CN101376651A - Andrographolide and water-soluble aminoacid ester derivative of dewatered andrographolide - Google Patents
Andrographolide and water-soluble aminoacid ester derivative of dewatered andrographolide Download PDFInfo
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- CN101376651A CN101376651A CNA2007101475741A CN200710147574A CN101376651A CN 101376651 A CN101376651 A CN 101376651A CN A2007101475741 A CNA2007101475741 A CN A2007101475741A CN 200710147574 A CN200710147574 A CN 200710147574A CN 101376651 A CN101376651 A CN 101376651A
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Abstract
The invention aims to provide derivatives of amino-acid esters of andrographolidume and dehydrated andrographolidume shown as formulae Ia and Ib. In Ia and Ib, R1, R2 and R3 are H, and the residue of amino acid such as acyl, L-alanyl, L-leucyl, L-valyl or L-isoleucyl; in Ia, R1, R2 and R3 cannot be H at the same time; and in Ib, R2 and R3 can not be H at the same time.
Description
Technical field
The present invention relates to the derivative of the amino acid ester of new rographolide and deoxydidehydrorographolide, and non-toxicity pharmacy acceptable salt, these derivatives have better water solubility and higher oral administration biaavailability.
Background technology
Rographolide (Andrographolide) is the diterpene ginkgolide that extraction obtains in acanthaceous plant Herba Andrographis, is one of main effective constituent of Chinese medicine Herba Andrographis, has functions such as clearing heat and detoxicating, cool blood detumescence.Modern pharmacological research shows, rographolide and derivative thereof such as deoxydidehydrorographolide, 14-deshydroxy 11,12-two dehydrogenation rographolides-3,19-disuccinic acid half ester monopotassium salt (potassium dehydroandrographolide succinate), 14-deshydroxy-11,12-two dehydrogenation rographolides-3,19-disuccinic acid half ester k-na salt (potassium sodium dehydroandroan drographolide succinate), rographolide sulfonate (Xiyanping), rographolide sodium bisulfite affixture (Lian Bizhi) etc. can suppress early stage capillary permeability and increase and inflammatory exudation and oedema, excited specifically hypophysis-adrenal cortex function, promote ACTH to discharge, increase the biosynthesizing of ACTH in the prepituitary gland; Have the effect of multiple viruses such as antiphlogistic antibacterial, deactivation adenovirus, influenza virus, Respirovirus, be widely used in the treatment infantile pneumonia clinically, upper respiratory tract infection (1, Liu Xinjian, Wang Yifei, Li Guisheng.The pharmacological research progress [J] of rographolide and derivative thereof.Chinese medicinal materials, 2003,26 (2): 135-138.2, Dai Guifu, Wang Junfeng, He Shuaiwei, etc.The pharmacology activity research progress [J] of rographolide and derivative thereof.Chinese patent medicine, 2006,28 (7): 1032-1035.)
Rographolide, deoxydidehydrorographolide and 14-deshydroxy 11,12-two dehydrogenation rographolides-3, the structure of 19-disuccinic acid half ester is as follows:
Rographolide deoxydidehydrorographolide deoxydidehydrorographolide disuccinic acid half ester
But, rographolide and deoxydidehydrorographolide poorly water-soluble, can occur in the clinical application irritated, side effects such as heating, thrombopenia (3, Wang Xipin, Li Hebai.The untoward reaction modern medicine health 2007,23 (1) of potasium dehydroandrographolisuccinate succinate injection: 95-96.); The preparation of its derivative and part medicine exist incompatibility (4, Jiang Jianwei.The compatibility stability of injection potassium sodium dehydroandroan drographolide succinate and common infusion fluid and medicine and taboo.The modern medicine health, 2006, l22 (10): 1565.)。
Summary of the invention
The derivative that the purpose of this invention is to provide the amino acid ester of the rographolide of formula Ia and Ib representative and deoxydidehydrorographolide:
Among formula Ia and the Ib, R
1, R
2, R
3For H, glycyl, L-alanyl, L-leucyl ,-amino acid whose residue such as L-valyl or L-isoleucyl-; In Ia, R
1, R
2, R
3Can not be H simultaneously, in Ib, R
2, R
3Can not be H simultaneously.
The present invention also provides the non-toxicity pharmacy acceptable salt of the amino acid ester derivative of rographolide shown in formula Ia and the Ib and deoxydidehydrorographolide.
The present invention also provides the amino acid ester derivative that contains rographolide shown in formula Ia and the Ib and deoxydidehydrorographolide and non-toxicity pharmacy acceptable salt thereof the pharmaceutical composition as activeconstituents.
