CN1673226A - Carboxylate medicine precursors of hydroxycamptothecine and its derivative and thei prepn and application - Google Patents
Carboxylate medicine precursors of hydroxycamptothecine and its derivative and thei prepn and application Download PDFInfo
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Abstract
The present invention discloses carboxylate medicine precursors of hydroxycamptothecine and its derivatives as shown in expression I and II, their preparation process and application in preparing nanometer liposome preparation and treating tumors.
Description
Technical field
The double carboxy acid ester of hydroxycamptothecine and derivative thereof and monocarboxylic acid fat, its preparation method, vitro stability are investigated and the application in nano liposome preparations and oncotherapy.
Background technology
Camptothecine is since 1994 go on the market first kind, because its determined curative effect, effect target uniqueness has become and used one of five maximum big series antineoplastic medicaments clinically.Camptothecine is the alkaloid that was separated to the distinctive camplotheca acuminata from China first in 1966 by Wall etc., because of its unique chemical structure and notable antitumor activity, cause whole world related personnel attention.The seventies, camptothecine enters clinical study with the form of the water-soluble sodium salt of its open loop structure, and side effects such as serious bone marrow depression, vomiting, diarrhoea and severe haemorrhage appear in the result, and open loop form activity reduces greatly, make clinical study be difficult to continue.1985, the result of study of the Hsiang of JohnHopkins university etc. shows, camptothecine is the specific inhibitor of DNA topoisomerase I, and topoisomerase I is a kind of ribozyme of cell, with the duplicating, transcribe, repair and recombinate relevant of DNA, all there is expression in its any stage in the cell cycle, and the content of topoisomerase I is than the content height in the normal cell in the known cancer cell, thereby this anti-tumor compounds has certain selectivity.This great discovery makes camptothecine become the focus of antitumor drug research again.The emphasis of research is increase this compounds water-soluble.
1994, (Irinotecan, CPT-11) listing was used for the treatment of colorectal cancer to the water-soluble irinotecan of drugs approved by FDA camptothecine.1996, the topotecan (Topotecan) that is used as ovarian cancer patient's second line treatment medicine was got permission listing again, and U.S. FDA was ratified its two wires smelting as small cell lung cancer (SCLC) again and treated medicine in 1999.Hydroxycamptothecine is extensive use of for many years in China, cures mainly digestive system tumors such as colorectal carcinoma, cancer of the stomach, liver cancer and carcinoma of the pancreas, and chronic myelocytic leukemia, kemia and ovarian cancer etc.What be in the clinical study stage has a 9-nitrocamptothecin (9-Nitrocamptothecin, Rubitecan) (the III phase is clinical), Lurtotecan (GI147211, GG211) Liposomal formulation OSI-211 (NX211) (the II phase is clinical), Exatecan (DX-8951f) (the III phase is clinical), CKD-602 (the II phase is clinical), BNP-1350 (Karenitecin) (the II phase is clinical), BN-80915 (Diflomotecan) (the II phase is clinical) and Gimatecan (ST-1481).Prodrug or polymer drug delivery system comprise: the polyglutamic acid derivative (the I phase is clinical) of the biodegradable polymer derivative DE-310 (the I phase is clinical) of water-soluble (glycoconjugate) prodrug Afeletecan (BAY38-3441) (the II phase is clinical), Exatecan, the polymer conjugates Prothecan (the II phase is clinical) of camptothecine and camptothecine.
But, because the activated lactone loop type of camptothecine and derivative thereof easily is hydrolyzed open loop in human plasma be the corresponding carboxylic acid form, and the albumin in the blood plasma (HSA) ordinary priority combines with its carboxylic acid form, makes hydrolysising balance move right, thereby reduces bioavailability of medicament greatly.In addition, the carboxylic acid form with albumin bound is released slowly generation hysteresis toxicity.Also because medicine and plasma albumin combination cause the effective concentration of medicine in blood plasma to reduce, make medicine can not effectively reach lesions position, this is a narrow major reason of its antitumor spectrum.Therefore, by the stability of structural modification increase lactonic ring, improve the preparation that its solvability is beneficial to preparation, perhaps reduce the residence time of medicine in blood plasma, make medicine by rapid absorption and adopt special preparation, make medicine effectively arrive target tissue and just seem particularly important.
