CN103848856B - There is the camptothecin derivative of anti-tumor activity - Google Patents
There is the camptothecin derivative of anti-tumor activity Download PDFInfo
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Abstract
The invention discloses the camptothecin derivative with anti-tumor activity, it is for having the compound of structure, enantiomer or its pharmaceutical salts shown in formula (I) or formula (II).The camptothecin analogues of the present invention has useful pharmaceutical properties, and it is inhibited to topoisomerase I and/or II and has anti-tumor activity.Experiment confirms that the compound of the present invention has antiviral activity, thus the compound of the present invention can be used in different treatment use, in terms of this compound, its enantiomer or its pharmaceutical salts are applied to prepare antitumor drug.
Description
Technical field
The invention belongs to drug world, be specifically related to a kind of there is anti-tumor activity camptothecin derivative, it is as the purposes of antitumor drug and the pharmaceutical composition that comprises them.
Background technology
Camptothecine (Campaotothecin, CPT, J.Am.Chem.Soc., 1966,88:3888) is the alkaloid at a kind of five rings extracted from Nyssaceae plant camptotheca acuminata (Camptothecaacuminata).Being a kind of pyrroles [3,4-b] quinoline alkaloid, its structural formula is:Containing five rings in its structure, 20 of E ring have a S type chiral centre, and there is a lactone structure on side.Camptothecine has broad-spectrum anti-tumor activity, particularly colon tumor resistant and other entity tumors and leukemic activity, but is not used in treatment owing to it shows as the high toxicity of hemorrhagic cystitis, gastrointestinal toxicity and bone marrow depression especially.
So far, existing a series of semi-synthetic and complete synthesis camptothecin derivative enters clinical practice or clinical trial.Main approach is by transforming the chemical constitution of parent nucleus, seeking character more preferable CPT derivant.At present, there are both at home and abroad four CPT derivants: irinotecan (ifinoteean, CPT-11), topotecan (topotecan.TPT), hydroxy camptothecin (hydroxycamptothecin, and Belotecan (Belotecan) HCPT), and at home and abroad list, it is respectively used to the treatment of colon cancer, ovarian cancer and small cell lung cancer etc. clinically.Other derivants specifically include that Rubitecan, Exatecan, Karenitecan, Diflomotecan, Gimatecan, Elomotecan, Siletecan and other derivant, carrying out clinical phase test, a series of derivant such as Chimmitecan, DTS-108 is in the preclinical study stage.
SN-38 (SN38) is that CPT-11 enters internal active metabolite, its external activity inhibition to tumor cell or topoisomerase I is significantly larger than CPT-11, the poorly water-soluble of SN38, its prodrug CPT-11 has good water solublity, to colon cancer, breast carcinoma, gastric cancer, cancer of pancreas, NSCLC, ovarian cancer and leukemia are evident in efficacy, clinic is mainly used in Advanced Colon Cancer, NSCLC, the treatment of ovarian cancer, but it has very important toxic and side effects, show as serious bone marrow depression (more than III degree), delayed is suffered from diarrhoea, severe diarrhea, acute cholinergic syndrome, severe nausea, the untoward reaction such as vomiting.
Topotecan (TPT) is semi-synthetic derivant, soluble derivative, leukemia, melanoma, NSCLC, ovarian cancer, colon cancer etc. had good anti-tumor activity, domestic clinic is mainly used in treatment advanced metastatic ovarian cancer warp chemotherapy loser and small cell lung cancer, its untoward reaction mainly shows as Nausea and vomiting, alopecia, diarrhoea, anaphylaxis etc., and serious shows as ablative suppression.
Belotecan is water soluble camptothecin derivatives, it is the research of Zhong Gentang drugmaker of Korea S, in Korea S's approval for ovarian cancer and the treatment of small cell lung cancer, same untoward reaction shows as Nausea and vomiting, alopecia, diarrhoea, anaphylaxis etc., and serious shows as ablative suppression.
Hydroxy camptothecin is to extract a class tryptophan-terpenes alkaloid anticarcinogen obtained in China the skin of distinctive Nyssaceae Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) plant camptotheca acuminata, fruit, belong to broad-spectrum anti-cancer drug, clinic is mainly used in gastric cancer, hepatocarcinoma, incidence cancer and leukemia treating, its untoward reaction mainly shows as serious bone marrow depression, leukocyte, platelet decline, with symptoms such as diarrhoea, pernicious, vomiting, serious alopecias.
9-NC (Rubitecan) is 9 substituted camptothecin derivatives, the oral treatment for cancer of pancreas, ovarian cancer and breast carcinoma has good activity, after converting in vivo because of it, lactone content is the lowest causes toxicity relatively big, terminates at the clinical III phase.
Diflomotecan be a class E ring ring expansion be the camptothecin derivative of beta-hydroxy lactone, improve the stability of lactonic ring, activity and toxicity are obtained for corresponding improvement.Being 10,11-difluoro derivatives, complete synthesis exploitation, phase II clinical trials result shows that its activity is superior to irinotecan and topotecan.