The present invention also provides the amino acid ester derivative and the non-toxicity pharmacy acceptable salt thereof of rographolide shown in formula Ia and the Ib and deoxydidehydrorographolide, and comprises the amino acid ester derivative of rographolide shown in formula Ia and the Ib and deoxydidehydrorographolide and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of the activeconstituents purposes as the anti inflammation and heat resolution analgesic.
Embodiment
The amino acid ester derivative of rographolide can prepare according to following synthetic route:
Rographolide and N-benzyloxycarbonyl amino acid condensation under the dicyclohexylcarbodiimide effect obtain O-(N-benzyloxycarbonyl amino acyl)-rographolide, and the catalytic hydrogenation deprotection obtains target compound.Among the formula Ia, R
1, R
2, R
3Be amino acid whose residues such as H, glycyl, L-alanyl, L-leucyl, L-valyl or L-isoleucyl-; But, R
1, R
2, R
3Can not be H simultaneously.
The amino acid ester derivative that can prepare similarly, deoxydidehydrorographolide:
Deoxydidehydrorographolide and N-benzyloxycarbonyl amino acid condensation under the dicyclohexylcarbodiimide effect obtain O-(N-benzyloxycarbonyl amino acyl)-deoxydidehydrorographolide, and the catalytic hydrogenation deprotection obtains target compound.Among the formula Ib, R
2, R
3Be amino acid whose residues such as H, glycyl, L-alanyl, L-leucyl, L-valyl or L-isoleucyl-; But, R
2, R
3Can not be H simultaneously.
14-O-aminoacyl rographolide can be prepared as follows:
Rographolide in tosic acid pyridine (PPTS) effect down and 2; the reaction of 2-Propanal dimethyl acetal obtains 3; 19-acetonylidene derivative; then with N-benzyloxycarbonyl amino acid condensation under the dicyclohexylcarbodiimide effect; obtain 14-O-(N-benzyloxycarbonyl amino acyl)-3; 19-acetonylidene deoxydidehydrorographolide, the catalytic hydrogenation deprotection, last hydrolysis obtains target compound.Among the formula Ia, R
1Be amino acid whose residues such as glycyl, L-alanyl, L-leucyl, L-valyl or L-isoleucyl-.
The following examples can further be described the present invention, yet these embodiment should be as the restriction to scope of the present invention.
Embodiment 13, and 14,19-O-three glycyl rographolide (Ia
1) preparation
3.5g rographolide, 10.5gN-carbobenzoxyglycine with the dissolving of 50ml dimethyl formamide, are added the 0.3ml Dimethylamino pyridine then, the 10.3g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,14,19-O-three-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 5.8 grams.
With 3,14,19-O-three-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 5.8 grams add 1.2 and restrain 5% palladium charcoal with the dissolving of 50ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
12.7 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.27 (br s, 2H); 8.16 (br s, 2H); 8.05 (brs, 2H); 6.74 (t, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.42 (br s, 1H); 3.86 (d, 1H); 3.82 (m, 6H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.12 (s, 3H); 0.73 (s, 3H).
Embodiment 23,19-O-two glycyl rographolide (Ia
2) preparation
3.5g rographolide, 6.3g N-carbobenzoxyglycine with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 3.9 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 3.9 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 40ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
21.6 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 6.72 (t, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.45 (br s, 1H); 3.86 (d, 1H); 3.79 (m, 4H); 3.51-3.42 (m, 2H); 3.18 (d, 1H); 2.50 (d, 1H); 2.47 (m, 1H); 2.03 (m, 1H); 1.86 (m, 1H); 1.76 (m, 1H); 1.65 (m, 1H); 1.57 (m, 1H); 1.49 (m, 1H); 1.24 (m, 1H); 1.13 (s, 3H); 0.75 (s, 3H).
Embodiment 33-O-glycyl rographolide (Ia
3) and 19-O-glycyl rographolide (Ia
4) preparation
3.5g rographolide, 2.1g N-carbobenzoxyglycine with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 0.8 gram, 19-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 2.1 grams.
3-O-(N-carbobenzoxy-(Cbz)-glycyl)-rographolide 0.8 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
30.24 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.20 (br s, 2H); 6.74 (t, 1H); 4.92 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.46 (br s, 1H); 4.14 (br s, 1H); 3.86 (d, 1H); 3.78 (m, 2H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.77 (m, 1H); 1.64 (m, 1H); 1.53 (m, 1H); 1.50 (m, 1H); 1.27 (m, 1H); 1.14 (s, 3H); 0.72 (s, 3H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz)-glycyl)-rographolide 2.1 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
41.02 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.17 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.47 (br s, 1H); 3.86 (d, 1H); 3.83 (m, 2H); 3.54-3.44 (m, 2H); 3.14 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.10 (s, 3H); 0.76 (s, 3H).
