CN105669823A - Piperazine-framework-containing glycyrrhetinic acid derivatives, and preparation method and application thereof - Google Patents
Piperazine-framework-containing glycyrrhetinic acid derivatives, and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical class C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 title claims abstract description 10
- 150000002342 glycyrrhetinic acids Chemical class 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 claims description 5
- 229960003720 enoxolone Drugs 0.000 claims description 5
- 238000011275 oncology therapy Methods 0.000 claims description 5
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 claims description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
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- 206010006187 Breast cancer Diseases 0.000 abstract description 4
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- 230000002401 inhibitory effect Effects 0.000 abstract description 4
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- 208000014018 liver neoplasm Diseases 0.000 abstract description 4
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- 108091008605 VEGF receptors Proteins 0.000 description 1
- 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 description 1
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- 229940058965 antiprotozoal agent against amoebiasis and other protozoal diseases nitroimidazole derivative Drugs 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 230000036212 malign transformation Effects 0.000 description 1
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- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical group CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses piperazine-framework-containing glycyrrhetinic acid derivatives, and a preparation method and application thereof. The structure of the synthesized glycyrrhetinic acid derivatives is disclosed in the specification. The glycyrrhetinic acid derivatives have obvious inhibiting actions on human liver cancer cells (HepG2), human mammary cancer cells (MCF-1), cervical cancer cell lines (Hela cells) and human lung adenocarcinoma cells (A549). Therefore, the piperazine-framework-containing glycyrrhetinic acid derivatives can be used for preparing antineoplastic drugs.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly relate to containing the Enoxolone derivative of piperazine skeleton, its preparation method and application.
Background technology
The multiple physiology of human body and pathological process have been directed to new vessels generation, and new vessels generates and refers to the process forming new blood vessel from the blood capillary being pre-existing in the mode of sprouting, and it plays an important role in growth and metastasis of tumours. Most important of which is that VEGF (VEGF), it is bred at tumor-blood-vessel growth, vascular permeability, activated endothelial cell and plays an important role in migrating. This VEGFR family includes VEGFR1, VEGFR2 and VEGFR3. Wherein VEGFR2 plays VEGF and drives the endotheliocyte adjustment effect significantly of response, is the propagation including blood vessel and mediation endotheliocyte, differentiation, and the tyrosine kinase receptor of microvascular permeability. VEGFR2 is current research focus, and their overexpression and abnormal activation generally can cause malignant transformation of cells. And they are bad with postoperative, radiation and chemotherapy tolerates and tumor-blood-vessel growth is relevant. The block of VEGFR2 has been become an effective method of oncotherapy by clinical verification.
In former research, enoxolone has been proved antiinflammatory, antiviral and anti-tumor activity, but tumor only has faint inhibitory action. Piperazine is heterocyclic compound, compared with the medicine of tradition organic synthesis, has good nitrogen balance structure. 30 hydroxyls that bridged piperazine derivatives replaces are likely to promise to be the lead compound that exploitation is new, effective and safe.
Summary of the invention
It is an object of the invention to provide a class as VEGFR2 inhibitor containing the Enoxolone derivative of piperazine skeleton, its preparation method and the application in cancer therapy drug thereof.
Technical scheme a: class is containing the Enoxolone derivative of piperazine skeleton, and its structure is such as shown in formula,
A kind of method of the Enoxolone derivative prepared containing piperazine skeleton, the structure of the described Enoxolone derivative containing piperazine skeleton is such as shown in formula,
Preparation method following steps:
Under room temperature condition, in reaction vessel, add 20mL dichloromethane solution, sequentially add DCC and HOBT, 30min is stirred at room temperature, add enoxolone and 20min is stirred at room temperature. Then bridged piperazine derivatives and triethylamine are stirred at room temperature 24h, TLC and follow the tracks of reaction, fully after reaction, obtain target compound.
The application in preparing cancer therapy drug of the Enoxolone derivative containing piperazine skeleton, its structure is such as shown in formula
A kind of cancer therapy drug, the such as compound shown in formula and medically acceptable carrier including structure,
The present invention is to human liver cancer cell (HepG2), human breast cancer cell (MCF-7), Human cervical cancer cell lines (HeLa cell) and human lung adenocarcinoma cell (A549) have obvious inhibitory action, and therefore the Enoxolone derivative containing piperazine skeleton of the present invention can apply to prepare antitumor drug.
