CN103288842B - Fluorine replaces E ring camptothecin analogues and the purposes as medicine thereof - Google Patents
Fluorine replaces E ring camptothecin analogues and the purposes as medicine thereof Download PDFInfo
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Abstract
The present invention relates to medical art, be specifically related to a class fluorine and replace E ring camptothecin analogues and the purposes as medicine thereof.The compounds of this invention structure, as shown in general formula I, comprises its racemic modification, diastereomeric form, and any mixture of its these forms or its pharmaceutical salts.Compound of the present invention has the effect suppressing topoisomerase I activity, can be used for preparing antitumor drug, also can prepare medicine that is antiviral, fungi infestation.
Description
Technical field
The present invention relates to medical art, relate to fluorine and replace E ring camptothecin analogues and the purposes as medicine thereof, be specifically related to Cmptothecine E ring 21 deoxidation fluoric compounds and the purposes as medicine thereof.
Background technology
Camptothecine (Camptothecin) is (J.Am.Chem.Soc.1966 such as Americanized scholar Wall in 1966,88,3888) a kind of alkaloid extracted from Chinese Nyssaceae plant camptotheca acuminata (Camtothecaacuminata), camptothecine is by indolizino [1,2-b] quinoline fragment and hexa-atomic-hydroxy-lactone condense the five rings rigid structure of composition, 20 carbon with-hydroxyl are asymmetrical, and its gives MD characteristic.Its structure is as follows:
Camptothecine be find the earliest, most study, use are the widest specificity topoisomerase I inhibitor (TopoI), be also the most classical TopoI specific inhibitor, good anti-tumor activity all shown to various human tumor cell line.Through structure activity study for many years, develop large quantities of camptothecin derivative with using value, wherein irinotecan (Irinotecan, and topotecan (Topotecan CPT-11), TPT) successively ratify listing by FDA, Bei Nuo was ratified listing in 2004 by Korea S for health.
Large quantity research shows the many merits such as camptothecine compounds has efficiently, wide spectrum, selectivity are good, but camptothecine still has the shortcomings such as internal metabolism unstable, water-soluble low, toxic action, species variation.Originally the open loop of camptothecine E ring is prepared into carboxylate form to make it improve water-soluble by investigator, but this change makes the activity of camptothecine significantly reduce, and result in its serious toxic side effect (CancerChemother.Rpt.1972,56,95).
For improving camptothecine compounds stability in vivo thus enhanced activity, 20-position hydroxy ester is changed into prodrug by investigator, so just effectively can stop the formation of 20 hydroxyls and adjacent carbonyl intramolecular hydrogen bond thus suppress lactonic ring to be hydrolyzed.1985, along with the discovery of camptothecine mechanism of action, it specificly can act on DNA topoisomerase I, thus had caused the second time upsurge that investigator furthers investigate camptothecine.1997, the people such as OlivierLavergne proposed the brand-new camptothecin analogues with beta-hydroxy seven yuan of lactonic rings of a class, also known as hCPT (homocamptothecin, hCPT) at WO97/00876.It not only enhances anti-tumor activity, and have that species variation is little, toxic side effect is low, to resistance Anti-tumor angiogenesis advantages of higher, cause the concern of investigator, representational at present have BN80915 (diflomotecan) (ExpertOpin.Investig.Drugs.2009,18,69), BN80927 (CancerRes.2004,64,4942) II phase, I phase clinical stage etc., is entered respectively.2003, the alpha-hydroxy five-ring ketone that had again investigator to synthesize, have excellent anti-tumor activity and TopoI inhibit activities too, and also representative compound enters clinical study (BioorgMedChemLett.2003,13,2731).
The camptothecin analogues of these E rings is compared to camptothecine, and internal metabolism stability improves really greatly, but part of compounds has occurred toxic side effect in various degree at clinical investigation phase, so that have impact on the further exploitation of such medicine.Therefore based on this kind of reason, our the crucial E ring of seminar to camptothecine has carried out further structural modification transformation, to the antitumor drug candidate of camptothecin finding that activity is more excellent, metabolic stability good, toxic side effect is less.Such novel compound of our research, at home and abroad also without any report, belongs to the novel compound of invention.