Embodiment 4 14-O-glycyl rographolide (Ia
5) preparation
1,3, the preparation of 19-isopropylidene rographolide
Rographolide 20g is added on 25ml 2, in the mixing solutions of 2-Propanal dimethyl acetal and 4ml methyl-sulphoxide, be heated with stirring to dissolving (about 50 ℃), cool to room temperature adds 2 of catalytic amount, 2-toluenesulphonic acids pyridine, stirring at room 2 hours adds 5ml triethylamine termination reaction, and reaction mixture is poured in the 200ml water, with dichloromethane extraction 3 times, 200ml/ time.United extraction liquid is with evaporated under reduced pressure behind the anhydrous sodium sulfate drying.Residue is separated with silica gel column chromatography, use methylene dichloride: acetone (95:5) wash-out obtains 3,19-isopropylidene rographolide 15.1g.
2,3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide
With 3,19-isopropylidene rographolide 3.1g, N-carbobenzoxyglycine 2.1g add the 0.1ml Dimethylamino pyridine then with the dissolving of 30ml dimethyl formamide, 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 2.9g.
3,14-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide
3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 2.9g mixes with the 200ml70% acetic acid solution, stirs 15 minutes, and reaction mixture is neutralized with sodium bicarbonate, uses dichloromethane extraction 3 times, 100ml/ time.United extraction liquid with evaporated under reduced pressure behind the anhydrous sodium sulfate drying, gets 14-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 1.9g.
4,14-O-glycyl-rographolide (Ia
5)
14-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 1.9g with the dissolving of 20ml milliliter dioxane, is added 0.2 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
51.24 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.02 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.55 (br s, 1H); 4.16 (br s, 1H); 3.86 (d, 1H); 3.84 (m, 2H); 3.54-3.44 (m, 2H); 3.15 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.76 (m, 1H); 1.68 (m, 1H); 1.53 (m, 1H); 1.47 (m, 1H); 1.24 (m, 1H); 1.08 (s, 3H); 0.74 (s, 3H).
Embodiment 53,19-O-two glycyl deoxydidehydrorographolide (Ib
1) preparation
3.3g deoxydidehydrorographolide, 6.3g N-carbobenzoxyglycine with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz) glycyl)-deoxydidehydrorographolide 4.2 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz) glycyl)-deoxydidehydrorographolide 4.2 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 50ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
11.9 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 7.68 (brs, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (brs, 1H); 3.86 (d, 1H); 3.81 (m, 4H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.46 (m, 1H); 2.08 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.07 (s, 3H); 0.75 (s, 3H).
Embodiment 6 3-O-glycyl deoxydidehydrorographolide (Ib
2) and 19-O-glycyl deoxydidehydrorographolide (Ib
3) preparation
3.3g deoxydidehydrorographolide, 2.1g N-carbobenzoxyglycine with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz) glycyl)-deoxydidehydrorographolide 0.9 gram, 19-O-(N-carbobenzoxy-(Cbz) glycyl)-rographolide 2.5 grams.
3-O-(N-carbobenzoxy-(Cbz) glycyl)-deoxydidehydrorographolide 0.9 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
20.32 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.26 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 4.17 (br s, 1H); 3.86 (d, 1H); 3.81 (m, 2H); 3.27 (d, 1H); 3.23 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.11 (s, 3H); 0.77 (s, 3H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz) glycyl)-deoxydidehydrorographolide 2.5 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
31.3 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.14 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 5.07 (br s, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 3.86 (d, 1H); 3.83 (m, 2H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.47 (m, 1H); 2.02 (m, 1H); 1.85 (m, 1H); 1.77 (m, 1H); 1.69 (m, 1H); 1.59 (m, 1H); 1.51 (m, 1H); 1.24 (m, 1H); 1.07 (s, 3H); 0.75 (s, 3H).
Embodiment 73, and 14,19-O-three-L-alanyl rographolide (Ia
6) preparation
3.5g rographolide, 11.2g N-carbobenzoxy-(Cbz)-L-L-Ala with the dissolving of 50ml dimethyl formamide, are added the 0.3ml Dimethylamino pyridine then, the 10.3g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,14,19-O-three-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 4.7 grams.
With 3,14,19-O-three-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 4.7 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 50ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
62.4 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.30 (br s, 2H); 8.19 (br s, 2H); 8.11 (brs, 2H); 6.74 (t, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.42 (br s, 1H); 3.95 (m, 3H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.01 (m, 1H); 1.91 (m, 1H); 1.79 (m, 1H); 1.70 (m, 1H); 1.57 (m, 1H); 1.46 (m, 1H); 1.27 (m, 1H); 1.23 (m, 9H); 1.12 (s, 3H); 0.77 (s, 3H).