Detailed description of the invention
In certain specific embodiment, the preparation process of the present invention and the structural formula of associated products are as described below:
A kind of method preparing the above-mentioned Enoxolone derivative containing piperazine skeleton, it comprises the following steps:
At room temperature, in reaction vessel, add 20mL dichloromethane solution, sequentially add each 1.2mmol of DCC and HOBT, 30min is stirred at room temperature, add enoxolone (1mmol) and 20min is stirred at room temperature. Then bridged piperazine derivatives (1.2mmol) and triethylamine (3mmol) are stirred at room temperature 24h, TLC and follow the tracks of reaction, fully after reaction, obtain target compound.
Embodiment one: 3 β hydroxyl-30-(4-phenyl-peiperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3a)
At room temperature, in reaction vessel, add 20mL dichloromethane solution, sequentially add each 1.2mmol of DCC and HOBT, 30min is stirred at room temperature, add enoxolone (1mmol) and 20min is stirred at room temperature. Then phenylpiperazine (1.2mmol) and triethylamine (3mmol) are stirred at room temperature 24h, TLC and follow the tracks of reaction, fully after reaction, obtain compound 3a. Yield:83%.M.p.282-284 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.20-7.27 (m, 2H, Ar-7 ', 9 '), 6.94 (d, J=7.92Hz, 2H, Ar-6 ', 10 '), 6.81 (t, J=7.24Hz, 1H, Ar-8 '), 5.48 (s, 1H, CH-12), 4.32 (d, J=5.16Hz, 1H ,-OH), 3.70 (s, 4H, CH2-1 ', CH2-4 '), 3.10 (t, J=4.60Hz, 4H, CH2-2 ', CH2-3 '), 2.98-3.05 (m, 1H, CH-3), 2.57 (d, J=13.32Hz, 1H, CH-18), 2.33 (s, 1H, CH-9), 2.26-1.36 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.02 (s, 6H, Me-25, Me-26), 0.96 (d, J=13.44Hz, 2H, CH2-1), 0.90 (s, 3H, Me-23), 0.73 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment two: 3 β hydroxyl-30-(4-(2,4-3,5-dimethylphenyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3b)
Preparation method reference example one. Yield:79%.M.p.175-177 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 6.88-7.00 (m, 3H, Ar-6 ' 7 ', 9 '), 5.52 (s, 1H, CH-12), 4.32 (d, J=5.16Hz, 1H ,-OH), 3.68 (s, 4H, CH2-1 ', CH2-4 '), 2.99-3.05 (m, 1H, CH-3), 2.75 (s, 4H, CH2-2 ', CH2-3 '), 2.57 (d, J=13.36Hz, 1H, CH-18), 2.33 (s, 1H, CH-9), 2.22 (d, J=7.04Hz, 6H, Me-8 ', Me-10 '), 2.17-1.37 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.03 (d, J=1.64Hz, 6H, Me-25, Me-26), 0.97 (d, J=14.32Hz, 2H, CH2-1), 0.91 (s, 3H, Me-23), 0.75 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment three: 3 β hydroxyl-30-(4-(4-nitrobenzophenone)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3c)
Preparation method reference example one.Yield:74%.M.p.252-254 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 8.09 (d, J=9.44Hz, 2H, Ar-7 ', 9 '), 7.00 (d, J=9.52Hz, 2H, Ar-6 ', 10 '), 5.50 (s, 1H, CH-12), 4.32 (d, J=5.16Hz, 1H ,-OH), 3.72 (s, 4H, CH2-1 ', CH2-4 '), 3.48 (d, J=4.56Hz, 4H, CH2-2 ', CH2-3 '), 2.99-3.05 (m, 1H, CH-3), 2.57 (d, J=13.36Hz, 1H, CH-18), 2.33 (s, 1H, CH-9), 2.24-1.36 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.03 (s, 6H, Me-25, Me-26), 0.97 (d, J=13.64Hz, 2H, CH2-1), 0.91 (s, 3H, Me-23), 0.74 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment four: 3 β hydroxyl-30-(4-(2,3-Dichlorobenzene base)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3d)
