CN105524076A - Diazeniumdiolate nitric oxide-donating type oridonin derivatives, preparation method and application - Google Patents
Diazeniumdiolate nitric oxide-donating type oridonin derivatives, preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/2022—Organic macromolecular compounds
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- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
Abstract
The invention relates to the field of pharmaceutical chemistry, specifically to C-14-modified diazeniumdiolate nitric oxide-donating type oridonin derivatives. The invention also discloses the preparation method for the diazeniumdiolate nitric oxide-donating type oridonin derivatives, and application of the derivatives in treatment of tumor diseases.
Description
Technical field
The present invention relates to natural product and medicinal chemistry art, be specifically related to a class azo two alkoxide nitric oxide donator type Oridonin derivative.The invention also discloses the preparation method of these azo two alkoxide nitric oxide donator type Oridonin derivatives and this kind of nitric oxide donator type Oridonin derivative for anti-tumor application.
Background technology
Rubescensine A (oridonin) is separated to obtain a kind of kaurene diterpenes (ent-kaurenediterpenoid) natural organic-compound from Labiatae Rabdosia (Rabdosia) plant Rabdosia rubescens, has clearing heat and detoxicating, promoting blood circulation and removing blood stasis, antisepsis and anti-inflammation, the effect such as antitumor.External activity research shows, rubescensine A has the effect (Wang Zhenni such as free radical and suppression toxic substance mutagenized cell DNA in inhibition tumor cell propagation, cell death inducing, regulate tumor cell signal path, scavenger cell, Wo Xingde, Chinese Medicine Leader, 2008,28,14).
Rubescensine A belongs to diterpene-kind compound, water insoluble, limits its application clinically.Our seminar has carried out structural modification to rubescensine A C-1 and C-14 position early stage, obtains active antineoplastic compound preferably (see ZL200710133915.X; JinyiXu, JingYiYang, etal.Bioorg.Med.ChemLett, 2008,18:4741);
Nitrogen protoxide (NO) gas molecule has the effect of short knurl and anti-knurl at different conditions, and this dual function depends on concentration that NO generates, time and effective-site.The NO continuing lower concentration can promote the growth of cell, and the NO of high density then plays anti-tumor activity by producing cytotoxicity.Azo two alkoxide cpd can discharge higher concentration NO in vivo.In view of the anti-tumor activity of rubescensine A is outstanding not, according to twin medicine principle, our the design and synthesis Oridonin derivative of azo glycol salt binding, obtaining the new antitumoral active compound with rubescensine A and NO donor dual function.
Summary of the invention
The invention discloses azo two alkoxide nitric oxide donator type Oridonin derivative, by carrying out structural modification and transformation to the C-14 position of Oridonin derivative, obtaining novel Oridonin derivative or its pharmacologically acceptable salt of general formula I.
The Oridonin derivative of nitric oxide donator type shown in general formula I or its pharmacologically acceptable salt:
Wherein R
1representation hydroxy, oxo, fat or aromatic series acyloxy, sulfonyloxy and replace sulfonyloxy, phosphorus acyloxy and replace phosphorus acyloxy or glucosides and replace glucosides;
R
2representative (CH
2)
2, (CH
2)
3, C
6h
4, CH=CH, CH
2c (CH
3)
2cH
2;
R
3the C representing hydrogen, do not replace or replace
1-12straight chained alkyl, the C not replacing or replace
3-12branched-chain alkyl, the C not replacing or replace
1-12straight-chain alkenyl, the C not replacing or replace
3-12branched-chain alkenyl, the benzyl not replacing or replace, the C not replacing or replace
1-4arylalkyl, the heteroaryl not replacing or replace;
R
4the C representing hydrogen, do not replace or replace
1-12straight chained alkyl, the C not replacing or replace
3-12branched-chain alkyl, the C not replacing or replace
1-12straight-chain alkenyl, the C not replacing or replace
3-12branched-chain alkenyl, the benzyl not replacing or replace, the C not replacing or replace
1-4arylalkyl, the heteroaryl not replacing or replace, or NR
3r
4for replacing or non-substituted pyrrolidinyl, morpholinyl, piperidyl, piperazinyl.
The nitric oxide donator type Oridonin derivative of general formula I of the present invention or its salt.
Wherein R
1preferred representation hydroxy, oxo, acetoxyl group;
R
2preferred representative (CH
2)
2, (CH
2)
3;
NR
3r
4preferably represent pyrrolidyl, morpholinyl.