Embodiment 83,19-O-two-L-alanyl rographolide (Ia
7) preparation
3.5g rographolide, 6.4g N-carbobenzoxy-(Cbz)-L-L-Ala with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 3.7 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 3.7 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 40ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
71.5 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 6.72 (t, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.45 (br s, 1H); 3.96 (m, 2H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.27 (m, 1H); 1.25 (m, 6H); 1.13 (s, 3H); 0.75 (s, 3H).
Embodiment 9 3-O-L-alanyl rographolide (Ia
8) and 19-O-L-alanyl rographolide (Ia
9) preparation
3.5g rographolide, 2.24g N-carbobenzoxy-(Cbz)-L-L-Ala with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 0.9 gram, 19-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 2.2 grams.
3-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 0.9 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets the Ia80.24 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.20 (br s, 2H); 6.74 (t, 1H); 4.92 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.46 (br s, 1H); 4.14 (br s, 1H); 3.92 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.27 (m, 1H); 1.26 (d, 3H); 1.12 (s, 3H); 0.72 (s, 3H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 2.2 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
91.02 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.17 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.47 (br s, 1H); 3.93 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.14 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.28 (m, 1H); 1.24 (d, 3H); 1.10 (s, 3H); 0.76 (s, 3H).
Embodiment 1014-O-L-alanyl rographolide (Ia
10) preparation
1,3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide
With 3.1g3,19-isopropylidene rographolide, 2.24g N-carbobenzoxy-(Cbz)-L-L-Ala add the 0.1ml Dimethylamino pyridine then with the dissolving of 30ml dimethyl formamide, 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 2.5g.
2,14-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide
With 2.5g3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide mixes with 200ml 70% acetic acid solution, stirs 15 minutes, and reaction mixture is neutralized with sodium bicarbonate, uses dichloromethane extraction 3 times, 100ml/ time.United extraction liquid with evaporated under reduced pressure behind the anhydrous sodium sulfate drying, gets 14-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 1.8g.
3,14-O-L-alanyl-rographolide (Ia
10)
14-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 1.8g with the dissolving of 20ml milliliter dioxane, is added 0.2 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
101.12 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.02 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.55 (br s, 1H); 4.16 (br s, 1H); 3.91 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.15 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.29 (m, 1H); 1.26 (d, 3H); 1.08 (s, 3H); 0.74 (s, 3H).
Embodiment 11 3,19-O-two-L-alanyl deoxydidehydrorographolide (Ib
4) preparation
3.3g deoxydidehydrorographolide, 6.4g N-carbobenzoxy-(Cbz)-L-L-Ala with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-alanyl)-deoxydidehydrorographolide 3.9 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-alanyl)-deoxydidehydrorographolide 3.9 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 50ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
41.6 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 3.92 (m, 2H); 3.86 (d, 1H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.28 (m, 1H); 1.25 (m, 6H); 1.07 (s, 3H); 0.75 (s, 3H).
Embodiment 12 3-O-L-alanyl deoxydidehydrorographolide (Ib
5) and 19-O-L-alanyl deoxydidehydrorographolide (Ib
6) preparation
3.3g deoxydidehydrorographolide, 2.24g N-carbobenzoxy-(Cbz)-L-L-Ala with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-deoxydidehydrorographolide 0.7 gram, 19-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-rographolide 2.4 grams.
3-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-deoxydidehydrorographolide 0.7 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
50.2 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.26 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 4.17 (br s, 1H); 3.90 (m, 1H); 3.86 (d, 1H); 3.27 (d, 1H); 3.23 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.27 (m, 1H); 1.25 (d, 3H); 1.11 (s, 3H); 0.77 (s, 3H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz)-L-alanyl)-deoxydidehydrorographolide 2.4 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
61.1 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.14 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 5.07 (br s, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 3.93 (m, 1H); 3.86 (d, 1H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.26 (m, 1H); 1.24 (d, 3H); 1.07 (s, 3H); 0.75 (s, 3H).
Embodiment 13 3, and 14,19-O-three-L-valyl rographolide (Ia
11) preparation
3.5g rographolide, 12.6g N-carbobenzoxy-(Cbz)-L-Xie Ansuan with the dissolving of 50ml dimethyl formamide, are added the 0.3ml Dimethylamino pyridine then, the 10.3g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,14,19-O-three-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 6.5 grams.
With 3,14,19-O-three-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 6.5 grams add 1.2 and restrain 5% palladium charcoal with the dissolving of 60ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
112.9 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.27 (br s, 2H); 8.16 (br s, 2H); 8.05 (br s, 2H); 6.74 (t, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.42 (br s, 1H); 3.96 (m, 3H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.14 (m, 3H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.12 (s, 3H); 0.91-1.05 (m, 18H); 0.78 (s, 3H).