Preparation method reference example one. Yield:86%.M.p.277-279 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.32-7.35 (m, H, Ar-7 ', 8 '), 7.14-7.18 (m, 1H, Ar-6 '), 5.52 (s, 1H, CH-12), 4.31 (d, J=5.16Hz, 1H ,-OH), 3.72 (s, 4H, CH2-1 ', CH2-4 '), 2.99-3.05 (m, 1H, CH-3), 2.95 (s, 4H, CH2-2 ', CH2-3 '), 2.58 (d, J=13.28Hz, 1H, CH-18), 2.33 (s, 1H, CH-9), 2.25-1.37 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.20 (s, 3H, Me-29), 1.03 (s, 6H, Me-25, Me-26), 0.97 (d, J=13.68Hz, 2H, CH2-1), 0.91 (s, 3H, Me-23), 0.75 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment five: 3 β hydroxyl-30-(4-(3,4-Dichlorobenzene base)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3e)
Preparation method reference example one. Yield:80%.M.p.283-285 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.42 (d, J=9.00Hz, 1H, Ar-7 '), 7.13 (d, J=2.88Hz, 1H, Ar-10 '), 6.92-6.96 (m, 1H, Ar-6 '), 5.48 (s, 1H, CH-12), 4.32 (d, J=5.16Hz, 1H ,-OH), 3.69 (s, 4H, CH2-1 ', CH2-4 '), 3.16 (t, J=4.72Hz, 4H, CH2-2 ', CH2-3 '), 2.99-3.05 (m, 1H, CH-3), 2.57 (d, J=13.32Hz, 1H, CH-18), 2.33 (s, 1H, CH-9), 2.25-1.35 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.02 (s, 6H, Me-25, Me-26), 0.96 (d, J=13.48Hz, 2H, CH2-1), 0.91 (s, 3H, Me-23), 0.73 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment six: 3 β hydroxyl-30-(4-(4-methoxyphenyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3f)
Preparation method reference example one.Yield:77%.M.p.218-220 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 6.90 (d, J=9.2,2H, Ar-6 ', 10 '), 6.89 (d, J=9.16,2H, Ar-7 ', 9 '), 5.50 (s, 1H, CH-12), 4.32 (d, J=5.16Hz, 1H ,-OH), 3.69 (s, 7H, CH2-1 ', CH2-4 ' ,-OCH3), 2.99-3.05 (m, 1H, CH-3), 2.96 (t, J=4.36Hz, 4H, CH2-2 ', CH2-3 '), 2.57 (d, J=13.36Hz, 1H, CH-18), 2.33 (s, 1H, CH-9), 2.25-1.35 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.03 (s, 6H, Me-25, Me-26), 0.97 (d, J=13.24Hz, 2H, CH2-1), 0.91 (s, 3H, Me-23), 0.73 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment seven: 3 β hydroxyl-30-(4-(2-fluorophenyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3g)
Preparation method reference example one. Yield:75%.M.p.253-255 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.10-7.18 (m, 2H, Ar-7 ', 9 '), 6.97-7.07 (m, 2H, Ar-8 ', 10 '), 5.51 (s, 1H, CH-12), 4.31 (d, J=5.04,1H ,-OH), 3.71 (s, 4H, CH2-1 ', CH2-4 '), 3.00-3.05 (m, 1H, CH-3), 2.97 (d, J=4.20,4H, CH2-2 ', CH2-3 '), 2.58 (d, J=13.36,1H, CH-18), 2.33 (s, 1H, CH-9), 2.27-1.36 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.03 (s, 6H, Me-25, Me-26), 0.97 (d, J=13.84,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.74 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment eight: 3 β hydroxyl-30-(4-(3-methoxyphenyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3h)