Over nearly 5 years, the document emerge in multitude of the various ester prodrugs of relevant preparation camptothecine and derivative thereof.Conclusion is got up, and comprises following several big class: the assorted oxygen fatty acid ester of 20 (S) fatty acid ester of camptothecine and derivative thereof, aryl esters, virtue or virtue, amino carboxylicesters, yoke and the thing (conjugates) that replaces and polymer drug delivery system etc.Though the foreign scholar is doing a lot of exploration work aspect the camptothecin prodrug, but they mostly with camptothecine as parent compound, enter Afeletecan, the Prothecan of clinical study and camptothecin polyglutamate etc. as mentioned above, the active ingredient that they discharge after being hydrolyzed in blood plasma is a camptothecine.Yet camptothecine itself there is no clinical use value, present clinical use be hydroxycamptothecine, irinotecan and topotecan.10 of these three medicines all have hydroxyl (camptothecine and topotecan) or its ester (irinotecan).
(Bioorganic Medicinal Chemistry Letters 1998:415-418) has prepared 10-decylate, 10-lauric acid ester, 10-16 carbonic ethers, 10-stearate and 10-20 carbonic ethers of hydroxycamptothecine to the Hiromitsu Takayama etc. of Japan with complete synthesis method.Vitro stability studies show that these compounds can be discharged corresponding parent compound by the human plasma hydrolysis.
Summary of the invention
The technical problem to be solved in the present invention is, be provided at 10 of widely used hydroxycamptothecine of China and derivative thereof, 20-double carboxy acid ester and 10-monocarboxylic acid fat provide its corresponding preparation method and the application in nanometer formulation and oncotherapy simultaneously as prodrug.
The technical problem to be solved in the present invention comprises that with hydroxycamptothecine and derivative thereof be starting raw material, with N, N-dicyclohexylcarbodiimide (DCC) and 4-(N, N-dimethylamino) pyridine (DMAP) is a catalyzer, has prepared 10 simultaneously, 20-double carboxy acid ester and 10-monocarboxylic acid fat, these compounds can increase the stability of lactonic ring effectively, prolong the activated lactone transformation period of form in blood, improve bioavailability, can also reduce toxicity, help the preparation of nanometer formulation simultaneously.
Technical scheme of the present invention is:
Following general formula (I) compound and general formula (II) compound
Wherein R represents C
1～30The aromatic ring of alkyl, aromatic ring, fragrant heterocycle, aralkyl, replacement, the fragrant heterocycle of replacement, the aralkyl of replacement; R
1Expression C
1～10Alkyl.And, do not comprise R in general formula (II) compound
1During=H, R=CH
3(CH
2)
8, CH
3(CH
2)
10, CH
3(CH
2)
14, CH
3(CH
2)
16And CH
3(CH
2)
18Compound.
In above-mentioned general formula (I) compound and general formula (II) compound, the aromatic ring of the replacement of R representative, the fragrant heterocycle of replacement, the aralkyl of replacement, being meant has C on the phenyl ring
1～10Alkyl, NO
2, F, Cl, Br or I single substituting group or multi-substituent.
In aforementioned formula (I) compound and general formula (II) compound, the aryl in the aralkyl of the aromatic ring of the aromatic ring of R representative, fragrant heterocycle, aralkyl, replacement, the fragrant heterocycle of replacement, replacement can be one or more F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group or the nitro benzene, biphenyl or the naphthalene that replace; Alkyl in the aralkyl of R representative can be C
1～10Alkyl.
In aforementioned formula (I) compound and general formula (II) compound, the heterocycle in the fragrant heterocycle of R representative, the fragrant heterocycle of replacement can be for containing five yuan, hexa-atomic or seven membered heterocyclic of one or more O, N, S atom.
Above-mentioned any one compound is used at the preparation nano liposome preparations with at the preparation antitumor drug.
The preparation method of above-mentioned general formula (I) compound and general formula (II) compound, this method may further comprise the steps:
A. hydroxycamptothecine and derivative thereof and carboxylic acid be under DCC and DMAP catalysis, 0-60 ℃ of stirring reaction 1～50 hour, and a step prepares general formula (I) compound and general formula (II) compound simultaneously;
B. reactant is through silica gel column chromatography, with methylene dichloride and acetone mixed solvent be elutriant carry out gradient elution (methylene dichloride/acetone: 30/1～1/1, v/v), increase the amount of acetone gradually, separate obtaining general formula (I) compound and general formula (II) compound.
Prodrug is meant in external lifeless matter activity, is activated the medicine into activeconstituents performance therapeutic action in vivo.Wherein, for ester class prodrug, general proteolysis in blood plasma in vivo discharges active pharmaceutical ingredient.Thereby we generally investigate the hydrolysis situation of prepared ester class prodrug in external blood plasma.