Embodiment 14 3,19-O-two-L-valyl rographolide (Ia
12) preparation
3.5g rographolide, 7.56g N-carbobenzoxy-(Cbz)-L-Xie Ansuan with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 4.6 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 4.6 grams add 1.0 and restrain 5% palladium charcoal with the dissolving of 40ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
122.1 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 6.72 (t, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.45 (br s, 1H); 3.96 (m, 2H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.16 (m, 2H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.13 (s, 3H); 0.90-1.02 (m, 12H); 0.75 (s, 3H).
Embodiment 15 3-O-L-valyl rographolide (Ia
13) and 19-O-L-valyl rographolide (Ia
14) preparation
3.5g rographolide, 2.52g N-carbobenzoxy-(Cbz)-L-Xie Ansuan with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 0.7 gram, 19-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 3.2 grams.
3-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 0.7 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
130.25 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.20 (br s, 2H); 6.74 (t, 1H); 4.92 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.46 (br s, 1H); 4.14 (br s, 1H); 3.88 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.15 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.12 (s, 3H); 0.95-1.01 (m, 6H); 0.78 (s, 3H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 3.2 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
141.4 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.17 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.47 (br s, 1H); 3.93 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.14 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.18 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.10 (s, 3H); 0.96-1.01 (m, 6H); 0.76 (s, 3H).
Embodiment 16 4-O-L-valyl rographolide (Ia
15) preparation
1,3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide
With 3.1g3,19-isopropylidene rographolide, 2.52g N-carbobenzoxy-(Cbz)-L-Xie Ansuan add the 0.1ml Dimethylamino pyridine then with the dissolving of 30ml dimethyl formamide, 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 3.4g.
2,14-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide
3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 3.4g mixes with the 200ml70% acetic acid solution, stirs 15 minutes, and reaction mixture is neutralized with sodium bicarbonate, uses dichloromethane extraction 3 times, 100ml/ time.United extraction liquid with evaporated under reduced pressure behind the anhydrous sodium sulfate drying, gets 14-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 1.8g.
3,14-O-L-valyl-rographolide (Ia
15)
14-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 1.8g with the dissolving of 20ml milliliter dioxane, is added 0.2 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
151.12 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.02 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.55 (br s, 1H); 4.16 (br s, 1H); 3.88 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.15 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.17 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.08 (s, 3H); 0.92-0.98 (m, 6H); 0.74 (s, 3H).
Embodiment 17 3,19-O-two-L-valyl deoxydidehydrorographolide (Ib
7) preparation
3.3g deoxydidehydrorographolide, 7.56g N-carbobenzoxy-(Cbz)-L-Xie Ansuan with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-valyl)-deoxydidehydrorographolide 4.7 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-valyl)-deoxydidehydrorographolide 4.7 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 50ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
72.3 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 3.91 (m, 2H); 3.86 (d, 1H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.16 (m, 2H); 2.04 (m, 1H); 1.87 (m, 1H); 1.76 (m, 1H); 1.68 (m, 1H); 1.55 (m, 1H); 1.50 (m, 1H); 1.27 (m, 1H); 1.07 (s, 3H); 0.91-1.04 (m, 12H); 0.75 (s, 3H).
Embodiment 18 3-O-L-valyl deoxydidehydrorographolide (Ib
8) and 19-O-L-valyl deoxydidehydrorographolide (Ib
9) preparation
3.3g deoxydidehydrorographolide, 2.52g N-carbobenzoxy-(Cbz)-L-Xie Ansuan with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz)-L-valyl)-deoxydidehydrorographolide 0.6 gram, 19-O-(N-carbobenzoxy-(Cbz)-L-valyl)-rographolide 2.6 grams.
3-O-(N-carbobenzoxy-(Cbz)-L-valyl)-deoxydidehydrorographolide 0.6 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
80.23 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.26 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 4.17 (br s, 1H); 3.90 (m, 1H); 3.86 (d, 1H); 3.27 (d, 1H); 3.23 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.15 (m, 1H); 2.02 (m, 1H); 1.85 (m, 1H); 1.78 (m, 1H); 1.69 (m, 1H); 1.56 (m, 1H); 1.47 (m, 1H); 1.25 (m, 1H); 1.11 (s, 3H); 0.93-0.98 (m, 6H); 0.77 (s, 3H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz)-L-valyl)-deoxydidehydrorographolide 2.6 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
91.1 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.14 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 5.07 (br s, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 3.93 (m, 1H); 3.86 (d, 1H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.17 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.07 (s, 3H); 0.96-1.01 (m, 6H); 0.75 (s, 3H).