Camptothecin derivative belongs to topoisomerase enzyme inhibitor, it optionally suppresses the activity of topoisomerase I (TopoI), reduce the DNA replication dna in tumor cell, recombinate, transcribe, the distorting stress of supercoiled DNA in repair process, reach antitumor action.Mainly act on S phase cell, G0 phase cell is not acted on, G1, G2 and M phase cell is had slight lethality.It can combine with TopoI-DNA cleavable complex reversibility, forms stable CPT-TopoI-DNA ternary coalition, thus stabilizes cleavable complex.Coalition and replicative enzyme effect, produce the damage of double-strand DN, causes replication fork and coalition " to be rebuffed ", forms the breach of unrepairable so that DNA synthesis is suppressed, thus the apoptosis of inducing cell.
Since camptothecin analogues finds, people are devoted to seek efficient, the camptothecin derivative medication oncotherapy of low toxicity always.
The toxicity of camptothecin derivative is essentially from its open loop carboxylate form, environment in vivo, human albumin (HSA) can preferentially be combined with the open loop form of camptothecin derivative, its binding ability is more than 100 times of HAS and lactonic ring binding ability, hydrolysising balance being moved to open loop form direction, thus causes the concentration of camptothecin derivative lactone ring form (activity form) to reduce, anti-tumor activity declines, open loop carboxylate form concentration raises, and toxicity increases.
Open loop camptothecin derivative demonstrates the distribution in high protein binding (particularly with albumin) and low tumor tissues.As a result, product is accumulated in the body, and the effect to tumor is the best.On the contrary, the highly lipophilic of lactone form promotes the absorption of camptothecin derivative and cell membrane, particularly erythrocyte, have impact on tissue/blood plasma distribution ratio.Therefore, at present research concentrates on two kinds of selectable methods: 1) the low protein binding product of the dissolubility that design has still had；2) design has the product of good antitumor curative effect and safety under low dosage.
Summary of the invention
It is an object of the invention to a kind of novel camptothecin derivatives with antineoplastic pharmacologically active.
It is a further object of the present invention to provide a kind of pharmaceutical composition containing above-mentioned camptothecin derivative.
The third object of the present invention is to provide the purposes of a kind of above-mentioned camptothecin derivative.
The purpose of the present invention can be reached by following measures:
The analog of Cmptothecine, it is for having the compound of structure, enantiomer or its pharmaceutical salts shown in formula (I) or formula (II):
R1Represent low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, low-grade halogenated alkyl, lower alkoxy loweralkyl or lower alkylthio low alkyl group；
R3Represent boronate or boric acid ester group；
R2、R4Represent hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, low-grade alkenyl, cyano group, lower cyanoalkyl, nitro, rudimentary 4-nitro alkyl, acylamino-, rudimentary amidoalkyl, diazanyl, rudimentary diazanyl alkyl, azido, rudimentary azido alkyl, (CH independently2)mNR6R7、(CH2)mOR6、(CH2)mSR6、(CH2)mCO2R6、(CH2)mNR6C(O)R8、(CH2)mC(O)R8、(CH2)mOC(O)R8、O(CH2)mNR6R7、OC(O)NR6R7、OC(O)(CH2)mCO2R6Or (CH2)n[N=Y]、OC(O)[N=Y]、(CH2)mOC(O)[N=Y]；
R5Represent hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, low-grade alkenyl, cyano group, lower cyanoalkyl, nitro, rudimentary 4-nitro alkyl, acylamino-, rudimentary amidoalkyl, diazanyl, rudimentary diazanyl alkyl, azido, rudimentary azido alkyl, (CH2)mNR6R7、(CH2)mOR6、(CH2)mSR6、(CH2)mCO2R6、(CH2)mNR6C(O)R8、(CH2)mC(O)R8、(CH2)mOC(O)R8、(CH2)mSiR6R9R10、(CH2)mOC(O)NR6R7、(CH2)mS(O)qR11、 (CH2)mP(O)R12R13、(CH2)2P(S)R12R13Or (CH2)n[N=Y]、(CH2)mOC(O)[N=Y]；
R6Or R7Represent hydrogen independently, halogen, low-grade halogenated alkyl, low alkyl group, lower alkoxy, low-grade alkenyl, cyano group, lower cyanoalkyl, nitro, rudimentary 4-nitro alkyl, acylamino-, rudimentary amidoalkyl, diazanyl, rudimentary diazanyl alkyl, azido, rudimentary azido alkyl, lower aryl alkyl, aryl or the aryl replaced by following one or more groups: low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl；