Part of compounds of the present invention is:
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-1,15-dioxo-7,20-oxo bridge-16-kaurene
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-1,15-dioxo-7,20-oxo bridge-16-kaurene
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-(1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-1,15-dioxo-7,20-oxo bridge-16-kaurene
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-1,15-dioxo-7,20-oxo bridge-16-kaurene
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
Azo two alkoxide nitric oxide donator type Oridonin derivative I of the present invention can prepare by following method:
A, nitrogen protoxide to be passed in tetramethyleneimine or morpholine ring methanol solution, to add sodium ethylate, add nano level titanium dioxide as catalyzer, stir 48 hours at normal temperatures and pressures;
B, step a product is added chloromethyl dimethyl sulfide, DMF (DMF), sodium carbonate, stirring at normal temperature, extraction into ethyl acetate, filter, organic layer Na
2sO
4drying, concentrated, column chromatography;
C, step b product is dissolved in methylene dichloride, under condition of ice bath, adds SULPHURYL CHLORIDE, stir.After 10min, remove ice bath, stirring at normal temperature 30min, be spin-dried for;
D, rubescensine A and each derivative parent nucleus thereof are dissolved in methylene dichloride, add EDCI, EMAP, Succinic anhydried or Pyroglutaric acid, stirring at normal temperature;
E, by step b product in dry DMF, add anhydrous Na
2cO
3, stirring at normal temperature, slowly adds the gradation of steps d product wherein.Extraction into ethyl acetate, uses a small amount of water washing, merges organic layer anhydrous Na
2sO
4drying, concentrated, column chromatography.
Here is the pharmacological results of part of compounds of the present invention:
Experimental installation and reagent
Instrument Bechtop (Chinese mugwort Kelin, Suzhou treating plant company limited)
Constant temperature CO
2incubator (Japanese SANYO)
Enzyme-linked immunosorbent assay instrument (U.S. BIO-RAD)
Inverted biologic microscope (Japanese OLYMPUS)
Reagent penicillin and streptomycin mixed solution (Nanjing KaiJi Biology Science Development Co., Ltd)
Tryptic digestive juice (Nanjing KaiJi Biology Science Development Co., Ltd)
PBS (Nanjing KaiJi Biology Science Development Co., Ltd)
MTT(BIOSHARP)
DMSO(SIGMA)
Cell strain Human hepatoma cell line Bel-7402, human breast cancer cell line Bcap-37, human leukemia
Cell K562
Experimental technique
1. cell dissociation, to count, make concentration be 5 × 10
4the cell suspension of individual/mL, in 96 orifice plates, every hole adds 100 μ L cell suspension (every holes 5 × 10
3individual cell);
2.96 orifice plates are placed in 37 DEG C, 5%CO
224h is cultivated in incubator;
3. dilute medicine to desired concn with perfect medium, every hole adds the corresponding pastille substratum of 100 μ L, sets up negative control group, Vehicle controls group, positive controls simultaneously;
4.96 orifice plates are placed in 37 DEG C, 5%CO
272h is cultivated in incubator;
5. 96 orifice plates are carried out MTT dyeing, λ=490nm, measure OD value.
1) every hole adds 20 μ LMTT (5mg/mL), continues to cultivate 4h at incubator;
2) discard substratum, every hole adds 150 μ LDMSO and dissolves, and shaking table 10min mixes gently; λ=490nm, microplate reader reads the OD value in every hole, calculates inhibiting rate.
Experimental result
Table 1 embodiment is to the IC of 3 kinds of human cancer cell's strain antiproliferative activities
50value (μM)
Nitrogen protoxide extracorporeal releasing test proves, it is active that nitric oxide donator type Oridonin derivative of the present invention has good release in vitro, with anti-tumor activity in acting synergistically.
All tested materials are all dissolved in DMSO, and the stock concentration after dissolving with DMSO is 10
-2mol/L, then uses phosphoric acid buffer (pH7.4) to dilute, and makes its final concentration be 10
-5mol/L.Illustrate according to examination nitrogen protoxide agent box, by sample and the reagent mix prepared, 37 DEG C of hatching 10-60min, 1ml is extracted reaction solution in different time points, abundant vortex mixes 30 seconds, and room temperature leaves standstill 40min, 4000 revs/min, centrifugal 10min, get supernatant and add developer, mixing, room temperature leaves standstill 10min, 550nm, microplate reader measures each pipe absorbancy.Absorbancy is detected in 550nm place.