Summary of the invention
The object of the invention is to, provide a kind of fluorine to replace E ring camptothecin analogues and the purposes as medicine thereof, to overcome the above-mentioned shortcoming and defect existing for prior art.
The present invention, in conjunction with toxic side effect in the body caused due to E ring metabolic stability difference of camptothecine, carries out rational structure of modification to its E ring.According to the structure activity study result before camptothecine, we remain 20 hydroxyls played a crucial role to its activity, and the ester carbonyl group of previous hexa-atomic lactonic ring is removed, the substitute is fluorine atom, at this, we utilize the biological characteristics of fluorine atom to carry out structure of modification, obtain a class novel camptothecin E ring analogues.
The technical problem that will solve required for the present invention, can be achieved through the following technical solutions:
As a first aspect of the present invention, fluorine replaces E ring camptothecin analogues, comprises its racemic modification, diastereomeric form, and any mixture of its these forms or its pharmaceutical salts, and structure is as general formula I:
Wherein:
R
1, R
2, R
3, R
4represent following groups independently: hydrogen, hydroxyl, amino, low-grade alkyl amino, low alkyl group, halogen, low-grade halogenated alkyl, lower alkoxy, low-grade alkenyl, cyano group, lower cyanoalkyl, nitro, rudimentary 4-nitro alkyl, amide group, rudimentary amido alkyl, diazanyl, rudimentary diazanyl alkyl, azido-, rudimentary azido-alkyl, (CH
2)
mnR
7r
8, (CH
2)
moR
9, (CH
2)
msR
9, (CH
2)
mnR
10c (O) R
10, (CH
2)
mc (O) R
10, (CH
2)
moC (O) R
10, O (CH
2)
mnR
7r
8, OC (O) NR
7, OC (O) (CH
2)
moC (O) R
10or (CH
2)
n[N=X], OC (O) [N=X], (CH
2)
moC (O) [N=X] (in the present invention, [N=X] represents 4 to 7 yuan of heterocyclic radicals of nitrogen atom N, and N is an atom of heterocyclic group, and X represents all the other atoms forming these heterocycle needs, and they are selected from O, S, CH
2, CH, NR
7and COR
10), substituted or unsubstituted loweraralkyl, wherein substituting 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, or R
2and R
3form the chain of 3 or 4 yuan together, wherein the unit of this chain is selected from CH, CH
2, O, S or NR
11;
Preferred R
1, R
2, R
3, R
4represent following groups independently: hydrogen, hydroxyl, halogen, low alkyl group, lower alkoxy, nitro, amino, cyano group, (CH
2)
mnR
7r
8, (CH
2)
moR
9, (CH
2)
mc (O) R
10, (CH
2)
moC (O) R
10, substituted or unsubstituted loweraralkyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy, lower alkoxy loweralkyl, or R
2and R
3form the chain of 3 or 4 yuan together, wherein the unit of this chain is selected from CH, CH
2, O, S or NR
11;
R
5represent low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, low-grade halogenated alkyl, lower alkoxy loweralkyl or lower alkylthio low alkyl group.
Preferred R
5represent low alkyl group;
R
6represent hydrogen, hydroxyl, nitro, cyano group, halogen.
Preferred R
6represent hydroxyl, halogen;
R
7, R
8represent the rudimentary aminoalkyl of hydrogen, low alkyl group, Lower hydroxy alkyl, low alkyl group, rudimentary aminoalkyl, cycloalkyl, cycloalkyl low-grade alkyl, low-grade alkenyl, lower alkoxy loweralkyl, low-grade halogenated alkyl or substituted or unsubstituted loweraralkyl independently, wherein substituting group is low alkyl group, halogen, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl;
R
9, R
10represent hydrogen, low alkyl group, Lower hydroxy alkyl, amino, low-grade alkyl amino, the rudimentary aminoalkyl of low alkyl group, rudimentary aminoalkyl, cycloalkyl, cycloalkyl low-grade alkyl, low-grade alkenyl, lower alkoxy, lower alkoxy loweralkyl, low-grade halogenated alkyl and or replace or do not replace loweraralkyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl;
R
11the aryl representing hydrogen, low alkyl group, low-grade halogenated alkyl, aryl or replaced by following one or more group: low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, Lower hydroxy alkyl, lower alkoxy or lower alkoxy loweralkyl;
M is the integer between 0 to 6
N is 1 or 2;
[N=X] represents 4 to 7 yuan of heterocyclic radicals, and X has represented the chain of described heterocyclic radical needs and has been selected from O, S, CH
2, CH, NR
7, COR
10;
So-called low alkyl group is for containing 1 to 6 carbon atom straight chain or branched-chain alkyl; Lower alkoxy is for containing 1 to 6 carbon atom straight chain or branched alkoxy; Low-grade halogenated alkyl is the low alkyl group replaced containing 1 to 3 halogen atom; Loweraralkyl is the low alkyl group being connected with aryl.