Nanometer formulation is the novel form that development in recent years is got up.If insoluble drug is enclosed in the polymeric matrix, be processed into nano particle, specific surface area increases greatly, thereby solubleness and absorption rate increase greatly, improve homogeneity, the dispersiveness of preparation, greatly improve bioavailability, play the effect of target and slowly-releasing.Liposome can wrap up wetting ability or close ester medicine, and made nanometer formulation can make medicine arrive target tissue fast.External and domestic also have Many researchers to wish to solve by liposome nanometer formulation technology problems such as the toxicity of camptothecine and preparation, but hydroxycamptothecine and other two clinical medicines all can not be wrapped up by the nanometer formulation material, have only camptothecine itself can be processed into nanometer formulation, clinically without any meaning.And the double carboxy acid ester and the monocarboxylic acid fat prodrug of our prepared hydroxycamptothecine and derivative thereof can wrap up by the nanometer formulation material, is processed into nanometer formulation.Liposome is that phosphatide is dispersed in a kind of ester class double membrane structure material that aligns that forms in the water, can be used for the hydrophilic or lipophilic medicine of load.Nano level liposome generally belongs to macrovesicle (＜300 nanometer).The method for preparing liposome has film dispersion method, ultrasonic dispersion and solvent injection method at present.For overcoming the shortcoming of conventional liposome poor stability, the solid liposome nano particle (solid lipid nanoparticles) with higher stability becomes a research focus of nano liposome medicament transportation art in recent years.The method that is used to prepare the solid liposome nano particle mainly contains micro emulsion method, the emulsification precipitator method and heat and melts dispersion method etc., and commonly used is that heat is melted dispersion method.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 1
Hydroxycamptothecine 10, the preparation of the two capronates of 20-and hydroxycamptothecine-10-capronate
Hydroxycamptothecine (270mg), caproic acid (340mg), DCC (350mg), DMAP (245mg) and methylene dichloride (50ml) are added in the reaction flask, and stirring at room 5 hours is filtered, and filtrate is respectively with 5%K
2CO
3The aqueous solution (60ml), dilute hydrochloric acid (50ml), water (50ml) and saturated aqueous common salt (50ml) washing.Column chromatography, with methylene dichloride/acetone (20/1～5/1) wash-out, what wash-out came out at first is the little product of polarity, i.e. hydroxycamptothecine-10, the two capronate 210mg of 20-, yield 51.5%, mp202 ℃.
1HNMR(δ，ppm，CDCl
3)：8.35(1H，s)，8.21(1H，d，J＝9.17)，7.68(1H，d，J＝2.38)，7.57(1H，dd)，7.20((1H，s)，5.68(1H，d，J＝17.23)，5.41(1H，d，J＝17.23)，5.29(2H)，2.65(2H，t，J＝7.15Hz)，2.49(2H，m)，1.96-1.92(2H，m)，1.86-1.75(2H，m)，1.72-1.63(4H，m)，1.48-1.30(6H，m)，0.99-0.95(6H，m)，0.85(3H，t，J＝7.15Hz)；EI-MS(m/e)(M
+)：560(M
+)，444，346(base?peak)，318，303。
With methylene dichloride/acetone (20/1～5/1) wash-out, get than the big compound of above dibasic acid esters polarity i.e. hydroxycamptothecine-10-capronate 22mg, yield 6.8%, mp223 ℃ simultaneously.
1HNMR(δ，ppm，DMSO-d
6)：8.66(1H，s)，8.19(1H，d，J＝9.16Hz)，7.89(1H，d，J＝2.57Hz)，7.64(1H，dd，J＝9.16?and?2.57Hz)，7.34(1H，s)，5.41(2H，s)，5.28(2H，s)，2.66(2H，t，J＝7.34Hz)，1.87(2H，m)，1.69(2H，m)，1.38-1.21(4H，m)，0.92-0.85(6H，m)；EIMS(m/e)：462，418，364(base?peak)，348，320，305。
Embodiment 2
Hydroxycamptothecine-10, the preparation of the two decylates of 20-
With hydroxycamptothecine (HCPT) (300mg), capric acid (350mg), DCC (350mg), DMAP (250mg) and methylene dichloride (50ml) be added in the reaction flask, stirring at room 15 hours is filtered, filtrate is respectively with 5%K
2CO
3The aqueous solution (70ml), dilute hydrochloric acid (60ml), water (60ml) and saturated aqueous common salt (60ml) are washed.Column chromatography with methylene dichloride/acetone (20/1) wash-out, gets hydroxycamptothecine-10, the two decylate 305mg of 20-, yield 55%, mp156 ℃.