R8Represent hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, low-grade alkenyl, cyano group, lower cyanoalkyl, nitro, rudimentary 4-nitro alkyl, acylamino-, rudimentary amidoalkyl, diazanyl, rudimentary diazanyl alkyl, azido, rudimentary azido alkyl, lower aryl alkyl, aryl or the aryl replaced by following one or more groups: low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl；
R9Expression hydrogen, low alkyl group, lower alkoxy, low-grade halogenated alkyl, aryl or the aryl replaced by following one or more groups: low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl；
R10Expression hydrogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy, aryl or the aryl replaced by following one or more groups: low alkyl group, low-grade halogenated alkyl, Lower hydroxy alkyl or lower alkoxy loweralkyl；
R11Represent low alkyl group, aryl, (CH2)mOR14、(CH2)mSR14、(CH2)2NR14R15Or (CH2)m[N=Y]；
R12And R13Represent low alkyl group, aryl, lower alkoxy, aryloxy group or amino independently；
R14And R15Represent hydrogen, low alkyl group or amino independently；
R16Represent hydrogen or OR21；
R17Represent OR7Or NR6R7；
X indicate without or a carbon atom；
R18And R19Represent hydrogen, halogen, low alkyl group, lower alkoxy or hydroxyl independently；
R20Represent hydrogen or halogen；
R21Represent hydrogen, low alkyl group, CHO or C (O) (CH2)mCH3；
Rp represents hydrogen, (CH2)mSiR6R9R10Or-C (O)-W-NR22R23Group, wherein W straight or branched alkylidene, W is optionally by halogen, free or esterification or etherificate or become the hydroxyl of salt, free or esterification or one or more replacing of becoming in the carboxyl of salt, amino, low-grade alkyl amino；R22And R23Represent independently hydrogen, low alkyl group, Lower hydroxy alkyl, low alkyl group lower aminoalkyl, lower aminoalkyl, cycloalkyl, cycloalkyl low-grade alkyl, low-grade alkenyl, lower alkoxy loweralkyl, low-grade halogenated alkyl, lower aryl alkyl, aryl or by following one or more groups replace aryl: low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, low alkyl group or lower alkoxy loweralkyl；Or R22And R23Formed together containing one or more heteroatomic 5,6 or 7 rings in O, N, S；
M is the integer between 0 to 6；
N is 1 or 2；Q represents the integer of 0 to 2；
[N=Y] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom N.
In the preferred technical scheme of one, the analog of this camptothecine is for having the compound of structure, enantiomer or its pharmaceutical salts shown in formula (III) or formula (IV):
In the preferred technical scheme of one, the R in the present invention1Represent low alkyl group；Further, R1Represent C1-4Alkyl, most preferable, ethyl, n-pro-pyl, isopropyl.
In the preferred technical scheme of one, the R in the present invention2、R4Represent hydrogen, halogen or low alkyl group independently；Further, R2、R4Represent hydrogen independently.
In the preferred technical scheme of one, the R in the present invention3Represent boronate.
In the preferred technical scheme of one, the R in the present invention5Represent hydrogen, halogen, low alkyl group, (CH2)mNR6R7Or (CH2)mSiR6R9R10；Further, R5Represent C1-4Alkyl, (CH2)mNR6R7Or (CH2)mSiR6R9R10。
In the preferred technical scheme of one, the R in the present invention6Or R7Represent hydrogen, halogen, low alkyl group or lower alkoxy independently；Further, R6Represent C1-4Alkyl or C1-4Alkoxyl；R7Represent hydrogen.
In the preferred technical scheme of one, the R in the present invention9Or R10Represent hydrogen, low alkyl group or lower alkoxy independently；Further, R9Or R10Represent C1-4Alkyl or C1-4Alkoxyl.
In the preferred technical scheme of one, the m in the present invention is the integer between 1 to 4；Further, m is the integer between 1 to 2.
In the preferred technical scheme of one, the R in the present invention16Represent hydrogen or OR21；Further, R16Represent hydrogen, OH or C1-4Alkoxyl.
In the preferred technical scheme of one, the R in the present invention17Represent OR7Or NR6R7。
In the preferred technical scheme of one, the R in the present invention20Represent hydrogen or halogen.
In the preferred technical scheme of one, the R in the present invention21Represent hydrogen, low alkyl group, CHO or C (O) (CH2)mCH3。
In the preferred technical scheme of one, the Rp in the present invention represents hydrogen or (CH2)mSiR6R9R10。
The analog of the camptothecine of the present invention, is selected from following compound, its enantiomer or its pharmaceutical salts:
7-ethyl-10-boronate camptothecine；
7-tert-butoxy formamino-10-boronate camptothecine；
7-(2 '-trimethyl is silica-based) ethyl-10-boronate camptothecine.