Preparation method reference example one. Yield:70%.M.p.196-198 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.13 (t, J=8.20,1H, Ar-9 '), 6.53 (d, J=8.32,2H, Ar-10 '), 6.46 (s, 1H, Ar-6 '), 6.40 (d, J=8.04,1H, Ar-8 '), 5.48 (s, 1H, CH-12), 4.31 (d, J=5.04,1H,-OH), 3.72 (s, 3H ,-OCH3), 3.68 (s, 4H, CH2-1 ', CH2-4 '), 3.10 (s, 4H, CH2-2 ', CH2-3 '), 2.99-3.05 (m, 1H, CH-3), 2.57 (d, J=13.48,1H, CH-18), 2.33 (s, 1H, CH-9), 2.24-1.55 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.02 (s, 6H, Me-25, Me-26), 0.96 (d, J=13.64,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.73 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment nine: 3 β hydroxyl-30-(4-(3-(trifluoromethyl) phenyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3i)
Preparation method reference example one.Yield:78%.M.p.247-249 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.44 (t, J=8.04,1H, Ar-7 '), 7.23 (d, J=8.48,1H, Ar-6 '), 7.17 (s, 1H, Ar-10 '), 7.10 (d, J=7.56,1H, Ar-8 '), 5.49 (s, 1H, CH-12), 4.30 (d, J=5.16,1H,-OH), 3.71 (s, 4H, CH2-1, CH2-4 '), 3.22 (d, J=4.56,4H, CH2-2 ', CH2-3 '), 2.98-3.05 (m, 1H, CH-3), 2.57 (d, J=13.16,1H, CH-18), 2.33 (s, 1H, CH-9), 2.26-1.36 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.20 (s, 3H, Me-29), 1.03 (s, 6H, Me-25, Me-26), 0.97 (d, J=10.11,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.74 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment ten: 3 β hydroxyl-30-(4-(3-chlorphenyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3j)
Preparation method reference example one. Yield:78%.M.p.284-286 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.23 (t, J=8.12,1H, Ar-9 '), 6.95 (s, 1H, Ar-6 '), 6.90 (d, J=8.44,2H, Ar-10 '), 6.82 (m, 1H, Ar-8 '), 5.49 (s, 1H, CH-12), 4.30 (s, 1H ,-OH), 3.68 (s, 4H, CH2-1 ', CH2-4 '), 3.15 (t, J=4.56,4H, CH2-2 ', CH2-3 '), 2.98-3.05 (m, 1H, CH-3), 2.57 (d, J=13.60,1H, CH-18), 2.33 (s, 1H, CH-9), 2.25-1.37 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.02 (s, 6H, Me-25, Me-26), 0.96 (d, J=13.36,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.74 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment 11: 3 β hydroxyl-30-(4-(4-fluorophenyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3k)
Preparation method reference example one. Yield:72%.M.p.170-172 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 6.94-7.01 (m, 2H, Ar-7 ', 9 '), 6.88 (d, J=7.52,2H, Ar-6 ', 10 '), 5.51 (s, 1H, CH-12), 4.33 (s, 1H ,-OH), 3.68 (s, 4H, CH2-1 ', CH2-4 '), 2.99-3.05 (m, 1H, CH-3), 2.91 (s, 4H, CH2-2 ', CH2-3 '), 2.58 (d, J=13.28,1H, CH-18), 2.33 (s, 1H, CH-9), 2.26-1.38 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.19 (s, 3H, Me-29), 1.03 (s, 6H, Me-25, Me-26), 0.96 (d, J=12.28,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.74 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment 12: 3 β hydroxyl-30-(4-(2-pyridine radicals)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (31)
Preparation method reference example one.Yield:73%.M.p.272-274 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 8.11-8.14 (m, 1H, CH-6 '), 7.53-7.58 (m, 1H, CH-8 '), 6.82 (d, J=8.64,1H, CH-7 '), 6.66-6.69 (m, 1H, CH-9 '), 5.50 (s, 1H, CH-12), 4.31 (d, J=5.16,1H ,-OH), 3.67 (s, 4H, CH2-1 ', CH2-4 '), 3.46 (t, J=4.84,4H, CH2-2 ', CH2-3 '), 2.99-3.05 (m, 1H, CH-3), 2.57 (d, J=13.32,1H, CH-18), 2.33 (s, 1H, CH-9), 2.27-1.36 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.20 (s, 3H, Me-29), 1.02 (s, 6H, Me-25, Me-26), 0.97 (d, J=13.40,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.73 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment 13: 3 β hydroxyl-30-(4-(3-pyridine radicals)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3m)