Embodiment 19 3, and 14,19-O-three-L-isoleucyl-rographolide (Ia
16) preparation
3.5g rographolide, 13.32g N-carbobenzoxy-(Cbz)-L-Isoleucine with the dissolving of 50ml dimethyl formamide, are added the 0.3ml Dimethylamino pyridine then, the 10.3g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,14,19-O-three-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 6.1 grams.
With 3,14,19-O-three-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 6.1 grams add 1.2 and restrain 5% palladium charcoal with the dissolving of 50ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
162.8 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.31 (br s, 2H); 8.22 (br s, 2H); 8.10 (br s, 2H); 6.77 (t, 1H); 4.83 (br s, 1H); 4.53 (m, 1H); 4.41 (br s, 1H); 4.02 (m, 3H); 3.84 (d, 1H); 3.51-3.43 (m, 2H); 3.16 (d, 1H); 2.51 (d, 1H); 2.47 (m, 1H); 2.05 (m, 1H); 1.85 (m, 1H); 1.74 (m, 1H); 1.68 (m, 1H); 1.60 (m, 3H); 1.55 (m, 1H); 1.50 (m, 1H); 1.27 (m, 1H); 1.19-1.25 (m, 6H); 1.13 (s, 3H); 0.72-0.90 (m, 21H).
Embodiment 20 3,19-O-two-L-isoleucyl-rographolide (Ia
17) preparation
3.5g rographolide, 7.99g N-carbobenzoxy-(Cbz)-L-Isoleucine with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 3.7 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 3.8 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 40ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
171.9 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 6.72 (t, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.45 (br s, 1H); 3.89 (m, 2H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.60 (m, 2H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.18-1.23 (m, 4H); 1.13 (s, 3H); 0.72-0.90 (m, 15H).
Embodiment 213-O-L-isoleucyl-rographolide (Ia
18) and 19-O-L-isoleucyl-rographolide (Ia
19) preparation
3.5g rographolide, 2.66g N-carbobenzoxy-(Cbz)-L-Isoleucine with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 0.7 gram, 19-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 3.5 grams.
3-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 0.7 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
180.29 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.20 (br s, 2H); 6.74 (t, 1H); 4.92 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.46 (br s, 1H); 4.14 (br s, 1H); 3.93 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.17 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.74 (m, 1H); 1.67 (m, 1H); 1.59 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.26 (m, 1H); 1.19-1.22 (m, 2H); 1.12 (s, 3H); 0.72-0.90 (m, 9H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 3.5 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
191.8 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.17 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.91 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.47 (br s, 1H); 3.92 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.14 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.61 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.21-1.25 (m, 3H); 1.10 (s, 3H); 0.72-0.90 (m, 9H).
Embodiment 22 14-O-L-isoleucyl-rographolide (Ia
20) preparation
1,3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide
With 3.1g3,19-isopropylidene rographolide, 2.6g N-carbobenzoxy-(Cbz)-L-Isoleucine add the 0.1ml Dimethylamino pyridine then with the dissolving of 30ml dimethyl formamide, 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (1:9) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 3.3g.
2,14-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide
With 3.3g3,19-isopropylidene-14-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide mixes with the 200ml70% acetic acid solution, stirs 15 minutes, and reaction mixture is neutralized with sodium bicarbonate, uses dichloromethane extraction 3 times, 100ml/ time.United extraction liquid with evaporated under reduced pressure behind the anhydrous sodium sulfate drying, gets 14-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 2.1g.
3,14-O-L-isoleucyl--rographolide (Ia
20)
14-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 2.1g with the dissolving of 20ml milliliter dioxane, is added 0.2 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ia
201.12 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.02 (br s, 2H); 6.74 (t, 1H); 5.09 (br s, 1H); 4.83 (br s, 1H); 4.52 (m, 1H); 4.55 (br s, 1H); 4.16 (br s, 1H); 3.94 (m, 1H); 3.86 (d, 1H); 3.54-3.44 (m, 2H); 3.15 (d, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.68 (m, 1H); 1.62 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.20-1.23 (m, 2H); 1.08 (s, 3H); 0.72-0.90 (m, 9H).
Embodiment 233,19-O-two-L-isoleucyl-deoxydidehydrorographolide (Ib
10) preparation
3.3g deoxydidehydrorographolide, 7.99g N-carbobenzoxy-(Cbz)-L-Isoleucine with the dissolving of 40ml dimethyl formamide, are added the 0.2ml Dimethylamino pyridine then, the 6.18g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (2:8) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-deoxydidehydrorographolide 4.5 grams.