In the present invention, [N=Y] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom N, and N is an atom of heterocyclic group, and Y represents other atom constituting these heterocycle needs, and they are selected from O, S, CH2、CH、N、NR9And COR10, unsubstituted or be replaced aryl or the lower aryl alkyl of (i.e. at aryl or miscellaneous substitution in ring one to four time), wherein substituent group is low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl.R9Expression hydrogen, low alkyl group, low-grade halogenated alkyl, aryl or the aryl replaced by following one or more groups: low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl；R10Representing hydrogen, low alkyl group, low-grade halogenated alkyl, lower alkoxy, aryl or the aryl (i.e. having one to four substituent groups on aryl) replaced by one or more groups, substituent group is selected from low alkyl group, low-grade halogenated alkyl, Lower hydroxy alkyl or lower alkoxy loweralkyl.
In this article, " boronate " refers to-B (OH)2。
" boric acid ester group " refers to that one or two hydrogen in boronate is replaced by any group.
" acylamino-" refers to-NR1C (=O) R2 group, and wherein R1, R2 can be the group such as hydrogen or alkyl, heterocyclic radical, aryl, aryl alkyl independently.
The term " rudimentary " relevant with alkyl, alkylthio group and alkoxyl refers to the straight or branched saturated fat hydroxyl groups containing one to six carbon atom, such as, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, methyl mercapto, ethylmercapto group, methoxyl group and ethyoxyl.
The term " rudimentary " relevant with alkenyl or alkynyl group refers to containing 2 to 6 carbon atoms or the group of one or more double or triple bonds, such as, vinyl, pi-allyl, isopropenyl, pentenyl, hexenyl, acrylic, acetenyl, propinyl and butynyl.
" cycloalkyl " refers to the ring containing 3 to 7 carbon, such as, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
" aryl " refers to mono-, di-or tricyctic hydrocarbon compound, and wherein minimum of one ring is aromatic hydrocarbon ring, and each ring contains most 7 carbon atoms, such as, phenyl, naphthyl, anthryl, xenyl or indenyl.
" aryl alkyl " refers to formula-R3R4Group, wherein R3It is alkyl and R4It is one or more aromatic yl group defined above, such as benzyl, diphenyl methyl etc..The aryl moiety of aromatic yl alkyl group at random can be replaced as define above-mentioned aryl.The moieties of aromatic yl alkyl group can at random be replaced.
" heterocyclic radical " refers to by carbon atom and the non-aromatic ring radical of one to five stable three to ten eight Yuans formed selected from the hetero atom of nitrogen, oxygen and sulfur.For the application, heterocyclic radical can be monocycle, dicyclo or three-ring system, and it can comprise that condense or bridging member ring systems, and nitrogen, carbon or the sulphur atom in heterocyclyl groups can at random be aoxidized；Nitrogen-atoms can be by the most quaternized；And heterocyclyl groups can be the most saturated.
" diazanyl " refers to-NR5NR6R7, wherein R5、R6、R7Can be the group such as hydrogen or alkyl, heterocyclic radical, aryl, aryl alkyl independently.
" azido " ester-N3。
Term halogen refers to chlorine, bromine, iodine or fluorine.The group of corresponding term low-grade halogenated alkyl, lower cyanoalkyl, rudimentary 4-nitro alkyl, rudimentary amido alkyl, rudimentary diazanyl alkyl, rudimentary azido alkyl, lower aryl alkyl, Lower hydroxy alkyl, lower alkoxy loweralkyl, lower alkylthio low alkyl group and the rudimentary Sulfonylalkyl of low alkyl group is replaced by one to three halogen, cyano group, nitro, amide groups, diazanyl, azido, aryl, hydroxyl, low alkyl group, lower alkylthio or rudimentary Sulfonylalkyl respectively.Low-grade alkyl amino can contain one or two low alkyl group, such as, represent NHCH3、NHCH2CH3、N(CH3)2Or N (CH2)(CH3)。
Free or esterification or etherificate or one-tenth salt the hydroxyl of term refers to OH, OCOR6、OR7Group and its alkoxide.
Free or esterification or one-tenth salt the carboxyl of term refers to COOH, COOR5、COOR6With its any form of salt.
The compound of the present invention has two kinds of possible enantiomers, i.e. R and S configuration.The present invention includes two kinds of enantiomeric forms and their mixture, including R, S racemic mixture.For simplicity, when not pointing out the particular configuration in structural formula, it is thus understood that represent two enantiomers and mixture thereof.
The invention discloses a kind of pharmaceutical composition, it includes arbitrary described compound, its enantiomer or its pharmaceutical salts in the present invention of pharmaceutically acceptable carrier and therapeutically effective amount.
The camptothecin analogues of the present invention has useful pharmaceutical properties, and it is inhibited to topoisomerase I and/or II and has anti-tumor activity.Experiment confirms that the compound of the present invention has antiviral activity, thus the compound of the present invention can be used in different treatment use, in terms of this compound, its enantiomer or its pharmaceutical salts are applied to prepare antitumor drug.The present invention provides a kind of and has had the pharmacologically active of camptothecins anti-tumor, can solve the novel camptothecin derivatives of the series of problems such as camptothecine dissolubility, stability, toxic and side effects be the best.