1HNMR(δ，ppm，CDCl
3)：8.34(1H，s)，8.22(1H，d，J＝9.2Hz)，7.69(1H，d，J＝2.48Hz)，7.57(1H，dd，J＝Hz)，7.19(1H，s)，5.68(1H，)，5.41(1H，d，J＝17.17Hz)，5.28(2H)，2.65(2H，t，J＝7.41Hz)，1.97-1.94(2H，m)，1.84-1.74(4H，m)，1.67-1.60(2H，m)，1.47-1.1?2(56H，m)，0.97(3H，t，J＝7.55Hz)，0.89(3H，t，J＝5.91Hz)，0.82(3H，t，J＝6.73Hz)；EI-MS(m/e)：672(M
+)，501，500，346(base?peak)，318，303。
Embodiment 3
Hydroxycamptothecine-10, the preparation of 20-bilaurate
With hydroxycamptothecine (HCPT) (300mg), lauric acid (360mg), DCC (350mg), DMAP (250mg) and methylene dichloride (50ml) be added in the reaction flask, stirring at room 15 hours is filtered, filtrate is respectively with 5%K
2CO
3The aqueous solution (70ml), dilute hydrochloric acid (60ml), water (60ml) and saturated aqueous common salt (60ml) are washed.Column chromatography with methylene dichloride/acetone (20/1) wash-out, gets hydroxycamptothecine-10,20-bilaurate 360mg, yield 60%, mp148 ℃.
1HNMR(δ，ppm，CDCl
3)：8.35(1H，s)，8.21(1H，d，J＝9.16Hz)，7.69(1H，d，J＝2.56Hz)，7.57(1H，dd，J＝9.16?and?2.56Hz)，7.20(1H，s)，5.68(1H，d，J＝17.23Hz)，5.41(1H，d，J＝17.23Hz)，5.28(1H，s)，2.65(2H，t)，2.47(2H，m)，1.82-1.78(2H，m)，1.64-1.59(2H，m)，1.28-1.17(34H，m)，0.97(3H，t)，0.89-0.84(6H，m)；EI-MS(m/e)：728(M
+)，528，346(base?peak)，318，303。
Embodiment 4:
Hydroxycamptothecine-10, the preparation of the two stearates of 20-
With hydroxycamptothecine (HCPT) (300mg), stearic acid (500mg), DCC (350mg), DMAP (250mg) and methylene dichloride (50ml) be added in the reaction flask, stirring at room 15 hours is filtered, filtrate is respectively with 5%K
2CO
3The aqueous solution (70ml), dilute hydrochloric acid (60ml), water (60ml) and saturated aqueous common salt (60ml) are washed.Column chromatography with methylene dichloride/acetone (20/1) wash-out, gets hydroxycamptothecine-10, the two stearate 360mg of 20-, yield 49%, mp140 ℃.
1HNMR(δ，ppm，CDCl
3)：8.34(1H，s)，8.22(1H，d，J＝9.2Hz)，7.69(1H，d，J＝2.47Hz)，7.57(1H，dd，J＝9.2?and?2.47Hz)，7.19(1H，s)，5.68(1H，d，J＝17.17Hz)，5.41(1H，d，J＝17.17Hz)，5.28(2H)，2.64(2H，t，J＝7.41Hz)，2.48(2H，m)，1.96-1.94(2H，m)，1.82-1.65(2H，m)，1.63-1.59(2H，m)，1.29-1.18(56H，m)，0.97(3H，t，J＝7.41Hz)，0.89-0.86(6H，m)；EI-MS(m/e)(M
+)：854，852，346，303，284，98(base?peak)。
Embodiment 5:
(7-ethyl-10-hydroxycamptothecine) (SN-38)-10, the two capronates of 20-and (7-ethyl-10-hydroxycamptothecine) (SN-38)-preparation of 10-capronate
SN-38 (150mg), caproic acid (106mg), DCC (87mg), DMAP (56mg) and methylene dichloride (25ml) are added in the reaction flask, and stirring at room 6 hours is filtered, and filtrate is respectively with 5%K
2CO
3The aqueous solution (30ml), dilute hydrochloric acid (30ml), water (30ml) and saturated aqueous common salt (30ml) washing.Column chromatography, with methylene dichloride/acetone (20/1～5/1) wash-out, what wash-out came out at first is the little product of polarity, i.e. (SN-38)-10, the two capronate 135mg of 20-, yield 72%, mp247-9 ℃.
1HNMR(δ，ppm，CDCl
3)：8.21(1H，d，J＝9.06Hz)，7.82(1H，d，J＝2.35Hz)，7.56(1H，dd，J＝9.06?and2.35Hz)，7.18(1H，s)，5.68(1H，d，J＝17.12Hz)，5.41(1H，d，J＝17.12?Hz)，5.25(1H，s)，5.24(1H，s)，3.15(2H，q)，2.66(2H，t)，2.48-2.46(2H，m)，1.83-1.80(2H，m)，1.66-1.28(15H，m)，0.98-0.94(6H，m)，0.85(3H，t)；EI-MS(m/e)：588(M
+)，472，374(base?peak)，346，331。
Column chromatography with methylene dichloride/acetone (20/1～5/1) wash-out, is got simultaneously than the big compound of above dibasic acid esters polarity, i.e. (SN-38)-10-capronate 15mg, yield 7.4%, mp172-3 ℃.
