CN102786576B - Triptolide derivatives, and preparation methods, medicinal composition and uses thereof - Google Patents
Triptolide derivatives, and preparation methods, medicinal composition and uses thereof Download PDFInfo
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Abstract
The invention discloses fifteen new triptolide derivatives, a medicinal composition containing one or more of the derivatives, and uses of the derivatives in the inhibition of the generation of NO by macrophages, especially anti-inflammation and immunological suppression, as medicines. The above compounds treat triptolide as a raw material, the fourteenth hydroxy group of triptolide and aromatic groups comprising benzoic acid, cinnamic acid and benzene sulfonic acid analogs are acylated to form ester derivatives. Active evaluation shows that the compounds have substantial inhibition activities on the generation of the inflammation factor NO by the macrophages.
Description
Technical field
The present invention relates to the research of 15 kinds of new triptolide derivant, its preparation method and anti inflammatory immunity inhibit activities thereof.
Background technology
Triptolide (triptolide) is one of main active of Chinese traditional herbs Radix Tripterygii Wilfordii (TripterygiumwilfordiiHook f), that one has a α, the Diterpene compound of the configuration uniqueness of β-unsaturated lactone ring five membered fragment and three three-membered ring oxygen groups, has the biological activitys such as obvious antiinflammatory, immunosuppressant, antitumor and anti-male fertility.
AIA: anti-inflammatory activity; ISA: immunosuppressive activity; TI: therapeutic index; CSF: safety coefficient; LESD: minimum effective dose; AFA: Antifertility Activity
Along with going deep into of studying triptolide, people to the understanding of its pharmacology, toxicity, pharmacokinetics and clinical practice also more and more deeply and extensively.It is except having higher biological activity, and the untoward reaction also having larger toxicity and cause has had a strong impact on the exploitation of triptolide.Therefore, structure of modification is carried out to triptolide, become the main target of researcher with the monomer obtaining high-efficiency low-toxicity.According to existing bibliographical information, the derivant introducing aromatic rings triptolide 14 by esterification is less, and the active reporter about this analog derivative is also less.Therefore the present invention passes through acylation reaction; the aromatic rings such as cinnamyl, benzoyl, benzenesulfonyl are introduced in triptolide; obtain 15 new triptolide derivants; pass through it to the inhibit activities evaluation of macrophages produce inflammatory factor NO simultaneously; anti-inflammatory activity research is carried out to it, thus has completed the present invention.
Summary of the invention
The object of the present invention is to provide the triptolide derivant of 15 kinds of novel structures;
Another object of the present invention is to provide the triptolide derivant about 15 kinds of novel structures to produce NO and based on the application in this mechanism of action at suppression macrophage;
Another object of the present invention is to provide about the triptolide derivant of 15 kinds of novel structures and compositions thereof as antiinflammatory, the application of immunosuppressive drug;
Another object of the present invention is to provide the triptolide derivant about 15 kinds of novel structures or the compositions containing them at treatment rheumatism, the purposes of the aspects such as autoimmune disease.
Specifically, the present invention relates to the triptolide derivant of 15 kinds of novel structures.
The synthetic route of the triptolide derivant of the series structure novelty that the present invention relates to is as follows:
Triptolide and acylating reagent (acyl chlorides) are joined in anhydrous methylene chloride; take anhydrous pyridine as catalyst and acid binding agent; stirring at room temperature 24 hours; the pyridine in reactant liquor is washed away with dilute hydrochloric acid; neutrality is adjusted to, anhydrous sodium sulfate drying, evaporated under reduced pressure with saturated sodium bicarbonate aqueous solution; through purification by silica gel column chromatography, obtain triptolide derivant.
The present invention by In vitro cell experiment, determines the activity that 15 kinds of new triptolide derivant inflammation-inhibiting factor NO generate, thus tentatively completes the evaluation of its anti-inflammatory activity.
Accompanying drawing explanation
Fig. 1, the IC of compound 3
50=2.38E-07
Fig. 2, the IC of compound 5
50=1.43E-07
Fig. 3, the IC of compound 13
50=7.23E-08
Detailed description of the invention
To contribute to understanding the present invention by following specific implementation method, but be not restricted to content of the present invention.
The synthesis of embodiment 1 compound 1
36mg (0.1mmol) triptolide and 140mg (1mmol) Benzenecarbonyl chloride. are dissolved in 20ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 37mg and be compound 1, yield is about 87%.
Compound 1C
27h
28o
7, ESI-MS m/z:465 [M+H]
+.