Detailed description of the invention
The preparation of embodiment 17-ethyl-10-boronate camptothecine (HD-302)
The synthesis of 1a, 7-ethyl-10-trimethyl fluoride sulfonyl epoxide camptothecine
By SN-38(0.1g, 0.255mmol) it is suspended under nitrogen protection in anhydrous DMF (2.5ml), the suspension obtained adds triethylamine (52mg, 0.51mmol).Under stirring, then it is added thereto to double (fluoroform sulphonyl) imines (137mg, 0.383mmol) of N-phenyl, room temperature reaction 16 hours (TLC controls main material reaction completely).Adding dichloromethane (5ml), water (2 × 10ml), agitator treating after reaction completely, collect organic facies, anhydrous sodium sulfate is dried, and filters and be concentrated in vacuo and to obtain off-white color solid (134mg, 0.255mmol).
The synthesis of 1b, 7-ethyl-10-trimethyl fluoride sulfonyl Oxy-1 silica-based camptothecine of 6-O-triethyl group
Under nitrogen protection by 7-ethyl-10-trimethyl fluoride sulfonyl epoxide camptothecine (0.15g; 0.286mmol) add N; in dinethylformamide (7.5ml); under stirring; then imidazoles (0.243g, 3mmol), DMAP (0.035g, 0.28mmol), chlorotriethyl silane (0.431g are added to it; 2.8mmol), room temperature reaction overnight (TLC controls main material reaction completely).Having reacted addition 45ml water, 20ml dichloromethane stirs washes layering, collects organic facies.Organic facies is washed with ammonium chloride saturated solution 20ml, saturated brine 10ml respectively, and anhydrous sodium sulfate is dried, filtering and concentrating, and petroleum ether obtains 340mg solid.
The synthesis of 1c, 7-ethyl-10-pinacol monoborane base silica-based camptothecine of-16-O-triethyl group
By 7-ethyl-10-trimethyl fluoride sulfonyl Oxy-1 6-O-triethyl group silica-based camptothecine (0.5g; 0.78mmol), the protection of dioxane (15ml) nitrogen is lower adds in the single port bottle that 50ml is dried; stirring; add 1 respectively; the double Diphenyl phosphino ferrocene palladium chloride (0.057g of 1'-; 0.78mmol), connection boric acid pinacol ester (0.298g, 1.2mmol), potassium acetate (0.2307g, 2.3mmol).It is stirred at room temperature 10 minutes, then is warming up to 100 DEG C of reactions 7 hours (TLC detection reaction is completely).Adding 100ml ethyl acetate, 100ml water, agitator treating after having reacted, add a small amount of suction filtered through kieselguhr, organic facies is collected in layering.Organic facies is washed with 100ml saturated brine again, and layering, organic facies is dried and is concentrated to give dark brown solid 0.4g.
The synthesis of 1d, 7-ethyl-10-boronate camptothecine (HD-302)
7-ethyl-10-pinacol monoborane silica-based the camptothecine of base-16-O-triethyl group (0.4g, 0.65mmol) is joined in potassium bifluoride aqueous solution (20ml, 90mmol), methanol (140ml), three day (TLC detection reaction completely) is stirred at room temperature.Concentrating under reduced pressure methanol, concentrated solution adds 200ml acetone, sucking filtration, filter cake acetone drip washing, collects filtrate and is concentrated to give yellow solid.Adding water 50ml, acetonitrile 100ml, Lithium hydrate adjusts pH to 10, and reaction 2.5 hour (TLC detection reaction completely) is stirred at room temperature.Adding ammonium chloride saturated solution 100ml, dropping 1M hydrochloric acid adjusts pH to 3, and ethyl acetate 150ml extracts, and is dried and is concentrated to give yellow solid 240mg.
1HNMR (400MHz, CD3OD):δ0.92(t,J=9Hz,3H);1.32(t,J=9Hz,3H);1.83-1.91(m,2H);3.17(q,J=8Hz,2H);5.13(s,2H);5.28(d,J=20Hz,1H);5.48(d,J=20Hz,1H);7.54(s,1H);7.92-8.04(m,2H);8.51(s,1H).
Embodiment 2
The synthesis of 2a, 7-tert-butoxy formamino-10-hydroxycamptothecine
10-hydroxyl-7-formoxyl camptothecine (50mg) is added in ethanol (10ml), pyridine (1.5ml); O-t-butylhydroxylamine hydrochlorate (55mg) is added under stirring; back flow reaction 5h, concentrating under reduced pressure, cross post (dichloromethane: methanol) and purify to obtain 30mg yellow solid.