With 3,19-O-two-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-deoxydidehydrorographolide 4.5 grams add 0.8 and restrain 5% palladium charcoal with the dissolving of 50ml milliliter dioxane, after stirring 4 hours under 1 the atmospheric hydrogen, and the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
102.3 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.25 (br s, 2H); 8.14 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 3.91 (m, 2H); 3.86 (d, 1H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.66 (m, 1H); 1.61 (m, 2H); 1.56 (m, 1H); 1.48 (m, 1H); 1.19-1.25 (m, 5H); 1.07 (s, 3H); 0.72-0.90 (m, 15H).
Embodiment 24 3-O-L-isoleucyl-deoxydidehydrorographolide (Ib
11) and 19-O-L-isoleucyl-deoxydidehydrorographolide (Ib
12) preparation
3.3g deoxydidehydrorographolide, 2.6g N-carbobenzoxy-(Cbz)-L-Isoleucine with the dissolving of 30ml dimethyl formamide, are added the 0.1ml Dimethylamino pyridine then, the 2.06g dicyclohexylcarbodiimide, the stirring at room reaction is spent the night, and filters, with the filtrate decompression evaporate to dryness.Residue is separated with silica gel column chromatography, use methylene dichloride: sherwood oil (3:7) mixed solvent wash-out, collect required component, evaporated under reduced pressure, get 3-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-deoxydidehydrorographolide 0.6 gram, 19-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-rographolide 3.4 grams.
3-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-deoxydidehydrorographolide 0.6 gram with the dissolving of 10ml milliliter dioxane, is added 0.1 and restrains 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
110.32 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.26 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 4.17 (br s, 1H); 3.91 (m, 1H); 3.86 (d, 1H); 3.27 (d, 1H); 3.23 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.77 (m, 1H); 1.65 (m, 1H); 1.56 (m, 1H); 1.60 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.19-1.22 (m, 2H); 1.11 (s, 3H); 0.72-0.90 (m, 9H).
Similarly, 19-O-(N-carbobenzoxy-(Cbz)-L-isoleucyl-)-deoxydidehydrorographolide 3.4 grams with the dissolving of 20ml milliliter dioxane, are added 0.2 and restrain 5% palladium charcoal, after stirring 4 hours under 1 the atmospheric hydrogen, the elimination catalyzer.Filtrate decompression is concentrated, separate with silica gel column chromatography then, use methylene dichloride: sherwood oil: triethylamine (5:5:0.1) mixed solvent wash-out, collect required component, evaporated under reduced pressure gets Ib
121.3 gram.Proton nmr spectra δ (ppm, DMSO-d
6): 8.14 (br s, 2H); 7.68 (br s, 1H); 6.76 (dd, 1H); 6.17 (d, 1H); 5.07 (br s, 1H); 4.91 (br s, 2H); 4.73 (br s, 1H); 4.43 (br s, 1H); 3.93 (m, 1H); 3.86 (d, 1H); 3.27 (d, 1H); 3.25 (m, 1H); 2.49 (d, 1H); 2.45 (m, 1H); 2.06 (m, 1H); 1.84 (m, 1H); 1.75 (m, 1H); 1.67 (m, 1H); 1.59 (m, 1H); 1.56 (m, 1H); 1.48 (m, 1H); 1.25 (m, 1H); 1.20-1.23 (m, 2H); 1.07 (s, 3H); 0.72-0.90 (m, 9H).
The restraining effect of rat fever due to 25 pairs of dry yeast of embodiment
(5. Han Guang one, Du Gangjun, Xu Qitai, Yang Songsong for reference.Synthetic and the antipyretic and anti-inflammatory effect research of rographolide three toxilic acid monoesters, Chinese Pharmaceutical Journal, 2005; 40 (8): 628-631.) method, with the refrigeration function of rat fever trial model evaluation objective compound due to the dry yeast.Select the rat of body weight 150-180g for use, in experiment preceding 2 days, survey body temperature every day 1 time, select body temperature and change, and self body temperature changes and be lower than 0.3 ℃ animal at 37～38.5 ℃, male and female half and half are divided 5 groups at random, 5 every group.Administration was measured body temperature in preceding 2 hours, as 0 o'clock basal body temperature; The fresh dry yeast suspension (1mL/100g) of subcutaneous injection immediately 20% behind the thermometric; Testing sample is suspended or be dissolved in 0.5% carboxymethylcellulose sodium solution, after 2 hours, press the dosage of 200mg/kg, distinguish gastric infusion rographolide, deoxydidehydrorographolide and target compound, compare with physiological saline, measure after the administration 1,2,3,5,7,9 hours body temperature.The results are shown in Table 1.