1h-NMR (500MHz, CDCl
3) δ: 1.256 (1H, m, H-1a), 1.591 (1H, m, H-1b), 1.898 ~ 2.172 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.729 (1H, m, H-5), 3.537 (1H, d, J=5.5Hz, H-7), 3.886 (1H, d, J=1.5Hz, H-11), 3.583 (1H, br.s, H-12), 5.294 (1H, s, H-14), 0.984 (3H, d, J=6.5Hz, H-16), 0.871 (3H, d, J=6.5Hz, H-17), 4.659 (2H, m, H-19), 1.016 (3H, s, H-20), 8.143 (2H, d, J=6.5Hz, H-2 ', 6 '), 7.470 (2H, m, H-3 ', 5 '), 7.585 (1H, m, H-4 ').
13c-NMR (500MHz, CDCl
3) δ: 16.789 (C-1), 23.744 (C-2), 125.492 (C-3), 159.992 (C-4), 40.352 (C-5), 28.789 (C-6), 55.726 (C-7), 63.441 (C-8), 63.730 (C-9), 35.655 (C-10), 55.775 (C-11), 59.943 (C-12), 71.645 (C-13), 71.798 (C-14), 28.160 (C-15), 16.184 (C-16), 17.531 (C-17), 173.790 (C-18), 69.921 (C-19), 13.549 (C-20), (133.247 C-1 '), 128.363, 128.567, 129.449, 130.057, 130.203 (C-2 ', 3 ', 4 ', 5 ', 6 ').
The synthesis of embodiment 2 compound 2
36mg (0.1mmol) triptolide and 0.15ml (1mmol) parachlorobenzoyl chloride are dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 20mg, be compound 2, yield is about 40%.
Compound 2C
27h
27clO
7, ESI-MS m/z:499 [M+H]
+.
1h-NMR (400MHz, CDCl
3) δ: 1.247 (1H, m, H-1a), 1.584 (1H, m, H-1b), 1.890 ~ 2.316 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.711 (1H, m, H-5), 3.529 (1H, d, J=5.6Hz, H-7), 3.883 (1H, d, J=2.4Hz, H-11), 3.576 (1H, d, J=2.4Hz, H-12), 5.260 (1H, s, H-14), 0.971 (3H, d, J=7.2Hz, H-16), 0.851 (3H, d, J=7.2Hz, H-17), 4.659 (2H, m, H-19), 1.024 (3H, s, H-20), 8.071 (2H, d, J=8.4Hz, H-2 ', 6 '), 7.439 (2H, d, J=8.4Hz, H-3 ', 5 ').
The synthesis of embodiment 3 compound 3
50mg (0.13mmol) triptolide and 0.5ml are dissolved in 10ml anhydrous methylene chloride to methyl benzoyl chloride, drip 0.5ml anhydrous pyridine, stirred at ambient temperature reaction 48h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 37mg, be compound 3, yield is about 77.8%.
Compound 3C
28h
30o
7, ESI-MS m/z:479 [M+H]
+.
1h-NMR (400MHz, CDCl
3) δ: 1.254 (1H, m, H-1a), 1.599 (1H, m, H-1b), 1.897 ~ 2.325 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.721 (1H, m, H-5), 3.535 (1H, d, J=5.6Hz, H-7), 3.884 (1H, d, d, J=2.8Hz, H-11), 3.580 (1H, d, J=2.8Hz, H-12), 5.292 (1H, d, J=3, 0Hz, H-14), 0.983 (3H, d, J=6.8Hz, H-16), 0.857 (3H, d, J=6.8Hz, H-17), 4.659 (2H, m, H-19), 1.039 (3H, s, H-20), 8.038 (2H, d, J=7.6Hz, H-2 ', 6 '), 7.270 (2H, d, J=7.6Hz, H-3 ', 5 '), 2.420 (3H, s, H-8 '). the synthesis of embodiment 4 compound 4
36mg (0.1mmol) triptolide and 165mg (1mmol) 4-cyano-benzoyl chloride are dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 12h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 30mg, yield is about 61%.
Compound 4C
28h
27nO
7, ESI-MS m/z:512 [M+Na]
+.