1HNMR(δ，ppm，DMSO-d
6)：8.20(1H，d，J＝9.16Hz)，7.98(1H，d，J＝2.44Hz)，7.64(1H，dd，J＝9.16?and?2.44Hz)，7.32(1H，s)，6.4(br.)，5.42(2H，s)，5.32(2H，s)，3.19(2H，q)，2.66(2H，t)，1.90-1.82(2H，m)，1.72-1.67(2H，m)，1.40-1.24(m，4H)，0.93-0.83(9H，m)；EI-MS(m/e)：490(M
+)，392(base?peak)，348。
Embodiment 6
(SN-38)-10, the preparation of two stearates of 20-and (SN-38)-10-stearate
With SN-38 (7-ethyl-10-hydroxycamptothecine) (150mg), stearic acid (130mg), DCC (87mg), DMAP (56mg) and methylene dichloride (25ml) be added in the reaction flask, stirring at room 8 hours is filtered, filtrate is respectively with 5%K
2CO
3The aqueous solution (30ml), dilute hydrochloric acid (30ml), water (30ml) and saturated aqueous common salt (30ml) are washed.Column chromatography, with methylene dichloride/acetone (20/1～10/1) wash-out, what wash-out came out at first is the little product of polarity, i.e. hydroxycamptothecine-10, the two stearate 20mg of 20-, yield 5.6%, mp66-7 ℃.
1HNMR(δ，ppm，CDCl
3)：8.23(1H，d，J＝9.23Hz)，7.83(1H，d，J＝2.52Hz)，7.56(1H，dd，J＝9.23?and?2.52Hz)，7.22(1H，s)，5.67(1H，d，J＝17.12Hz)，5.41(1H，d，J＝17.12Hz)，5.26(1H，s)，5.25(1H，s)，3.16(2H，q)，2.66(2H，t)，2.36-2.33(4H，m)，1.83-1.80(2H，m)，1.66-1.61(2H，m)，1.31-1.25(56H，m)，0.97(3H，t)，0.89-0.86(9H，m)；EI-MS(m/e)：658，614，348(base?peak)，333。
Column chromatography with methylene dichloride/acetone (20/1～10/1) wash-out, is got simultaneously than the big compound of above dibasic acid esters polarity, i.e. (SN-38)-10-stearate 150mg, yield 59.6%, mp193-5 ℃.
1HNMR(δ，ppm，DMSO-d
6)：8.21(1H，d，J＝8.85Hz)，7.98(1H，d，J＝2.47Hz)，7.64(1H，dd，J＝8.85?and?2.47Hz)，7.33(1H，s)，5.42(2H，s)，5.33(2H，s)，3.19(2H，q)，2.66(2H，t)，1.88-1.84(2H，m)，1.71-1.69(2H，m)，1.30-1.21(28h，m)，0.89-0.82(9H，m)；EI-MS(m/e)：658(M
+)，640，612，374，284，98(base?peak)。
Embodiment 7
Hydroxycamptothecine-10, the preparation of 20-pair-(3-furancarboxylic acid) ester and hydroxycamptothecine-10-(3-furancarboxylic acid) ester
Hydroxycamptothecine (150mg), 3-furancarboxylic acid (99mg), DCC (90mg), DMAP (57mg) and methylene dichloride (25ml) are added in the reaction flask, and stirred overnight at room temperature is filtered, and filtrate is respectively with 5%K
2CO
3The aqueous solution (30ml), dilute hydrochloric acid (30ml), water (30ml) and saturated aqueous common salt (30ml) are washed.Column chromatography, with methylene dichloride/acetone (15/1～4/1) wash-out, what wash-out came out at first is the little product of polarity, i.e. hydroxycamptothecine-10, two (3-furancarboxylic acid) the ester 50mg of 20-, yield 22%, mp135 ℃ (dec.).