In this article, the term " rudimentary " relevant with alkyl, alkylthio and alkoxyl group refers to the straight or branched saturated fatty hydrocarbyl group containing 1 to 6 carbon atom, such as, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, methylthio group, ethylmercapto group, methoxyl group and oxyethyl group, the term " rudimentary " relevant with term alkenyl or alkynyl group refers to the group containing 2 to 6 carbon atoms and one or more double bond or triple bond, such as: vinyl, allyl group, isoolefine propyl group, pentenyl, hexenyl, propenyl, ethynyl, proyl and butynyl.Term cycloalkyl refers to the ring containing 3 to 7 carbon, such as, and cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Term aryl refers to list, two or tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, each ring containing maximum 7 carbon atoms, such as, phenyl, naphthyl, anthryl, xenyl or indenyl.Term halogen refers to chlorine, bromine, iodine or fluorine.Corresponding to term low-grade halogenated alkyl, lower cyanoalkyl, rudimentary 4-nitro alkyl, rudimentary amido alkyl, rudimentary diazanyl alkyl, lower alkoxy loweralkyl, rudimentary azido-alkyl, loweraralkyl, Lower hydroxy alkyl, the group of lower alkylthio low alkyl group and the rudimentary Sulfonylalkyl of low alkyl group is respectively by one to three halogen, cyano group, nitro, amide group, diazanyl, alkoxyl group, azido-, aryl, hydroxyl, low alkyl group sulfenyl low alkyl group or rudimentary Sulfonylalkyl replace.Low-grade alkyl amino can contain one or two low alkyl group, such as, represent NHCH
3, NHCH
2cH
3, N (CH
3)
2or CH
3nCH
2cH
3.Formula (I) compound is selected from:
(S, S)-21-fluorine camptothecine
(S, R)-21-fluorine camptothecine
(R, S)-20,21-difluoro camptothecine
(S, S)-9-nitro-21-fluorine camptothecine
(S, S)-7-ethyl-10-methoxyl group-21-fluorine camptothecine
(S, S)-10-methoxyl group-21-fluorine camptothecine
(S, S)-10-benzyloxy-21-fluorine camptothecine
(S, S)-10-hydroxyl-21-fluorine camptothecine
(S, S)-7-ethyl-10-benzyloxy-21-fluorine camptothecine
(S, S)-7-ethyl-10-hydroxyl-21-fluorine camptothecine
(S, S)-7-methyl-21-fluorine camptothecine
(S, S)-7-ethyl-21-fluorine camptothecine
(S, S)-7-propyl group-21-fluorine camptothecine
(S, S)-7-normal-butyl-21-fluorine camptothecine
(S, S)-7-sec.-propyl-21-fluorine camptothecine
(S, S)-7-(cyclopropyl-methyl fluoride)-21-fluorine camptothecine
(S, S)-7-cyclobutyl-21-fluorine camptothecine
(S, S)-7-cyclopentyl-21-fluorine camptothecine
(S, S)-7-cyclohexyl-21-fluorine camptothecine
20 and 21 carbon atoms of the compounds of this invention are chiral carbon atom, and wherein 20 carbon atoms remain the parent configuration of camptothecine, i.e. S configuration, and 21 carbon atoms have R and S two kinds of configurations.This compounds just has S like this, R and S, S two diastereomers, and these two diastereomers can obviously differentiate on thin layer plate, what is interesting is S, and the Compound ira vitro anti-tumor activity of S configuration is obviously better than S, R configuration.Simultaneously in the process of this compounds of synthesis, we also obtain the structure that 20 and 21 two fluorine replace, and it is poor that external activity test result in earlier stage shows this type of antitumor activity of compound.The present invention includes the enantiomorph configuration of these compounds, diastereomer and their various combinations.