1HNMR (400MHz, CD3OD):δ0.88(t,H3-18E+H3-18Z,J=7.35Hz),1.35(s,t-BuZ),1.45(s,t-BuE),1.80-1.90(m,H2-19E+H2-19Z),5.10-5.40(m,H2-5E+H2-5Z+H2-17E+H2-17Z),6.53(s,OH),7.25-7.50(m,H-14E+H-14Z+H-11E+H-11Z+H-9Z),7.70(d,.H-9E,J=2.57Hz)8.05(d,H-12E+H-12Z,J=9.19Hz),8.25(s,CH=NZ),9.0(s,CH=NE)10.35(s,10-OH)。
The synthesis of 2b, 7-tert-butoxy formamino-10-trimethyl fluoride sulfonyl epoxide camptothecine
Being suspended under nitrogen protection in anhydrous DMF (2.5ml) by 7-tert-butoxy formamino-10-hydroxycamptothecine (140mg), the suspension obtained adds triethylamine (52mg, 0.51mmol).Under stirring, then it is added thereto to double (fluoroform sulphonyl) imines (137mg, 0.383mmol) of N-phenyl, room temperature reaction 16 hours (TLC controls main material reaction completely).Adding dichloromethane (5ml), water (2 × 10ml), agitator treating after reaction completely, collect organic facies, anhydrous sodium sulfate is dried, and filters and be concentrated in vacuo and to obtain off-white color solid (145mg)
The synthesis of 2c, 7-tert-butoxy formamino-10-trimethyl fluoride sulfonyl Oxy-1 silica-based camptothecine of 6-O-triethyl group
Under nitrogen protection 7-tert-butoxy formamino-10-trimethyl fluoride sulfonyl epoxide camptothecine (0.2g) is added N; in dinethylformamide (7.5ml); under stirring; then imidazoles (0.25g), DMAP (0.035g), chlorotriethyl silane (0.45g) are added to it, room temperature reaction overnight (TLC controls main material reaction completely).Having reacted addition 45ml water, 20ml dichloromethane stirs washes layering, collects organic facies.Organic facies is washed with ammonium chloride saturated solution 20ml, saturated brine 10ml respectively, and anhydrous sodium sulfate is dried, filtering and concentrating, and petroleum ether obtains 350mg solid.
The synthesis of 2d, 7-tert-butoxy formamino-10-pinacol monoborane base silica-based camptothecine of-16-O-triethyl group
In the single port bottle that the 7-tert-butoxy formamino-10-trimethyl fluoride sulfonyl silica-based camptothecine of Oxy-1 6-O-triethyl group (0.6g), dioxane (15ml) nitrogen protection lower addition 50ml are dried; stirring; add 1 respectively, the double Diphenyl phosphino ferrocene palladium chloride (0.06g) of 1'-, connection boric acid pinacol ester (0.3g), potassium acetate (0.24g).It is stirred at room temperature 10 minutes, then is warming up to 100 degree of reactions 7 hours (TLC detection reaction is completely).Adding 100ml ethyl acetate, 100ml water, agitator treating after having reacted, add a small amount of suction filtered through kieselguhr, organic facies is collected in layering.Organic facies is washed with 100ml saturated brine again, and layering, organic facies is dried and is concentrated to give dark brown solid 0.45g.
The synthesis of 2e, 7-tert-butoxy formamino-10-boronate camptothecine
The 7-tert-butoxy formamino-10-pinacol monoborane silica-based camptothecine of base-16-O-triethyl group (0.45g) is joined in potassium bifluoride aqueous solution (20ml, 90mmol), methanol (140ml), three day (TLC detection reaction completely) is stirred at room temperature.Concentrating under reduced pressure methanol, concentrated solution adds 200ml acetone, sucking filtration, filter cake acetone drip washing, collects filtrate and is concentrated to give yellow solid.Adding water 50ml, acetonitrile 100ml, Lithium hydrate adjusts pH to 10, and reaction 2.5 hour (TLC detection reaction completely) is stirred at room temperature.Adding ammonium chloride saturated solution 100ml, dropping 1M hydrochloric acid adjusts pH to 3, and ethyl acetate 150ml extracts, and is dried and is concentrated to give yellow solid 228mg, m/e:491.
Embodiment 3
The synthesis of 3a, 7-(2 '-trimethyl is silica-based) ethyl-10-hydroxycamptothecin
Adding green-vitriol (2g), 30% sulphuric acid (12.5ml) in 100ml there-necked flask, 20min is stirred at room temperature, the silica-based propanol of trimethyl (4.8g), glycol (50ml) solution are added dropwise in reaction bulb stir 15min.This reactant liquor is added dropwise to containing SN-38(2.5g), 30% sulphuric acid (137.5ml), 30% hydrogen peroxide (0.81ml) reaction bulb in (about 30min), be stirred at room temperature reaction 1h, then to its dropping hydrogen peroxide (2.43ml), be stirred overnight.
Normal hexane (3 × 25ml) washing reaction liquid, abandon normal hexane layer, reactant liquor extracts with dichloromethane (3 × 125ml) again, merges organic facies, and low temperature (less than 40 DEG C) concentrating under reduced pressure obtains crude product, add N, dinethylformamide (80ml), is heated to 120 DEG C and dissolves clarification, 25 DEG C of crystallizations, sucking filtration, is dried to obtain 1.2 grams of solids.