Embodiment:
Embodiment 1
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
By 1-pyrroles-1 base-O of existing system
2-chloromethyl azo two alkoxide is dissolved in dry DMF, adds anhydrous Na
2cO
3(1eq.), stirring at normal temperature, by ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-acyl group propionic acid)-15-oxo-7,20-oxo bridge-16-kaurene gradation slowly adds wherein, and TLC monitors reaction, until reaction raw materials disappears.Extraction into ethyl acetate, with few most water washing repeatedly, merge organic layer anhydrous Na
2sO
4drying, concentrated, column chromatography (DCM: MeOH=200: 1v/v), obtains white solid (yield 11.2%).
1HNMR(300MHz，CDCl
3)δ(ppm)6.09(s，2H)，5.84(s，1H)，5.67(dd，J＝14.3，7.1Hz，2H)，5.47(s，1H)，5.24(s，1H)，4.24(d，J＝10.3Hz，1H)，3.99(d，J＝10.2Hz，1H)，3.67(d，J＝5.9Hz，1H)，3.52(t，J＝6.6Hz，4H)，3.42(dd，J＝10.9，5.7Hz，1H)，3.07(m，1H)，2.17(m，1H)，1.90(t，J＝6.6Hz，4H)，1.37(d，J＝3.0Hz，1H)，1.14(m，2H)，1.04(s，3H)，0.81(t，J＝6.4Hz，1H)；
13CNMR(75MHz，CDCl
3)δ(ppm)234.84，206.58，170.73，169.49，149.88，120.41，96.05，87.49，86.32，77.51，77.10，76.65，76.15，74.28，73.38，71.93，63.41，62.39，61.91，59.48，54.64，52.28，50.69，44.95，41.30，38.64，35.88，33.73，32.59，30.48，29.90，29.65，29.24，28.81，23.57，22.98，21.71，19.82，-4.50.
Embodiment 2
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 15.3%):
1hNMR (300MHz, CDCl
3) δ (ppm) 6.06 (s, 1H), 6.02 (m, 1H), 5.79 (s, 1H), 5.65 (s, 2H), 5.47 (s, 1H), 5.43 (s, 1H), 4.21 (d, J=10.3Hz, 1H), 3.98 (d, J=10.2Hz, 1H), 3.66 (m, 1H), 3.48 (t, J=6.6Hz, 4H), 3.41 (m, 1H), 3.07 (d, J=9.5Hz, 1H), 2.51 (m, 1H);
13cNMR (75MHz, CDCl
3) δ (ppm) 205.99,170.89,170.76,149.32,133.65,119.77,95.63,86.81,76.97,76.55,76.12,75.80,74.36,73.63,72.92,62.90,61.37,59.13,54.10,50.21,40.81,38.13,33.23,32.84,32.35,32.07,29.99,29.50,22.49,21.18,19.30,18.93,12.23.
Embodiment 3
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 10.5%):
1hNMR (300MHz, Chloroform-d) δ (ppm) 6.20-6.12 (m, 2H), 5.91 (d, J=1.4Hz, 1H), 5.82-5.75 (m, 2H), 5.54 (s, 1H), 4.30 (dd, J=10.4, 1.4Hz, 1H), 4.13 (s, 1H), 4.06 (dd, J=10.1, 1.7Hz, 1H), 3.87-3.82 (m, 4H), 3.73 (dd, J=10.8, 6.9Hz, 1H), 3.53-3.42 (m, 4H), 3.18-3.09 (m, 1H), 2.66 (dt, J=10.6, 3.1Hz, 2H), 2.59 (tt, J=5.6, 3.5Hz, 3H), 2.32-2.14 (m, 1H), 2.00-1.88 (m, 1H), 1.83-1.68 (m, 1H), 1.10 (s, 7H), 0.92-0.80 (m, 2H),
13cNMR (75MHz, CDCl
3) δ (ppm) 206.02,170.23,170.15,149.36,119.90,95.51,86.89,75.52,73.83,72.87,65.09,62.88,61.45,58.94,54.15,50.77,40.80,38.14,33.19,32.10,30.00,29.41,29.17,28.70,28.28,21.21,19.36.