1h-NMR (300MHz, CDCl
3) δ: 1.274 (1H, m, H-1a), 1.604 (1H, m, H-1b), 1.902 ~ 2.313 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.719 (1H, m, H-5), 3.561 (1H, d, J=5.4Hz, H-7), 3.916 (1H, d, J=2.7Hz, H-11), 3.608 (1H, d, J=2.7Hz, H-12), 5.268 (1H, s, H-14), 0.990 (3H, d, J=6.9Hz, H-16), 0.870 (3H, d, J=6.9Hz, H-17), 4.685 (2H, m, H-19), 1.039 (3H, s, H-20), 8.248 (2H, d, J=8.4Hz, H-2 ', 6 '), 7.788 (2H, d, J=8.4Hz, H-3 ', 5 ').
The synthesis of embodiment 5 compound 5
36mg (0.1mmol) triptolide and 185mg (1mmol) 4-nitrobenzoyl chloride are dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 12h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 32mg, yield is about 64%.
Compound 5C
27h
27nO
9, ESI-MS m/z:544 [M+Cl]
-.
1h-NMR (300MHz, CDCl
3) δ: 1.281 (1H, m, H-1a), 1.6010 (1H, m, H-1b), 1.889 ~ 2.370 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.725 (1H, m, H-5), 3.572 (1H, d, J=5.4Hz, H-7), 3.921 (1H, d, J=2.7Hz, H-11), 3.621 (1H, d, J=2.7Hz, H-12), 5.299 (1H, s, H-14), 0.998 (3H, d, J=6.9Hz, H-16), 0.878 (3H, d, J=6.9Hz, H-17), 4.688 (2H, m, H-19), 1.043 (3H, s, H-20), 8.325 (4H, s, H-2 ', 3 ', 5 ', 6 ').
The synthesis of embodiment 6 compound 6
36mg (0.1mmol) triptolide and 158mg (1mmol) 4-fluorobenzoyl chloride are dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain the solid 20mg of white, be compound 6, yield is about 42%.
Compound 6C
27h
27fO
7, ESI-MS m/z:517 [M+Cl]
-.
1h-NMR (300MHz, CDCl
3) δ: 1.263 (1H, m, H-1a), 1.603 (1H, m, H-1b), 1.908 ~ 2.368 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.708 (1H, m, H-5), 3.545 (1H, d, J=5.7Hz, H-7), 3.896 (1H, d, d, J=2.7Hz, H-11), 3.589 (1H, d, J=2.7Hz, H-12), 5.275 (1H, s, H-14), 0.990 (3H, d, J=6.9Hz, H-16), 0.866 (3H, d, J=6.9Hz, H-17), 4.676 (2H, m, H-19), 1.046 (3H, s, H-20), 8.168 (2H, m, H-2 ', 6 '), 7.147 (2H, t, J=8.7Hz, H-3 ', 5 ').
The synthesis of embodiment 7 compound 7
36mg (0.1mmol) triptolide and 170mg (1mmol) anisoyl chloride are dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain the solid 19mg of white, yield is about 38%.
Compound 7C
28h
30o
8, ESI-MS m/z:495 [M+H]
+.
1h-NMR (300MHz, CDCl
3) δ: 1.236 (1H, m, H-1a), 1.599 (1H, m, H-1b), 1.895 ~ 2.327 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.707 (1H, m, H-5), 3.536 (1H, d, J=5.4Hz, H-7), 3.890 (1H, d, J=2.7Hz, H-11), 3.580 (1H, d, J=2.7Hz, H-12), 5.276 (1H, s, H-14), 0.984 (3H, d, J=6.9Hz, H-16), 0.858 (3H, d, J=6.9Hz, H-17), 4.674 (2H, m, H-19), 1.042 (3H, s, H-20), 8.109 (2H, d, J=8.7Hz, H-2 ', 6 '), 6.956 (2H, d, J=8.7Hz, H-3 ', 5 '), 3.868 (3H, s, H-8 ').
The synthesis of embodiment 8 compound 8 and 9
72mg (0.2mmol) triptolide and 280mg (2mmol) acetyl salicylic acyl chlorides are dissolved in 40ml anhydrous methylene chloride, drip 2ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain 19mg compound 8,30mg compound 9.
Compound 8C
29h
30o
9, ESI-MS m/z:545 [M+Na]
+.