The synthesis of 3b, 7-(2 '-trimethyl is silica-based) ethyl-10-trimethyl fluoride sulfonyl epoxide camptothecine
Being suspended under nitrogen protection in anhydrous dimethyl formamide (2.5ml) by 7-(2 '-trimethyl is silica-based) ethyl-10-hydroxycamptothecin (0.12g), the suspension obtained adds triethylamine (55mg).Under stirring, then it is added thereto to double (fluoroform sulphonyl) imines (140mg) of N-phenyl, room temperature reaction 16 hours (TLC controls main material reaction completely).Adding dichloromethane (5ml), water (2 × 10ml), agitator treating after reaction completely, collect organic facies, anhydrous sodium sulfate is dried, and filters and be concentrated in vacuo and to obtain off-white color solid 145mg.
The synthesis of 3c, 7-(2 '-trimethyl the is silica-based) ethyl-10-trimethyl fluoride sulfonyl Oxy-1 silica-based camptothecine of 6-O-triethyl group
Under nitrogen protection 7-(2 '-trimethyl is silica-based) ethyl-10-trimethyl fluoride sulfonyl epoxide camptothecine (0.2g) is added N; in dinethylformamide (7.5ml); under stirring; then imidazoles (0.25g), DMAP (0.035g), chlorotriethyl silane (0.441g) are added to it, room temperature reaction overnight (TLC controls main material reaction completely).Having reacted addition 45ml water, 20ml dichloromethane stirs washes layering, collects organic facies.Organic facies is washed with ammonium chloride saturated solution 20ml, saturated brine 10ml respectively, and anhydrous sodium sulfate is dried, filtering and concentrating, and petroleum ether obtains 380mg solid.
The synthesis of 3d, 7-(2 '-trimethyl the is silica-based) ethyl-10-pinacol monoborane base silica-based camptothecine of-16-O-triethyl group
The protection of general-(2 '-trimethyl the is silica-based) ethyl-10-trimethyl fluoride sulfonyl silica-based camptothecine of Oxy-1 6-O-triethyl group (0.6g), dioxane (15ml) nitrogen is lower to add in the single port bottle that 50ml is dried; stirring; add 1 respectively, the double Diphenyl phosphino ferrocene palladium chloride (0.06g) of 1'-, connection boric acid pinacol ester (0.3g), potassium acetate (0.24g).It is stirred at room temperature 10 minutes, then is warming up to 100 DEG C of reactions 7 hours (TLC detection reaction is completely).Adding 100ml ethyl acetate, 100ml water, agitator treating after having reacted, add a small amount of suction filtered through kieselguhr, organic facies is collected in layering.Organic facies is washed with 100ml saturated brine again, and layering, organic facies is dried and is concentrated to give dark brown solid 0.46g.
The synthesis of 3e, 7-(2 '-trimethyl is silica-based) ethyl-10-boronate camptothecine
7-(2 '-trimethyl the is silica-based) ethyl-10-pinacol monoborane silica-based camptothecine of base-16-O-triethyl group (0.46g) is joined potassium bifluoride aqueous solution (20ml, 90mmol), in methanol (140ml), three day (TLC detection reaction completely) is stirred at room temperature.Concentrating under reduced pressure methanol, concentrated solution adds 200ml acetone, sucking filtration, filter cake acetone drip washing, collects filtrate and is concentrated to give yellow solid.Adding water 50ml, acetonitrile 100ml, Lithium hydrate adjusts pH to 10, and reaction 2.5 hour (TLC detection reaction completely) is stirred at room temperature.Adding ammonium chloride saturated solution 100ml, dropping 1M hydrochloric acid adjusts pH to 3, and ethyl acetate 150ml extracts, and is dried and is concentrated to give yellow solid 215mg, m/e:492.