Preparation method reference example one. Yield:72%.M.p.246-248 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 8.11 (d, J=3.72,1H, CH-6 '), 7.65 (s, 1H, CH-7 '), 6.92 (d, J=8.40,1H, CH-8 '), 6.73 (t, J=5.68,1H, CH-9 '), 5.49 (s, 1H, CH-12), 4.03 (d, J=5.16,1H,-OH), 3.68 (s, 4H, CH2-1 ', CH2-4 '), 3.50 (s, 4H, CH2-2 ', CH2-3 '), 2.99-3.05 (m, 1H, CH-3), 2.57 (d, J=4.4,1H, CH-18), 2.33 (s, 1H, CH-9), 2.24-1.39 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.35 (s, 3H, Me-27), 1.20 (s, 3H, Me-29), 1.02 (s, 6H, Me-25, Me-26), 0.97 (d, J=13.64,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.74 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment 14: 3 β hydroxyl-30-(4-ethyl-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3n)
Preparation method reference example one. Yield:82%.M.p.173-175 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 5.48 (s, 1H, CH-12), 4.30 (d, J=5.12,1H ,-OH), 3.52 (s, 4H, CH2-1, CH2-4 '), 2.98-3.05 (m, 1H, CH-3), 2.57 (d, J=13.48,1H, CH-18), 2.32 (s, 7H, CH-9, CH2-2 ', CH2-3 ', CH2-5 '), 2.20-1.38 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.34 (s, 3H, Me-27), 1.15 (s, 3H, Me-29), 1.03 (s, 6H, Me-25, Me-26), 0.99 (d, J=7.16,3H, Me-6 '), 0.95 (s, 2H, CH2-1), 0.91 (s, 3H, Me-23), 0.73 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment 15: 3 β hydroxyl-30-(4-benzhydryl-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3o)
Preparation method reference example one.Yield:81%.M.p.170-172 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.41-7.47 (m, 4H, Ar-2 ", 6 ", 8 " and, 12 "), 7.30 (t, J=7.24,4H, Ar-3 ", 5 "; 9 ", 11 "), 7.19 (t, J=7.28,2H; Ar-4 ", 10 "), 5.49 (s, 1H, CH-12); 4.31 (d, J=4.68,1H ,-OH), 4.27 (s; 1H, CH-5 '), 3.56 (s, 4H, CH2-1 ', CH2-4 '), 3.33 (s, 4H, CH2-2 ', CH2-3 '), 2.98-3.04 (m, 1H, CH-3), 2.58 (d, J=13.48,1H, CH-18), 2.31 (s, 1H, CH-9), 2.19-1.57 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.32 (s, 3H, Me-27), 1.11 (s, 3H, Me-29), 1.03 (d, J=3.08,6H, Me-25, Me-26), 0.95 (d, J=13.48,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.72 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment 16: 3 β hydroxyl-30-(4-(double; two (4-fluorophenyl) methyl)-1-piperazinyl)-olive-12-alkene-11, the preparation of 30-diketone (3p)
Preparation method reference example one. Yield:81%.M.p.169-171 DEG C.1HNMR (400MHz, DMSO-d6): δ (ppm) 7.41-7.50 (m, 4H, Ar-2 ", 6 ", 8 "; 12 "), 7.13 (t, J=8.28,4H, Ar-3 ", 5 ", 9 " and, 11 "), 5.49 (s, 1H, CH-12), 4.36 (s, 1H, CH-5 '), 4.30 (s, 1H,-OH), 3.55 (s, 4H, CH2-1 ', CH2-4 '), 2.98-3.05 (m, 1H, CH-3), 2.59 (d, J=13.24,1H, CH-18), 2.31 (s, 1H, CH-9), 2.25 (s, 4H, CH2-2 ', CH2-3 '), 2.19-1.36 (m, 16H, CH2-2, CH2-6, CH2-7, CH2-15, CH2-16, CH2-19, CH2-21, CH2-22), 1.32 (s, 3H, Me-27), 1.11 (s, 3H, Me-29), 1.03 (d, J=3.76,6H, Me-25, Me-26), 0.95 (d, J=4.40,2H, CH2-1), 0.91 (s, 3H, Me-23), 0.72 (s, 3H, Me-24), 0.71 (s, 1H, CH-5), 0.69 (s, 3H, Me-28).
