, and can be applied to preparation of drugs for preventing and treating breast cancer, colon cancer, lung cancer and liver cancer.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Detailed description of the preferred embodiment 1
Dissolving 400mg (1mmol) of alfacalcidol in 10m L of toluene, adding 0.4m L (2.5mmol) of triethylamine and 350mg (2mmol) of N, N-carbonyldiimidazole, reacting at room temperature for 48 hours, adding saturated sodium bicarbonate 10m L into the reaction solution, quenching the reaction solution, extracting 3 times with 10m L of toluene, combining organic phases, sequentially washing with water, washing with saturated salt water, and MgSO 34Drying, concentrating under reduced pressure, and performing column chromatography (prtroleum ether: EtOAc: 3:1, Rf0.3) to yield 330mg of a pale yellow solid, yield 67%, dissolving the solid in 10m L of N, N-dimethylformamide, slowly adding 0.15m L (1mmol) of 1, 8-diazabicycloundecen-7-ene (DBU) and 93mg (1mmol) of aniline at 0 ℃, heating the reaction mixture to room temperature, reacting for 12 hours, adding 10m L of water to quench the reaction, extracting the aqueous phase three times with 10m L of ethyl acetate, combining the organic phases, then washing with water, washing with saturated brine, MgSO L, washing with water, mixing the organic phases, washing with water, washing with saturated brine, and drying4Drying and drying under reduced pressure to give the crude product, dissolving the crude product in 15m L methanol, heating to 55 deg.C and stirring at this temperature for 20 hours, concentrating the reaction solution, column chromatography (prtraleum ether: EtOAc ═ 2:1, Rf0.3) gave 260mg of a pale yellow solid in 75% yield.
The nuclear magnetic resonance detection of 3-O- (phenylcarbamoyl) -alfacalcidol (2a) shows that:1H NMR(400MHz,CDCl3):7.51-7.49(2H,m,ArH×2),7.32(1H,d,J＝7.5Hz,ArH),7.20-7.18(2H,m,ArH×2),6.38(1H,d,J＝11.3Hz,H-6),6.02(1H,d,J＝11.3Hz,H-7),5.33(1H,t,J＝1.5Hz,H-19Z),5.01(1H,s,H-19E),4.44(1H,dd,J＝7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),2.83(1H,dd,J＝11.8,3.8Hz,H-14),2.60(1H,dd,J＝13.4,3.3Hz),2.32(1H,dd,J＝13.4,6.6Hz,H-4b),0.92(3H,d,J＝6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3)；HRMS(ESI):m/z calcd for C34H50NO3:520.3785；found:520.3790[M+H]+。
EXAMPLES 2 to 6(2b to 2f)
The following example compounds were prepared according to the method of example 1 above
The following are presented as physicochemical data for each of the compounds 2b-2 f:
2b：1H NMR(400MHz,CDCl3):7.54(d,J＝1.8Hz,ArH),7.52(d,J＝1.8Hz,ArH),7.21(1H,d,J＝2.1Hz,ArH),7.18(1H,d,J＝2.1Hz,ArH),6.38(1H,d,J＝11.3Hz,H-6),6.02(1H,d,J＝11.3Hz,H-7),5.33(1H,t,J＝1.5Hz,H-19Z),5.01(1H,s,H-19E),4.44(1H,dd,J＝7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),2.83(1H,dd,J＝11.8,3.8Hz,H-14),2.60(1H,dd,J＝13.4,3.3Hz),2.32(1H,dd,J＝13.4,6.6Hz,H-4b),0.92(3H,d,J＝6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3)；HRMS(ESI):m/z calcd for C34H49FNO3:538.3691；found:538.3697[M+H]+。
2c：1H NMR(400MHz,CDCl3):7.52(1H,d,J＝1.8Hz,ArH),7.44(1H,d,J＝2.1Hz,ArH),7.18(1H,d,J＝1.8Hz,ArH),7.15(1H,d,J＝1.8Hz,ArH),6.38(1H,d,J＝11.3Hz,H-6),6.02(1H,d,J＝11.3Hz,H-7),5.33(1H,t,J＝1.5Hz,H-19Z),5.01(1H,s,H-19E),4.44(1H,dd,J＝7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),2.83(1H,dd,J＝11.8,3.8Hz,H-14),2.60(1H,dd,J＝13.4,3.3Hz),2.32(1H,dd,J＝13.4,6.6Hz,H-4b),0.92(3H,d,J＝6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3)；HRMS(ESI):m/z calcd forC34H49ClNO3:554.3395；found:554.3391[M+H]+。