Anti-tumor activity test result:
The compounds of this invention using above-mentioned preparation carries out anti tumor activity in vitro test:
1, have detected compound suppression tumor cell proliferation effect by cellcountingkit-8 (CCK8) method, tester is SN38 and CPT-11, report relate to compound to Non-small cell lung carcinoma (A549), human colon carcinoma (HCT-116), human ovarian cancer (SK-OV-3), people's hepatocarcinoma (HepG2, SMMC-7721), compounds on ovarian cancer, colon cancer and the nonsmall-cell lung cancer of the result display present invention are more sensitive, more weak to hepatocarcinoma sensitivity (the results are shown in Table 1)
The table 1.HD-302 antitumor action to In vitro culture human tumor cells
2, have detected compound suppression tumor cell proliferation effect by cellcountingkit-8 (CCK8) method, tester is SN38 and CPT-11, report relate to compound and to people's normal chick embryo lung fibroblast toxicity, MRC-9 people's normal chick embryo lung fibroblast strain cytotoxicity, the compound of the result display present invention be less than SN38 (the results are shown in Table 2)
The table 2.HD-302 toxic action to vitro culture of human normal chick embryo lung fibroblast
The mensuration of cell inhibitory effect effect:
Choose humanized's Non-small Cell Lung Cancer A 549 strain respectively, humanized colon cancer cell line HCT-116, humanized Ovarian Cancer Cells SK-OV-3, humanized's hepatoma H22 cells, humanized's Liver cancer cell SMMC-7721, it is respectively placed in the F12K culture medium of the FBS containing 10%, the DMEM culture medium of the FBS of 10%, the RPMI1640 culture medium of the FBS of 10%, the EMEM culture medium of the FBS of 10%, the RPMI1640 culture medium of the BCS of 15% is cultivated, collect exponential phase cell, counting, with complete medium Eddy diffusion cell, adjust cell concentration to suitable concn (determining according to cell density optimization Test result), inoculate 96 orifice plates, every hole adds 100 μ l cell suspension.Cell at 37 DEG C, 100% relative humidity, 5%CO2After incubator is hatched 24 hours.Gradient dilution 8 times after testing compound being diluted to 500 μMs by culture medium.Cell is added by 25 μ l/ holes.3 candidate compound effect final concentrations from 100 μMs to 0 μMs, 4 times of gradient dilutions, totally 10 concentration point.Cell is placed in 37 DEG C, 100% relative humidity, 5%CO2Incubator is hatched 72 hours；Culture medium is abandoned in suction, and the addition complete medium containing 10%CCK-8 is placed in 37 DEG C of incubators hatches 2 ~ 4 hours.Measuring the absorbance at 450nm wavelength gently after concussion on SpectraMaxM5MicroplateReader, at 650nm, absorbance is as reference, calculates cell proliferation half suppression ratio IC50。
Experiment invention, the IC of embodiment of the present invention compound50Value is all between 0.01～2.27 μM.
Claims (5)
1. the analog of Cmptothecine, it is for having the compound or pharmaceutically acceptable salt thereof of structure shown in formula (III):
Wherein,
R1Represent C1-4Alkyl；
R3Represent boronate；
R2、R4Represent that hydrogen, halogen or low alkyl group, described low alkyl group are C independently1-6Alkyl；
R5Represent C1-4Alkyl, (CH2)mNR6R7Or (CH2)mSiR6R9R10；
R6、R9Or R10Represent C1-4Alkyl or C1-4Alkoxyl；
R7Represent hydrogen；
R20Represent hydrogen or halogen；
Rp represents hydrogen or (CH2)mSiR6R9R10；
M is the integer between 1 to 2.
The analog of camptothecine the most according to claim 1, wherein
R2、R4Represent hydrogen independently.
The analog of camptothecine the most according to claim 1, is selected from
7-ethyl-10-boronate camptothecine；
7-tert-butoxy formamino-10-boronate camptothecine；
7-(2 '-trimethyl is silica-based) ethyl-10-boronate camptothecine.
4. a pharmaceutical composition, it includes the compound or pharmaceutically acceptable salt thereof according to any one of claim 1-3 of pharmaceutically acceptable carrier and therapeutically effective amount.
5. the purposes in preparing antitumor drug of the compound or pharmaceutically acceptable salt thereof according to any one of claim 1-3.
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| CN102250104A (en) * | 2011-05-20 | 2011-11-23 | 南京大学 | Camptothecin derivative, and its synthetic method and application |
| CN102250103A (en) * | 2011-05-19 | 2011-11-23 | 南京大学 | Synthesis method of SN38 or intermediate thereof |
| CN102574866A (en) * | 2009-06-17 | 2012-07-11 | 施瑞修德制药公司 | Camptothecin derivatives |
| CN102670507A (en) * | 2011-03-07 | 2012-09-19 | 苏州法莫生物技术有限公司 | Long-circulated thermal sensitive liposome containing 7-ethyl-10-hydroxycamptothecin and preparation method thereof |
| CN102746314A (en) * | 2011-04-18 | 2012-10-24 | 华东师范大学 | Stable 7-membered lactonic ring-containing camptothecin compound and its preparation method and use |
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| CN102574866A (en) * | 2009-06-17 | 2012-07-11 | 施瑞修德制药公司 | Camptothecin derivatives |
| CN102670507A (en) * | 2011-03-07 | 2012-09-19 | 苏州法莫生物技术有限公司 | Long-circulated thermal sensitive liposome containing 7-ethyl-10-hydroxycamptothecin and preparation method thereof |
| CN102746314A (en) * | 2011-04-18 | 2012-10-24 | 华东师范大学 | Stable 7-membered lactonic ring-containing camptothecin compound and its preparation method and use |
| CN102250103A (en) * | 2011-05-19 | 2011-11-23 | 南京大学 | Synthesis method of SN38 or intermediate thereof |
| CN102250104A (en) * | 2011-05-20 | 2011-11-23 | 南京大学 | Camptothecin derivative, and its synthetic method and application |
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