Embodiment 19: the Anticancer Activity in vitro progress of the Enoxolone derivative containing piperazine skeleton
Adopt MTT [3-(4,5)-bis-methyl-2-thiazoles-(2,5)-phenyl bromination tetrazole is blue] method measures the pyrazoles nitro imidazole derivatives containing metronidazole skeleton to human liver cancer cell (HepG2), human breast cancer cell (MCF-7), the suppression ratio of Human cervical cancer cell lines (HeLa cell) and human lung adenocarcinoma cell (A549) reaches drug level (halfmaximalinhibitoryconcentration, IC when 50%50)。
(1) preparation of culture fluid: DMEM (basal medium) 89%, hyclone 10%, Penicillin Streptomycin Solution (10000IU/mL, 10000 μ g/mL) 1%.
The cultivation of (2) four kinds of adherent cancerous cell: utilize above-mentioned culture fluid (culture fluid volume is about the 1/10 of culture bottle capacity), at 37 DEG C, 5%CO2Incubator is cultivated, judges the generation time according to the growth conditions of cancerous cell.
(3) preparation of variable concentrations medicine: utilizing tri-distilled water (a small amount of DMSO hydrotropy) to prepare storing solution, in the every porocyte suspension after dosing, the final concentration of DMSO is usually no more than 0.05%-0.1%;With tri-distilled water, storing solution is diluted to six Concentraton gradient (10 μ g/mL, 2 μ g/mL, 0.4 μ g/mL, 0.08 μ g/mL, 0.016 μ g/mL, 0.003 μ g/mL); It is stored in-20 DEG C of refrigerators standby.
(4) cell incubation: trophophase tumor cell of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 105/mL, adds in (100 μ L/ hole) in 96 well culture plates after mixing, at 37 DEG C, 5%CO2Incubator is cultivated 24h.
(5) dosing: be added separately in 96 well culture plates by the medicine of the variable concentrations gradient diluted, each Concentraton gradient sets 3 flat hole, continues to cultivate 48h. Experiment is divided into experimental group (culture fluid, cell, medicine), matched group (culture fluid and cell) and blank group (only culture fluid).
(6) survivaling cell detection: in 96 orifice plates after having cultivated 48h, add MTT (5mg/mL) 10 μ L/ hole; After placing 4h at 37 DEG C, removing supernatant, add DMSO150 μ L/ hole, vibration to formazan crystallization is all dissolved; Automatic microplate reader is utilized to detect the optical density (OD value) in each hole at 570nrn wavelength place.
The calculating of suppression ratio:
(OD tests the average optical representing experimental group to growth inhibition ratio=(1-survival rate) × 100%=[1-(it is blank that OD tests-OD)/(it is blank that OD compares-OD)] × 100%, OD comparison represents the average optical of matched group, and OD blank represents the average optical of blank group).
Standard curve according to drug level-inhibitory rate of cell growth, seeks its IC50。
The present invention listed Enoxolone derivative containing the piperazine skeleton suppression IC to tumor cell50Value (μm ol/mL) is shown in following table
From above-mentioned experiment: the present invention is to human liver cancer cell (HepG2), human breast cancer cell (MCF-7), Human cervical cancer cell lines (HeLa cell) and human lung adenocarcinoma cell (A549) have obvious inhibitory action, compared with matched group, activity significantly improves.
Embodiment 20: the Enoxolone derivative anti tumor activity in vitro containing piperazine skeleton is about Cytotoxic research
The present invention tests newly synthesized compound 3a, 3c, 3d, 3e, 3h, 3i, the 3j cytotoxicity to people's renal epithelial cell (293T), cytotoxicity result is following table such as, the concentration (CC when toxicity of each compound suppresses 293T cell survival rate to 50%50) represent.