Embodiment 4
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 14.1%):
1hNMR (300MHz, Chloroform-d) δ (ppm) 6.16 (d, J=1.3Hz, 1H), 6.12 (d, J=10.7Hz, 1H), 5.90 (d, J=1.5Hz, 1H), 5.79 (t, J=1.4Hz, 2H), 5.53 (s, 1H), 4.32 (dd, J=10.2, 1.6Hz, 1H), 4.17 (s, 1H), 4.08 (dd, J=10.4, 1.7Hz, 1H), 3.91-3.81 (m, 4H), 3.75 (dd, J=10.6, 6.8Hz, 1H), 3.53-3.44 (m, 5H), 3.16 (d, J=9.8Hz, 2H), 2.62 (dt, J=14.0, 9.0Hz, 1H), 2.48-2.30 (m, 4H), 2.02-1.87 (m, 3H), 1.71-1.55 (m, 2H), 1.49-1.40 (m, 1H), 1.12 (s, 6H), 0.95-0.80 (m, 3H), 13CNMR (75MHz, CDCl3) δ (ppm) 205.97,170.74,149.34,119.75,95.61,86.75,75.64,73.68,72.92,65.09,62.89,61.39,59.07,54.12,50.80,40.84,38.14,33.22,32.82,32.32,32.07,31.41,30.00,29.81,29.49,29.19,26.19,22.18,21.19,19.32,18.91,13.61,0.51.
Embodiment 5
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-1,15-dioxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 12.1%):
1hNMR (300MHz, CDCl
3) δ (ppm) 6.19 (s, 1H), 5.90 (d, J=18.3Hz, 1H), 5.67 (q, J=7.1Hz, 2H), 5.58 (s, 1H), 5.23 (s, 0H), 4.22 (d, J=10.6Hz, 1H), 3.93 (m, 1H), 3.69 (m, 1H), (3.52 t, J=6.7Hz, 4H), (3.03 d, J=9.3Hz, 1H), (2.85 d, J=23.1Hz, 1H), 1.87 (m, 7H), 1.12 (s, 3H), 0.92 (s, 3H);
13cNMR (75MHz, CDCl
3) δ (ppm) 211.08,204.38,170.37,170.14,148.95,123.23,121.67,110.74,96.34,87.02,76.95,76.53,76.10,73.87,72.85,64.37,60.81,59.23,50.19,48.03,40.92,37.88,35.22,32.33,29.99,29.50,29.17,28.75,28.35,22.67,22.49,18.66,13.78.
Embodiment 6
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-1,15-dioxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 13.4%):
1hNMR (300MHz, Chloroform-d) δ (ppm) 6.18 (s, 1H), 5.85 (s, 1H), 5.67 (s, 2H), 5.56 (s, 1H), 4.22 (dd, J=10.5, 1.4Hz, 1H), 3.95 (dd, J=10.7, 1.7Hz, 1H), 3.75-3.65 (m, 1H), 3.50 (t, 4H), 3.02 (d, J=9.4Hz, 1H), 2.56-2.41 (m, 1H), 2.20-2.08 (m, 1H), 1.72-1.48 (m, 3H), 1.35 (d, J=1.5Hz, 1H), 0.93 (s, 3H),
13cNMR (75MHz, CDCl
3) δ (ppm) 211.09,204.34,170.99,170.81,148.93,121.57,96.38,86.79,76.11,73.74,72.79,64.38,60.78,59.31,50.19,48.04,40.99,37.90,35.23,32.78,32.38,32.34,29.99,29.51,29.18,22.68,22.48,18.89,18.63,13.60.
Embodiment 7
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-(1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-1,15-dioxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 10.3%):
1hNMR (300MHz, Chloroform-d) δ (ppm) 6.19 (s, 1H), 5.87 (s, 1H), 5.79-5.62 (m, 2H), 5.58 (s, 1H), 5.36 (d, J=11.7Hz, 1H), 4.22 (dd, J=10.7, 1.4Hz, 1H), 4.11 (s, 1H), 3.94 (dd, J=10.7, 1.7Hz, 1H), 3.83-3.73 (m, 4H), 3.69 (dd, J=11.7, 8.9Hz, 1H), 3.47-3.36 (m, 4H), 3.02 (d, J=9.3Hz, 1H), 2.68-2.52 (m, 2H), 2.55-2.45 (m, 2H), 2.43-2.32 (m, 1H), 2.32-2.18 (m, 1H), 2.18-2.08 (m, 1H), 2.00-1.73 (m, 4H), 1.73-1.47 (m, 2H), 1.30-1.15 (m, 3H), 1.12 (s, 4H), 0.92 (s, 3H), 0.85-0.70 (m, 1H).