1HNMR(δ，ppm，CDCl
3)：8.36(1H，s)，8.26(1H，d，J＝0.67Hz)，8.22(1H，d，J＝9.23Hz)，8.18(1H，s)，7.79(1H，d，J＝2.52Hz)，7.65(1H，dd，J＝9.23?and2.52Hz)，7.55(1H，t)，7.47(1H，t)，7.25(1H，s)，6.91(1H，t)，6.77(1H，t)，5.74(1H，d，J＝17.12Hz)，5.45(1H，d，J＝17.12Hz)，5.30(1H，s)，5.29(1H，s)，2.39(1H，m)，2.25(1H，m)，1.05(3H，t)；EI-MS(m/e)(M
+)：552，440，412，397，95(base?peak)。
Column chromatography with methylene dichloride/acetone (20/1 ~ 4/1) wash-out, is got simultaneously than the big compound of above dibasic acid esters polarity, i.e. the preparation 60mg of hydroxycamptothecine-10-(3-furancarboxylic acid) ester, yield 31.8%, mp210-3 ℃.
1HNMR(δ，ppm，DMSO-d
6)：8.72(1H，s)，8.69(1H，s)，8.24(1H，d，J＝9.15Hz)，8.05(1H，d，J＝2.45Hz)，7.94(1H，d，J＝1.53Hz)，7.79(1H，dd，J＝9.15and?2.45Hz)，7.36(1H，s)，7.00(1H，s)，5.42(2H，s)，5.31(2H，s)，1.87(2H，q)，0.86(3H，t)；EI-MS(m/e)：458(M
+)，414，95(base?peak)。
Embodiment 8:
Hydroxycamptothecine-10, the preparation of 20-pair-(3-tolyl acid) ester and hydroxycamptothecine-10-(3-tolyl acid) ester
Hydroxycamptothecine (150mg), 3-tolyl acid (130mg), DCC (100mg), DMAP (70mg) and methylene dichloride (25ml) are added in the reaction flask, and stirring at room 48 hours is filtered, and filtrate is respectively with 5%K
2CO
3The aqueous solution (30ml), dilute hydrochloric acid (30ml), water (30ml) and saturated aqueous common salt (30ml) are washed.Column chromatography, with methylene dichloride/acetone (20/1～5/1) wash-out, what wash-out came out at first is the little product of polarity, i.e. hydroxycamptothecine-10,20-is two-(3-tolyl acid) ester 35mg, yield 14%, mp128 ℃ (dec.).
1HNMR(δ，ppm，CDCl
3)：8.36(1H，s)，8.20(1H，d，J＝9.23Hz)，8.04-8.03(2H，m)，7.93-7.88(4H，m)，7.79(1H，d，J＝2.35Hz)，7.66(1H，dd，J＝9.23?and?2.35Hz)，7.49(1H，d，J＝7.89Hz)，7.44(1H，t)，7.37(1H，d，J＝8.06Hz)，5.77(1H，d，J＝17.12Hz)，5.48(1H，d，J＝17.12Hz)，5.30(2H，s)，2.47(2H，t)，2.42(3H，t)，2.40(3H，t)，1.09(3H，t)；EI-MS(m/e)：365，304，284，237，136(base?peak)，91。
Column chromatography with methylene dichloride/acetone (20/1 ~ 5/1) wash-out, is got simultaneously than the big compound of above dibasic acid esters polarity, i.e. hydroxycamptothecine-10-(3-tolyl acid) ester 60mg, yield 30.2%, mp200-3 ℃ (dec.).
1HNMR(δ，ppm，DMSO-d
6)：8.70(1H，s)，8.26(d，1H，J＝9.0Hz)，8.08(d，1H，J＝2.44Hz)，8.00(1H，t)，7.83(1H，dd，J＝9.0?and?2.44Hz)，7.61(1H，t)，7.53(1H，t)，7.36(1H，s)，6.48(1H，s)，5.42(2H，s)，5.31(2H，s)，5.31(2H，s)，2.44(3H，s)，1.87(2H，m)，0.89(3H，t)；EI-MS(m/e)：482(M
+)，438，119(base?peak)，91。
The screening of embodiment 9 anti tumor activity in vitro
Adopt tetrazole (MTT) reduction method to carry out the experiment of cell in vitro poison.The result shows, the basic nontoxicity of dibasic acid esters is compared and the toxicity of 10 monoesters is lower than parent compound, and toxicity reduces greatly, meets principle of pro-drug.Following table provides the cytotoxic activity data of monoesters.