1h-NMR (300MHz, CDCl
3) δ: 1.253 (1H, m, H-1a), 1.604 (1H, m, H-1b), 1.921 ~ 2.306 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.718 (1H, m, H-5), 3.515 (1H, d, J=5.7Hz, H-7), 3.875 (1H, d, J=2.4Hz, H-11), 3.568 (1H, d, J=2.4Hz, H-12), 5.244 (1H, s, H-14), 0.975 (3H, d, J=6.9Hz, H-16), 0.837 (3H, d, J=6.9Hz, H-17), 4.669 (2H, m, H-19), 1.064 (3H, s, H-20), 7.115 (1H, d, J=8.1Hz, H-3 '), 7.360 (1H, t, J=7.5Hz, H-4 '), 7.586 (1H, t, J=7.8Hz, H-5 '), 8.191 (1H, d, J=7.8Hz, H-6 '), 2.346 (3H, s, H-9 ')
Compound 9C
27h
28o
6, ESI-MS m/z:479 [M-H]
-.
1h-NMR (300MHz, CDCl
3) δ: 1.253 (1H, m, H-1a), 1.607 (1H, m, H-1b), 1.919 ~ 2.331 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.731 (1H, m, H-5), 3.554 (1H, d, J=5.4Hz, H-7), 3.915 (1H, d, J=3.0Hz, H-11), 3.597 (1H, d, J=3.0Hz, H-12), 5.305 (1H, s, H-14), 0.992 (3H, d, J=7.2Hz, H-16), 0.867 (3H, d, J=7.2Hz, H-17), 4.674 (2H, m, H-19), 1.047 (3H, s, H-20), 6.972 (2H, m, H-3 ', 4 '), 7.491 (1H, t, J=7.2Hz, H-5 '), 8.002 (1H, d, J=7.2Hz, H-6 ').
The synthesis of embodiment 9 compound 10
36mg (0.1mmol) triptolide and 209mg (1mmol) 3,4-dichlorobenzoyl chloride is dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, wash away pyridine with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, cross silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain the solid 19mg of white, be compound 10, yield is about 38%.
Compound 10C
27h
26cl
2o
7, ESI-MS m/z:567 [M+Cl]
-.
1h-NMR (300MHz, CDCl
3) δ: 1.264 (1H, m, H-1a), 1.606 (1H, m, H-1b), 1.899 ~ 2.342 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.708 (1H, m, H-5), 3.544 (1H, d, J=5.7Hz, H-7), 3.749 (1H, d, J=2.4Hz, H-11), 3.593 (1H, d, J=2.4Hz, H-12), 5.251 (1H, s, H-14), 0.987 (3H, d, J=6.9Hz, H-16), 0.869 (3H, d, J=6.9Hz, H-17), 4.678 (2H, m, H-19), 1.046 (3H, s, H-20), 7.250 ~ 7.996 (3H, m, H-2 ', 5 ', 6 ').
The synthesis of embodiment 10 compound 11
36mg (0.1mmol) triptolide and 126ul (1mmol) 3,4-difluoro benzoyl chloride is dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, wash away pyridine with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, cross silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain the solid 30mg of white, be compound 11, yield is about 60%.
Compound 11C
27h
26f
2o
7, ESI-MS m/z:500 [M+H+Na]
+.
1h-NMR (300MHz, CDCl
3) δ: 1.105 (1H, m, H-1a), 1.447 (1H, m, H-1b), 1.748 ~ 2.174 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.569 (1H, m, H-5), 3.386 (1H, d, J=5.4Hz, H-7), 3.741 (1H, d, J=2.7Hz, H-11), 3.440 (1H, d, J=2.7Hz, H-12), 5.009 (1H, s, H-14), 0.824 (3H, d, J=6.9Hz, H-16), 0.708 (3H, d, J=6.9Hz, H-17), 4.521 (2H, m, H-19), 0.883 (3H, s, H-20), 8.054 (1H, s, H-2 '), 7.406 (1H, d, J=8.4Hz, H-5 '), 7.815 (1H, dd, J=8.4, 1.2Hz, H-6 ').
The synthesis of embodiment 11 compound 12
36mg (0.1mmol) triptolide and 133ul (1mmol) phenyllacetyl chloride are dissolved in 20ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 10mg and be compound 12, yield is about 21%.,
Compound 12C
28h
30o
7, ESI-MS m/z:479 [M+H]
+.
1h-NMR (300MHz, CDCl
3) δ: 1.220 (1H, m, H-1a), 1.581 (1H, m, H-1b), 1.747 ~ 2.325 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.677 (1H, m, H-5), 3.432 (1H, d, J=5.6Hz, H-7), 3.819 (1H, br.s, H-11), 3.514 (1H, br.s, H-12), 5.299 (1H, s, H-14), 0.877 (3H, d, J=8.5Hz, H-16), 0.764 (3H, d, J=8.5Hz, H-17), 4.661 (2H, m, H-19), 1.042 (3H, s, H-20), 7.239 ~ 7.370 (5H, m, H-2 ', 3 ', 4 ', 5 ', 6 '), 3.689 (1H, d, J=14.8Hz, H-7 ' a), 3.777 (1H, d, J=14.8Hz, H-7 ' b).