Embodiment 8
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-1,15-dioxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 14.1%):
1hNMR (300MHz, Chloroform-d) δ (ppm) 6.23 (s, 1H), 5.91 (s, 1H), 5.76 (s, 2H), 5.61 (d, J=1.3Hz, 1H), 5.45 (d, J=11.7Hz, 1H), 4.27 (m, J=10.5, 6.8, 3.2Hz, 2H), 4.00 (dd, J=10.6, 1.7Hz, 1H), 3.87-3.80 (m, 4H), 3.74 (dd, J=11.8, 8.9Hz, 1H), 3.51-3.38 (m, 5H), 3.07 (d, J=9.2Hz, 1H), 2.52 (ddt, J=13.7, 10.9, 6.0Hz, 1H), 2.45-2.35 (m, 2H), 2.31 (t, J=7.2Hz, 2H), 2.23-2.13 (m, 1H), 1.89 (ddd, J=11.5, 9.0, 5.7Hz, 5H), 1.79-1.51 (m, 3H), 1.17 (s, 4H), 0.97 (s, 4H), 0.90-0.79 (m, 1H),
13cNMR (75MHz, CDCl
3) δ (ppm) 211.60,204.89,171.42,171.32,149.46,122.09,96.87,87.23,74.13,73.31,71.88,65.59,64.87,61.29,59.74,51.30,50.66,49.76,48.52,41.52,38.37,35.72,33.26,32.84,30.48,30.01,29.66,23.17,19.36,19.13,18.98.
Embodiment 9
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 14.2%):
1hNMR (300MHz, Chloroform-d) δ 6.12 (s, 1H), 6.07 (d, J=10.7Hz, 1H), 5.80 (s, 1H), 5.73 (d, J=2.7Hz, 2H), 5.49 (s, 1H), 4.66-4.53 (m, 1H), 4.29 (d, J=10.7Hz, 1H), 4.10 (d, J=10.5Hz, 1H), 3.84 (s, 1H), 3.76-3.81 (m, 4H), 3.79-3.68 (m, 1H), 3.62 (d, J=5.0Hz, 1H), 3.44-3.42 (m, 4H), 3.15 (d, J=9.6Hz, 1H), 1.92 (s, 6H), 1.08 (s, 6H).
Embodiment 10
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid (yield 14.2%):
1hNMR (300MHz, Chloroform-d) δ 6.08 (s, 1H), 6.03 (d, J=10.7Hz, 1H), 5.78 (s, 1H), 5.71 (d, J=2.4Hz, 2H), 5.38 (s, 1H), 4.69-4.58 (m, 1H), 4.26 (d, J=10.2Hz, 1H), 4.11 (d, J=10.2Hz, 1H), 3.82 (s, 1H), 3.76-3.80 (m, 4H), 3.79-3.69 (m, 1H), 3.66 (d, J=5.0Hz, 1H), 3.42-3.40 (m, 4H), 3.13 (d, J=9.6Hz, 1H), 1.98 (s, 6H), 1.09 (s, 6H).
Embodiment 11
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid 41mg (yield 11.1%):
1hNMR (300MHz, Chloroform-d) δ 6.10 (s, 1H), 6.05 (d, J=10.7Hz, 1H), 5.81 (s, 1H), 5.72 (d, J=2.7Hz, 2H), 5.48 (s, 1H), 4.61-4.49 (m, 1H), 4.22 (d, J=10.7Hz, 1H), 4.12 (d, J=10.5Hz, 1H), 3.97 (s, 1H), 3.80-3.76 (m, 4H), 3.74-3.65 (m, 1H), 3.61 (d, J=5.0Hz, 1H), 3.44-3.41 (m, 4H), 3.08 (d, J=9.8Hz, 1H), 1.93 (s, 6H), 1.06 (s, 6H),
13cNMR (75MHz, CDCl
3) δ 170.68,120.79,95.90,87.44,77.45,77.02,76.60,75.90,75.38,74.20,65.61,63.52,59.95,53.79,51.30,41.09,39.74,38.13,33.55,32.43,30.21,29.69,29.22,28.79,25.14,21.60,21.51,18.08.