2d：1H NMR(400MHz,CDCl3):7.51-7.49(2H,m,ArH×2),7.02-6.98(2H,m,ArH×2),6.38(1H,d,J＝11.3Hz,H-6),6.02(1H,d,J＝11.3Hz,H-7),5.33(1H,t,J＝1.5Hz,H-19Z),5.01(1H,s,H-19E),4.44(1H,dd,J＝7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),3.78(3H,s,OCH3)2.83(1H,dd,J＝11.8,3.8Hz,H-14),2.60(1H,dd,J＝13.4,3.3Hz),2.32(1H,dd,J＝13.4,6.6Hz,H-4b),0.92(3H,d,J＝6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3)；HRMS(ESI):m/z calcd for C35H52NO4:550.3891；found:550.3882[M+H]+。
2e:1H NMR(400MHz,CDCl3):7.52(1H,s,ArH),7.44(1H,d,J＝2.1Hz,ArH),7.21(1H,s,ArH),7.10(1H,s,ArH),6.38(1H,d,J＝11.3Hz,H-6),6.02(1H,d,J＝11.3Hz,H-7),5.33(1H,t,J＝1.5Hz,H-19Z),5.01(1H,s,H-19E),4.44(1H,dd,J＝7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),2.83(1H,dd,J＝11.8,3.8Hz,H-14),2.60(1H,dd,J＝13.4,3.3Hz),2.32(1H,dd,J＝13.4,6.6Hz,H-4b),0.92(3H,d,J＝6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3)；HRMS(ESI):m/z calcd for C34H49FNO3:538.3691；found:538.3693[M+H]+。
2f：1H NMR(400MHz,CDCl3):7.98-7.97(2H,m,ArH×2),7.82-7.80(2H,m,ArH×2),6.38(1H,d,J＝11.3Hz,H-6),6.02(1H,d,J＝11.3Hz,H-7),5.33(1H,t,J＝1.5Hz,H-19Z),5.01(1H,s,H-19E),4.44(1H,dd,J＝7.8,4.3Hz,H-1b),4.26-4.25(1H,m,H-3a),2.83(1H,dd,J＝11.8,3.8Hz,H-14),2.60(1H,dd,J＝13.4,3.3Hz),2.32(1H,dd,J＝13.4,6.6Hz,H-4b),0.92(3H,d,J＝6.5Hz,CH3),0.88-0.87(6H,m,CH3×2),0.55(3H,s,CH3)；HRMS(ESI):m/z calcd for C34H49N2O5:565.3636；found:565.3641[M+H]+。
in order to better understand the essence of the invention, the pharmacological experiment results of the inhibitory action of the alfacalcidol carbamate derivative provided by the invention on the growth of four tumor cell lines are used for explaining the new application of the alfacalcidol carbamate derivative 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: compounds 2a to 2f and calcitriol were tested for cytotoxic activity on breast cancer cells (MCF-7):
human breast cancer cells MCF-7 were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100U/m L penicillin and 100U/m L streptomycin at 5 × 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 2f were dissolved in DMSO to prepare 1 × 10-2Diluting the mother liquor of mol/L to corresponding concentration with complete culture medium, inoculating cells in logarithmic growth phase into 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 dimethyl sulfoxide 150 mu L, oscillating for 10min, measuring absorbance (A) value at 570nm with enzyme labeling instrument, and calculating half Inhibition Concentration (IC)50) Specifically, the examples are shown in Table 1. As can be seen from Table 1, IC of Compound 2a50Is 9 × 10-9M, and IC of positive control calcitriol on MCF-7 cells50Is 16 × 10-9M。
Drug experimental examples 2 to 4: the cytotoxic activity of the compounds 2a to 2f and calcitriol on human colon cancer cells (HCT-116), human lung adenocarcinoma cells (A549) and human liver cancer cells (HepG2) was tested:
pharmacological experiments were conducted on the growth inhibitory effects of human colon cancer cells (HCT-116), human lung adenocarcinoma cells (A549) and human liver cancer cells (HepG2) by the method shown in pharmaceutical Experimental example 1, and the median Inhibitory Concentration (IC) was calculated50) Specifically, the examples are shown in Table 1.