The synthesis of embodiment 12 compound 13
36mg (0.1mmol) triptolide and 166mg (1mmol) cinnamoyl chloride are dissolved in 20ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 30mg, be compound 13, yield is about 61.2%.
Compound 13C
29h
30o
7, ESI-MS m/z:491 [M+H]
+.
1h-NMR (500MHz, CDCl
3) δ: 1.577 (1H, m, H-1a), 1.218 (1H, m, H-1b), 1.912 ~ 2.291 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.695 (1H, m, H-5), 3.508 (1H, d, J=6.0Hz, H-7), 3.857 (1H, d, J=2.0Hz, H-11), 3.561 (1H, d, J=2.0Hz, H-12), 5.209 (1H, s, H-14), 0.982 (3H, d, J=7.0Hz, H-16), 0.853 (3H, d, J=7.0Hz, H-17), 4.659 (2H, m, H-19), 1.056 (3H, s, H-20), 7.382 (3H, m, H-3 ', 4 ', 5 '), 7.550 (2H, br.s, H-2 ', 6 '), 7.784 (1H, d, J=16Hz, H-7 '), 6.540 (1H, d, J=16Hz, H-8 ').
13c-NMR (500MHz, CDCl
3) δ: 16.993 (C-1), 23.372 (C-2), 125.456 (C-3), 160.012 (C-4), 40.313 (C-5), 29.768 (C-6), 54.998 (C-7), 63.414 (C-8), 63.622 (C-9), 35.639 (C-10), 55.354 (C-11), 59.761 (C-12), 61.087 (C-13), 70.917 (C-14), 28.250 (C-15), 16.705 (C-16), 17.549 (C-17), 173.173 (C-18), 69.920 (C-19), 13.689 (C-20), (130.486 C-1 '), 128.821 (C-2 ', 6 '), 128.256 (C-3 ', 5 '), (117.203 C-4 '), (146.430 C-7 '), (134.177 C-8 '), (166.256 C-9 ').
The synthesis of embodiment 13 compound 14
36mg (0.1mmol) triptolide and 184mg (1mmol) 4-fluorine Cortex cinnamomi japonici (Ramulus Cinnamomi) acyl chlorides are dissolved in 10ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain the solid 20mg of white, yield is about 39%.
Compound 14C
29h
29fO
7, ESI-MS m/z:509 [M+H]
+.
1h-NMR (300MHz, CDCl
3) δ: 1.584 (1H, m, H-1a), 1.240 (1H, m, H-1b), 1.899 ~ 2.339 (5H, m, H-2a, 2b, 6a, 6b, 15), 2.702 (1H, m, H-5), 3.511 (1H, d, J=5.4Hz, H-7), 3.860 (1H, d, J=2.7Hz, H-11), 3.559 (1H, d, J=2.7Hz, H-12), 5.200 (1H, s, H-14), 0.978 (3H, d, J=8.9Hz, H-16), 0.849 (3H, d, J=8.9Hz, H-17), 4.666 (2H, m, H-19), 1.056 (3H, s, H-20), 7.544 (2H, dd, J=8.7, 5.4Hz, H-2 ', 6 '), 7.074 (2H, t, J=8.7, Hz H-3 ', 5 '), 7.740 (1H, d, J=15.9Hz, H-7 '), 6.460 (1H, d, J=15.9Hz, H-8 ').
The synthesis of embodiment 14 compound 15
36mg (0.1mmol) triptolide and 105mg (5mmol) parachloroben-zenesulfonyl chloride are dissolved in 20ml anhydrous methylene chloride, drip 1ml anhydrous pyridine, stirred at ambient temperature reaction 24h, TLC detection reaction is complete, stop stirring, pyridine is washed away with 1M diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution is adjusted to neutrality, anhydrous sodium sulfate drying, evaporated under reduced pressure, crosses silica gel column chromatography, with cyclohexane-acetone (10:1-7:1) gradient elution, obtain white solid 20mg and be compound 15, yield is about 37.4%.
Compound 15C
26h
27clO
8s, ESI-MS m/z:569 [M+Cl]
-.