| Concentration (M) | Estimate | |||||
| ????10 -4 | ????10 -5 | ????10 -6 | ????10 -7 | ????10 -8 | ||
| Hydroxycamptothecine-10-capronate | ????100 | ????99.7 | ????95.3 | ????81.6 | ????62.4 | The weak effect |
| (SN-38)-the 10-capronate | ????100 | ????99.5 | ????96.3 | ????83.5 | ????75.6 | The weak effect |
| Hydroxycamptothecine-10-(3-furancarboxylic acid) ester | ????100 | ????99.7 | ????92.5 | ????72.1 | ????52.5 | The weak effect |
| Hydroxycamptothecine-10-(3-tolyl acid) ester | ????100 | ????99.1 | ????95.4 | ????73.9 | ????36.8 | The weak effect |
| SN-38 | ????100 | ????97.7 | ????96.6 | ????94.6 | ????92.8 | Potent |
| Hydroxycamptothecine | ????100 | ????99.7 | ????95.1 | ????80.8 | ????71.4 | Potent |
Embodiment 10
External investigation the stability of prepared prodrug in mice plasma and pH7.4 phosphoric acid buffer
Storing solution: 300 μ g/ml acetonitrile solutions
Method: the phosphoric acid buffer of mice plasma and pH4 is added to respectively in the 2ml Appendorf plastics tubing for 1.6 milliliters, put into 37 ℃ of waters bath with thermostatic control and be incubated half an hour, add storing solution 0.4ml, behind the vortex 30s, with 1ml disposable syringe sampling 0.1ml, these two kinds of solution continue to be incubated in 37 ℃ of waters bath with thermostatic control.In getting 0.1ml sample, add 0.4ml freezing (30 ℃) acetonitrile, vortex 30s, centrifugal 5min (10000 change/min), get supernatant liquor carry out HPLC analyze the integral area during t=0.After this at 0.5h, 1.5h, 2.5h, 4h, 6h takes a sample respectively, and aftertreatment is with aforementioned method.
The calculating of percentage composition
Chromatographic condition:
Instrument: Hewlett HP1100
Chromatographic column: RP-C18,4.6*250mm
Flow velocity: 1.0ml/min
Sample size: 10 μ l
Investigate sample: hydroxycamptothecine 10, the two decylates (HCPTDC10) of 20-
Moving phase: methyl alcohol (100), t
R=6.3-6.4min detects wavelength 254nm
| ????t＝0 | ????t＝0.5 | ????t＝1.5 | ????t＝2.5 | ????t＝4 | ????t＝6 | |||||||
| Area | ??％ | Area | ??％ | Area | ??％ | Area | ??％ | Area | ??％ | Area | ??％ | |
| Mice plasma | ??78.8 | ??100 | ??48.5 | ??61.5 | ??46.4 | ??58.8 | ??42.7 | ??54.2 | ??39.2 | ??49.7 | ??23.5 | ??29.8 |
| The PH7.4 phosphoric acid buffer | ??233.6 | ??100 | ??211.4 | ??90.4 | ??198.1 | ??84.8 | ??189.0 | ??80.9 | ??155.3 | ??66.5 | ??108.5 | ??46.4 |
Above-mentioned experimental data shows: hydroxycamptothecine 10, and the two decylates of 20-can both be hydrolyzed in this two media and discharge active pharmaceutical ingredient, and its hydrolysis rate in mice plasma is bigger than damping fluid.
The preparation of embodiment 11 liposome medicine-carried nano particles
Hard ester acid (12g) after heating fusion in 80 ℃ of water-baths, is added hydroxycamptothecine-10, the two hard ester acid (2g) of 20-, Yelkin TTS (10g) and ethanol (10g), the slight stirring forms clear microemulsion.Then micro emulsion is distributed to (200ml) in the distilled water that contains sodium lauryl sulphate, cooling makes the lipid sclerosis rapidly again, just obtains the solid liposome medicine-carried nano particles.Then the medicine grinding and processing is become nano suspension, be suitable for comprising administrations such as oral, injection.
Claims (9)
1, hydroxycamptothecinederivatives derivatives general formula (I) and general formula (II) compound
Wherein R represents C
1～30The aromatic ring of alkyl, aromatic ring, fragrant heterocycle, aralkyl, replacement, the fragrant heterocycle of replacement, the aralkyl of replacement; R
1Expression C
1～10Alkyl.
2. hydroxycamptothecinederivatives derivatives general formula according to claim 1 (I) and general formula (II) compound is characterized in that: work as R
1During=H, R=CH
3(CH
2)
8, CH
3(CH
2)
10, CH
3(CH
2)
14, CH
3(CH
2)
16And CH
3(CH
2)
18
3. hydroxycamptothecinederivatives derivatives general formula (I) compound according to claim 1 and general formula (II) compound is characterized in that: the aryl in the aralkyl of the aromatic ring of the aromatic ring of R representative, fragrant heterocycle, aralkyl, replacement, the fragrant heterocycle of replacement, replacement can be one or more F, Cl, Br, I, C
1～10Alkyl, C
1～10Alkoxyl group or the nitro benzene, biphenyl or the naphthalene that replace; Alkyl in the aralkyl of R representative can be C
1～10Alkyl.