TABLE 1 cytotoxic Activity test results for Compounds 2 a-2 f and paclitaxel
As can be seen from Table 1, the alfacalcidol carbamate derivative provided by the invention has important biological activity, and cytotoxic activity tests of four tumor cells including human breast cancer cells (MCF-7), human colon cancer cells (HCT-116), human lung adenocarcinoma cells (A549) and human liver cancer cells (HepG2) in vitro show that: the alfacalcidol carbamate derivative with the structure shown in the formula (1) has an inhibiting effect on the growth of tumor cells, and can be possibly developed into a novel tumor prevention and treatment drug. From the pharmacological examples, the compounds show stronger cytotoxic activity on the four tumor cells, the cytotoxic activity exceeds or is equivalent to that of positive control calcitriol, 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 (4)
1. An alfacalcidol carbamate derivative, characterized in that it has the structure represented by formula (I):
wherein the R substituents are: H. c1-C6Alkyl of (C)3-C7Cycloalkyl of, C1-C6Alkoxy, nitro, amino, hydroxy, cyano, halogen, trifluoromethyl.
2. The alfacalcidol carbamate derivative according to claim 1, wherein the alfacalcidol carbamate derivative has a structure as shown in any one of formulas 2a to f:
wherein,
when R is hydrogen, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 a; compound 2 a: 3-O- (phenylcarbamoyl) -alfacalcidol;
when R is 4-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 b; compound 2 b: 3-O- (4' -fluorophenylcarbamoyl) -alfacalcidol;
when R is 4-chlorphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 c; compound 2 c: 3-O- (4' -chlorophenylcarbamoyl) -alfacalcidol;
when R is 4-methoxyphenyl, the alfacalcidol carbamate derivative is a compound with a structure shown in a formula 2 d; compound 2 d: 3-O- (4' -methoxyphenylcarbamoyl) -alfacalcidol;
when R is 3-fluorophenyl, the alfacalcidol carbamate derivative is a compound with a structure shown as a formula 2 e; compound 2 e: 3-O- (3' -fluorophenylcarbamoyl) -alfacalcidol;
when R is 4-nitrophenyl, the alfacalcidol carbamate derivative is a compound having a structure shown by formula 2 f; compound 2 f: 3-O- (4' -nitrophenylcarbamoyl) -alfacalcidol.
3. A process for the preparation of an alfacalcidol carbamate derivative according to claim 1, comprising the steps of:
the alfacalcidol is reacted with N, N-Carbonyldiimidazole (CDI) in toluene to obtain 3-O-imidazolecarboxylatol, then the 3-O-imidazolecarboxylatol is reacted with substituted aniline and 1, 8-diazabicycloundecen-7-ene (DBU) in N, N-dimethylformamide, and then the reaction is carried out in methanol at 55 degrees to obtain the alfacalcidol;
wherein the reaction has the formula:
4. use of the alfacalcidol carbamate derivative according to claim 1 in the preparation of a medicament for the prevention and treatment of breast cancer, colon cancer, lung cancer and liver cancer.
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