Experimental technique:
(1) cultivate people's renal epithelial cell (293T) until reaching its logarithmic growth end of term cell and tending to merging, digest cell dispersion with cell dissociation buffer, be configured to the cell suspension of 1 × 104/mL with cell culture fluid. Take 96 well culture plates, every hole adds the cell suspension of 100 μ L. Horizontally rotating culture plate gently makes cell be evenly dispersed in the surface in ware hole.
(2) it is placed in containing 5%CO2In cell culture incubator, at 37 ± 2 DEG C of temperature, cultivate 24h. Discarding original fluid, every hole adds the blank liquid of 100 μ L, negative controls, positive control solution, the test specimen lixiviating solution of 100% and 50% concentration. Often organize and at least set 8 holes. Note: lixiviate stock solution or make the serial lixiviate diluent of diluent with culture medium. When adopting 0.9% sodium chloride injection lixiviate, use 2 times of culture medium of concentration when diluting lixiviate.
(3) it is placed in containing 5%CO2In incubator, cultivate at 37 ± 2 DEG C of temperature. Cultivate 48h.
(4) after date between each cultivation, every hole adds MTT solution 20 μ L, is placed in containing 5%CO2In incubator, at 37 ± 2 DEG C of temperature, cultivate 5h.
(5) discarding liquid in hole, every hole is separately added into 200 μ LDMSO, and culture plate is placed 10min, and level is rocked and made solution colour in hole uniform.
(6) measuring absorbance by microplate reader, wavelength adopts 570nm.
The CC recorded50See shown in following table.
From above-mentioned experiment: people's renal epithelial cell (293T) is shown quite or is better than the cytotoxicity of positive control medicine by the present invention, it is possible to be used for producing antitumor drug.
The preferred embodiment of the present invention described in detail above; but, the present invention is not limited to the detail in above-mentioned embodiment, in the technology concept of the present invention; technical scheme can being carried out multiple equivalents, these equivalents belong to protection scope of the present invention. It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, in reconcilable situation, it is possible to be combined by any suitable mode. In order to avoid unnecessary repetition, various possible compound modes are no longer illustrated by the present invention separately. Additionally, can also carry out combination in any between the various different embodiment of the present invention, as long as it is without prejudice to the thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (4)
1. the Enoxolone derivative of a class piperazine skeleton, its structure is such as shown in formula,
2. the method for the Enoxolone derivative prepared containing piperazine skeleton, it is characterised in that the structure of the described Enoxolone derivative containing piperazine skeleton is such as shown in formula,
Preparation method step is as follows:
Under room temperature condition, in reaction vessel, add 20mL dichloromethane solution, sequentially add DCC and HOBT, 30min is stirred at room temperature, add enoxolone and 20min is stirred at room temperature. Then bridged piperazine derivatives and triethylamine are stirred at room temperature 24h, TLC and follow the tracks of reaction, fully after reaction, obtain target compound.
Wherein, R is selected from following:
3. containing the application in preparing cancer therapy drug of the Enoxolone derivative of piperazine skeleton, it is characterised in that its structure is such as shown in formula
4. a cancer therapy drug, it is characterised in that include the structure such as compound shown in formula and medically acceptable carrier,
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| CN108558986A (en) * | 2018-05-29 | 2018-09-21 | 亿利耐雀生物科技有限公司 | Enoxolone analog derivative containing piperazine structure and preparation method thereof and purposes |
| CN108558986B (en) * | 2018-05-29 | 2021-03-05 | 亿利耐雀生物科技有限公司 | Glycyrrhetinic acid derivative containing piperazine structure and preparation method and application thereof |
| CN110143995A (en) * | 2019-06-03 | 2019-08-20 | 沈阳药科大学 | Azacyclo- replaces 18 β-Enoxolone derivative and its preparation and application |
| CN110143995B (en) * | 2019-06-03 | 2022-03-01 | 沈阳药科大学 | Azacyclo-substituted 18 beta-glycyrrhetinic acid derivative and preparation and application thereof |
| CN110551169A (en) * | 2019-09-10 | 2019-12-10 | 陈昱西 | Glycyrrhetinic acid derivative and preparation method and application thereof |
| CN110551169B (en) * | 2019-09-10 | 2022-07-15 | 陈昱西 | Glycyrrhetinic acid derivative and preparation method and application thereof |
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