Embodiment 12
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene
With reference to the synthetic method of embodiment 1, obtain white solid 47mg (yield 13.2%):
1hNMR (300MHz, Chloroform-d) δ 6.17 (s, 1H), 6.09 (d, J=10.7Hz, 1H), 5.80 (s, 1H), 5.79 (d, J=2.7Hz, 2H), 5.48 (s, 1H), 4.61-4.49 (m, 1H), 4.24 (d, J=10.7Hz, 1H), 4.10 (d, J=10.5Hz, 1H), 3.96 (s, 1H), 3.81-3.79 (m, 4H), 3.72-3.66 (m, 1H), 3.60 (d, J=5.0Hz, 1H), 3.45-3.42 (m, 4H), 3.09 (d, J=9.8Hz, 1H), 1.92 (s, 6H), 1.07 (s, 6H),
13cNMR (75MHz, CDCl
3) δ 171.64,121.03,95.33,87.43,77.87,77.43,76.87,75.28,75.18,74.67,65.92,63.27,59.81,53.54,51.36,41.03,39.12,38.19,33.54,32.93,31.09,29.34,29.23,28.73,26.79,21.20,20.16,13.02.
Embodiment 13
Get above-mentioned formula, be prepared into tablet by ordinary method.
Claims (7)
1. the alkoxide of azo two shown in general formula I nitric oxide donator type Oridonin derivative or its pharmacologically acceptable salt:
Wherein R
1representation hydroxy, oxo, fat or aromatic series acyloxy, sulfonyloxy and replace sulfonyloxy, phosphorus acyloxy and replace phosphorus acyloxy or glucosides and replace glucosides;
R
2representative (CH
2)
2, (CH
2)
3, C
6h
4, CH=CH, CH
2c (CH
3)
2cH
2;
R
3the C representing hydrogen, do not replace or replace
1-12straight chained alkyl, the C not replacing or replace
3-12branched-chain alkyl, the C not replacing or replace
1-12straight-chain alkenyl, the C not replacing or replace
3-12branched-chain alkenyl, the benzyl not replacing or replace, the C not replacing or replace
1-4arylalkyl, the heteroaryl not replacing or replace;
R
4the C representing hydrogen, do not replace or replace
1-12straight chained alkyl, the C not replacing or replace
3-12branched-chain alkyl, the C not replacing or replace
1-12straight-chain alkenyl, the C not replacing or replace
3-12branched-chain alkenyl, the benzyl not replacing or replace, the C not replacing or replace
1-4arylalkyl, the heteroaryl not replacing or replace, or NR
3r
4for replacing or non-substituted pyrrolidinyl, morpholinyl, piperidyl, piperazinyl.
2. the azo two alkoxide nitric oxide donator type Oridonin derivative of claim 1 or salt, wherein R
1preferred representation hydroxy, oxo, acetoxyl group.
3. the azo two alkoxide nitric oxide donator type Oridonin derivative of claim 1 or salt, wherein R
2preferred representative (CH
2)
2, (CH
2)
3.
4. the azo two alkoxide nitric oxide donator type Oridonin derivative of claim 1 or salt, wherein NR
3r
4preferably represent pyrrolidyl, morpholinyl.
5. the compound of claim 1 formula of I can be having structure:
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene;
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene;
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene;
Ent-1 α, 6 β, 7 β-trihydroxy--(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene;
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-1,15-dioxo-7,20-oxo bridge-16-kaurene;
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-1,15-dioxo-7,20-oxo bridge-16-kaurene;
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-(1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-1,15-dioxo-7,20-oxo bridge-16-kaurene;
Ent-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-1,15-dioxo-7,20-oxo bridge-16-kaurene;
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene;
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-pyrroles-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene;
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) propionyl))-15-oxo-7,20-oxo bridge-16-kaurene;
Ent-1 α-acetoxyl group-6 β, 7 beta-dihydroxyies-(14 β-O-((1-morpholine-1-base-O
2-methoxyl group acyl group azo two alkoxide) butyryl radicals))-15-oxo-7,20-oxo bridge-16-kaurene.
6. an antitumor medicine composition, the Oridonin derivative of general formula (I) wherein containing claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
7. the Oridonin derivative of the general formula (I) of claim 1 or its pharmacy acceptable salt are for the preparation of the purposes for the treatment of tumor disease medicine.
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| CN106866695A (en) * | 2017-02-22 | 2017-06-20 | 石家庄学院 | Oridonin derivative and its preparation and application |
| CN110483419A (en) * | 2019-09-11 | 2019-11-22 | 泰州学院 | A kind of two alkoxide derivative of ligustrazine/azo, preparation method and its usage |
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