1h-NMR (300MHz, CDCl
3) δ: 1.2 ~ 2.3 (7H, m, H-1a, 1b, 2a, 2b, 6a, 6b, 15), 2.618 (1H, m, H-5), 3.581 (1H, d, J=5.4Hz, H-7), 3.781 (1H, d, J=3.0Hz, H-11), 3.570 (1H, d, J=3.0Hz, H-12), 4.619 (1H, s, H-14), 1.702 (3H, d, J=6.9Hz, H-16), 0.887 (3H, d, J=6.9Hz, H-17), 4.607 (2H, m, H-19), 0.703 (3H, s, H-20), 7.926 (2H, d, J=8.4Hz, H-2 ', 6 '), 7.487 (2H, d, J=8.4, HzH-3 ', 5 ').
The activity rating that embodiment 15 suppresses macrophage inflammatory factor NO to generate
Macrophage, performs body non-specific immunity, can produce NO etc. under the inductions such as bacteria lipopolysaccharide LPS, participates in and inducing inflammatory reaction, in the autoimmune disease inflammatory immune process initial stages such as asthma and pathological development process, all has higher level.Generated by the mouse macrophage NO of original cuiture and detect, can be used as external preliminary observation and screen the indicator and model having the compound of certain anti-inflammatory activity.
1) laboratory animal
C57BL6J mice (18 ~ 20g), 6 ~ 8 weeks, male.
2) compounding medicine
It is 1 × 10 that dexamethasone (positive drug) and testing compound are all mixed with concentration with DMSO
-2the stock solution of mol/L, deposits for-20 DEG C, is diluted to required concentration before use.
3) experimental technique NO generates-Griess reducing process
1, experiment point blank group (only adding Cell sap), LPS group, administration group (10
-5mol/L, 10
-6the medicine of mol/L), (final concentration is 10 to positive controls
-5mol/L, 10
-6the Dex of mol/L).
2, C57BL6J mouse peritoneal injection mercaptoethanol sodium 1.2ml/ only, injects fasting in evening in the 3rd day, injects mice sacrificed by decapitation after the 4th day.Lumbar injection D, Hanks physiological buffer 8ml, fully slowly liquid in sucking-off abdominal cavity after massage, centrifugal 5 minutes of 1000rpm, careful abandoning supernatant, cell RPMI1640 is resuspended, and cell concentration is adjusted to 1.0 × 10 by counting cells
6cell/ml.
3, inoculating cell is in 48 porocyte culture plates, every hole inoculation 500ul.37 DEG C, 5%CO
2adhere-wall culture 2 hours, makes cell attachment.Incline culture medium, rinse twice with PBS physiological buffer, remove non-attached cell, the RPMI1640 culture medium 500ul/ hole that every hole adds containing 5%FBS is stand-by.
4, blank group only adds culture medium, and after medicine and cell hatch 1 hour altogether, add the LPS that final concentration is 1ug/ml, LPS group adds LPS, 37 DEG C, 5%CO
2cultivate 24 hours.
5, taking-up supernatant 100ul and equivalent Griess reagent mix on micro oscillator, and are placed on left at room temperature 10 minutes.Reading is measured, according to NO under 550nm
2 -standard curve calculates the content of NO.
4) cytotoxicity is observed---mtt assay
Macrophage preparation method is the same.Experiment is divided into blank group (not adding MTT), matched group, administration group, and (final concentration is 10 to positive controls
-5mol/L, 10
-6the Dex of mol/L).
Macrophage suspension is added and causes 96 porocyte culture plates, 100ul/ hole, if 3 multiple holes, place 37 DEG C, 5%CO
2incubator cultivates 24 hours, terminates to add MTT10ul/ hole in first 4 hours in cultivation, continues cultivation 4 as a child, and adds cell pyrolysis liquid, in 570nm colorimetric.
Table 1 compound 1 ~ 15 is 10
-5nO suppression ratio during mol/L and cytotoxicity
Table 2 gained compound is 10
-6nO suppression ratio during mol/L
The Concentraton gradient evaluation and the Cytotoxic evaluation that NO are generated to suppression ratio of table 3 compound 3,5,13
Claims (5)
1. following triptolide derivant shown in structure,
2. the triptolide derivant of claim 1 is preparing the application in antiinflammatory, immunosuppressive drug.
3. the triptolide derivant of claim 1 is at preparation treatment rheumatism, the application in the medicine of autoimmune disease.
4. the triptolide derivant of claim 1 suppresses the application in the medicine of NO generation in preparation.
5. a pharmaceutical composition, is characterized in that, containing being selected from least one compound of claim 1 and pharmaceutically acceptable carrier.
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