4. hydroxycamptothecinederivatives derivatives general formula (I) compound according to claim 1 and general formula (II) compound is characterized in that: the heterocycle in the fragrant heterocycle of R representative, the fragrant heterocycle of replacement is five yuan, the hexa-atomic or seven membered heterocyclic that contains one or more O, N, S atom.
5. the preparation method of hydroxycamptothecinederivatives derivatives general formula (I) compound as claimed in claim 1 and general formula (II) compound, this method may further comprise the steps:
A. hydroxycamptothecine and derivative thereof and carboxylic acid are under DCC and DMAP catalysis, and 0-60 ℃ was stirred 1～50 hour, got reactant;
B. reactant is that elutriant carries out gradient elution through silica gel column chromatography with methylene dichloride and acetone mixed solvent, separates to obtain general formula (I) compound and general formula (II) compound.
6. the preparation method of hydroxycamptothecinederivatives derivatives general formula (I) compound according to claim 5 and general formula (II) compound is characterized in that optimal reaction temperature is 10-30 ℃.
7. the preparation method of hydroxycamptothecinederivatives derivatives general formula (I) compound according to claim 5 and general formula (II) compound, it is characterized in that it is methylene dichloride and acetone solvent that Xian takes off liquid, its gradient is methylene dichloride/acetone: 30/1～1/1 (v/v), increase the amount of acetone gradually, wherein at first wash-out come out for the less dibasic acid esters of polarity.
8. according to any one compound in described hydroxycamptothecinederivatives derivatives general formula (I) compound of claim 1～4 and general formula (II) the chemical combination items, it is characterized in that, adopt heat commonly used to melt dispersion method, the medicine, phosphatide and the emulsification at high temperature of stearic oily mixture that are about to recipe quantity are distributed in the water that contains tensio-active agent, cooling makes the lipid sclerosis rapidly again, just obtains the solid liposome medicine-carried nano particles.
9. the purposes of hydroxycamptothecinederivatives derivatives general formula (I) compound as claimed in claim 1 and general formula (II) compound is used in the preparation antitumor drug.
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|---|---|---|---|
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|---|---|---|---|
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ID=35046028
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| CN105315294A (en) * | 2014-06-26 | 2016-02-10 | 王杭祥 | 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and application thereof |
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| CN105777770A (en) * | 2014-12-26 | 2016-07-20 | 中国人民解放军第二军医大学 | Saturated long-chain fatty acid-modified 7-ethyl-10-hydroxycamptothecin compound and long-circulating liposome thereof |
| CN106588946A (en) * | 2017-01-25 | 2017-04-26 | 郑州大学 | 10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof |
| CN108484624A (en) * | 2018-05-21 | 2018-09-04 | 扬子江药业集团有限公司 | A kind of irinotecan hydrochloride impurity and its synthetic method and application |
| CN110357897A (en) * | 2019-07-26 | 2019-10-22 | 上海健康医学院 | A kind of camptothecin derivative with anti-tumor activity and its preparation method and application |
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2004
- 2004-03-23 CN CN 200410017128 patent/CN1673226A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315294A (en) * | 2014-06-26 | 2016-02-10 | 王杭祥 | 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and application thereof |
| CN105777770A (en) * | 2014-12-26 | 2016-07-20 | 中国人民解放军第二军医大学 | Saturated long-chain fatty acid-modified 7-ethyl-10-hydroxycamptothecin compound and long-circulating liposome thereof |
| CN105777770B (en) * | 2014-12-26 | 2018-05-25 | 中国人民解放军第二军医大学 | A kind of the 7-Ethyl-10-hydroxycamptothecin compound and its long circulating liposome of saturated long chain fatty acid modification |
| CN105561331A (en) * | 2016-01-26 | 2016-05-11 | 北京大学 | Anti-tumor medicine coupler decorated with saturated fatty acid and self-assembling nanometer system and preparation method of anti-tumor medicine coupler |
| CN106588946A (en) * | 2017-01-25 | 2017-04-26 | 郑州大学 | 10-HCPT (10-hydroxycamptothecine) derivative, synthesis method and application thereof |
| CN108484624A (en) * | 2018-05-21 | 2018-09-04 | 扬子江药业集团有限公司 | A kind of irinotecan hydrochloride impurity and its synthetic method and application |
| CN110357897A (en) * | 2019-07-26 | 2019-10-22 | 上海健康医学院 | A kind of camptothecin derivative with anti-tumor activity and its preparation method and application |
| CN115073483A (en) * | 2022-07-27 | 2022-09-20 | 泽升科技(广州)有限公司 | Preparation method of enantiomer of irinotecan |
| CN115073483B (en) * | 2022-07-27 | 2022-10-25 | 泽升科技(广州)有限公司 | Preparation method of enantiomer of irinotecan |
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