The restraining effect of rat fever due to the table 1 pair dry yeast
26 pairs of egg white of embodiment cause the influence of rat paw edema
(6. Han Guang one, Du Gangjun, Xu Qitai, Yang Songsong for reference.Synthetic and the antipyretic and anti-inflammatory effect research Chinese Pharmaceutical Journal of rographolide three toxilic acid monoesters, 2005; 40 (8): 628-631.) method, cause the anti-inflammatory action of rat paw edema trial model evaluation objective compound with egg white.Select the rat of body weight 180-220g for use, male and female half and half, random packet, 6 every group.With the right ankle joint flooding boundary of marking pen mark rat, cause the right sufficient Volume of Displacement of scorching preceding rat before the administration with the measurement of Volume of Displacement method.Testing sample is suspended or be dissolved in 0.5% carboxymethylcellulose sodium solution, press the dosage of 200mg/kg, distinguish gastric infusion rographolide, deoxydidehydrorographolide and target compound.After the administration immediately in the right back sole subcutaneous injection of rat fresh albumen (0.1mL/ only).Measure after the administration 1,2,3, the rat foot Volume of Displacement during 5h.The results are shown in Table 2.
The restraining effect of rat paw edema due to the table 2 pair egg white
Embodiment 27 mouse hot-plate tests
Measure analgesic activities with the mouse hot-plate test.Female mice is placed on 55 ℃ of hot plates, and timing at once ends when for the first time occurring licking or stamp metapedes, and the gained time is the basic threshold of pain before the administration.Random packet then, every group of 8 animals; Testing sample is suspended or be dissolved in 0.5% carboxymethylcellulose sodium solution, press the dosage of 200mg/kg, distinguish gastric infusion rographolide, deoxydidehydrorographolide and target compound.Different time points is surveyed the threshold of pain again after administration, the results are shown in Table 3.
The analgesic activities of table 3 compound
Claims (4)
1, the derivative of the amino acid ester of the rographolide of formula Ia and Ib representative and deoxydidehydrorographolide:
Among formula Ia and the Ib, R
1, R
2, R
3For H, glycyl, L-alanyl, L-leucyl ,-amino acid whose residue such as L-valyl or L-isoleucyl-; In Ia, R
1, R
2, R
3Can not be H simultaneously, in Ib, R
2, R
3Can not be H simultaneously.
2, the non-toxicity pharmacy acceptable salt of the amino acid ester derivative of described rographolide of claim 1 and deoxydidehydrorographolide.
3, the non-toxicity pharmacy acceptable salt of the amino acid ester derivative of described rographolide of claim 1 and deoxydidehydrorographolide is as the pharmaceutical composition of activeconstituents.
4, the amino acid ester derivative of claim 1,2 and 3 described rographolides and deoxydidehydrorographolide and non-toxicity pharmacy acceptable salt thereof, and comprise the amino acid ester derivative of rographolide shown in formula Ia and the Ib and deoxydidehydrorographolide and non-toxicity pharmacy acceptable salt thereof as the pharmaceutical composition of activeconstituents purposes as the anti inflammation and heat resolution analgesic.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964320A (en) * | 2012-11-27 | 2013-03-13 | 中国药科大学 | 19-carboxyl andrographolide derivative, preparation method and medicinal application thereof |
| CN103479617A (en) * | 2013-09-09 | 2014-01-01 | 哈尔滨珍宝制药有限公司 | Dehydroandrographolide derivative composition and preparation method as well as application thereof |
| CN103739576A (en) * | 2014-01-24 | 2014-04-23 | 北京普瑞博思投资有限公司 | Novel antiviral andrographolide derivative and preparation method and application thereof |
| CN105367558A (en) * | 2015-08-27 | 2016-03-02 | 沈阳药科大学 | Andrographolide derivative and preparation method and application thereof |
-
2007
- 2007-08-28 CN CNA2007101475741A patent/CN101376651A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964320A (en) * | 2012-11-27 | 2013-03-13 | 中国药科大学 | 19-carboxyl andrographolide derivative, preparation method and medicinal application thereof |
| CN103479617A (en) * | 2013-09-09 | 2014-01-01 | 哈尔滨珍宝制药有限公司 | Dehydroandrographolide derivative composition and preparation method as well as application thereof |
| CN103739576A (en) * | 2014-01-24 | 2014-04-23 | 北京普瑞博思投资有限公司 | Novel antiviral andrographolide derivative and preparation method and application thereof |
| CN103739576B (en) * | 2014-01-24 | 2016-08-24 | 北京普瑞博思投资有限公司 | A kind of antivirus andrographolide derivative and its preparation method and application |
| CN105367558A (en) * | 2015-08-27 | 2016-03-02 | 沈阳药科大学 | Andrographolide derivative and preparation method and application thereof |
| CN105367558B (en) * | 2015-08-27 | 2018-07-03 | 沈阳药科大学 | Andrographolidume derivative and its preparation method and application |
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Application publication date: 20090304 |