Present invention also offers the preparation method of such novel camptothecin E ring analogues.Synthetic route is as follows:
Formula I compound can be prepared by described below and for preferred compound citing of the present invention method.
The different starting intermediates III replaced is obtained by camptothecine parent nucleus derivatize, can with reference to camptothecine A and B ring derivatives synthetic method [Chem.Pharm.Bull.1991,39,2574; Synthesis2006 (12) 1940-1942 etc.] obtain, the reduction then they being carried out 21 ester carbonyl groups obtains dihydroxy intermediate II, under the effect of fluoro reagent, finally obtain our target compound.Below for camptothecine, describe concrete synthesis step in detail:
1, for formula III compound, R
1, R
2, R
3, R
4when being all hydrogen, then initiator is just camptothecine parent nucleus, camptothecine is suspended in specific solvent, usually adopts polarity or non-polar solvent as methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF), acetic acid, toluene, benzene etc., particular methanol or ethanol polar solvent.The reductive agent used that reduces can select POTASSIUM BOROHYDRIDE, sodium borohydride, lithium aluminium hydride etc., at this we particularly preferably POTASSIUM BOROHYDRIDE as reductive agent.
2, intermediate II 21-hydroxycamptothecine is suspended in suitable solvent, usually adopts polarity or non-polar solvent as ethyl acetate, acetonitrile, tetrahydrofuran (THF), chloroform, methylene dichloride, toluene, benzene etc., the medium polar solvents such as preferred methylene dichloride or chloroform.Fluoro reagent can select diethylin sulfur trifluoride (DAST), two (dimethoxy-ethyl) amino sulfur trifluoride (Deoxo-Fluor), hydrofluoric acid, Potassium monofluoride, N, N-diethyl-1,1,2,3,3,3-hexafluoro propylamine (Ishikawareagent), sulfur tetrafluoride (SF
4), tribromide fluorine (FBr
3), triethylamine trihydrofluoride (Et
3n.3HF) etc., we preferred DAST is fluoro reagent herein.The temperature of reaction can within the scope of 0 DEG C ~-78 DEG C, at this we preferably-50 DEG C ~-78 DEG C.
It will be clear that and work as R
1, R
2, R
3, R
4when having replacement respectively, adopting uses the same method also can obtain similar compound, as: R
3when being methoxyl group, first obtain 21-hydroxyl-10-Methoxycamptothecine; R
3, R
421-hydroxyl-10,11-difluoro camptothecine is when all having F to replace; R
3, R
4become ethylenedioxy, obtain 21-hydroxyl-10,11-ethylenedioxy camptothecine.Then the camptothecin analogues of corresponding E cyclic ketal just can be obtained by above-mentioned route.
Some compound of the present invention conventionally can be prepared as the form of pharmaceutical salts.Comprise its organic acid salt and inorganic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, bisphosphate, Hydrogen bromide, nitric acid etc., organic acid includes, but is not limited to acetic acid, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
Type I compound of the present invention has the effect suppressing topoisomerase, and has anti-tumor activity.Prior art implies that compound of the present invention has antiviral activity [Chiang.J.Li etc., TheJournalofBiologicalChemistry, 269:7051 (1994)] and anti-mycotic activity [FostelJ. etc., FEMSMicrobiologyLetters, 138:105 (1996)], therefore compound of the present invention can be used for preparing corresponding medicine.
As a second aspect of the present invention, fluorine replaces E ring camptothecin analogues, is selected from its racemic modification, diastereomeric form, and any mixture of its these forms or its pharmaceutical salts, is preparing the application in topoisomerase I inhibitor.
Formula I compound of the present invention has the effect suppressing topoisomerase, and has anti-tumor activity.Prior art implies that compound of the present invention has antiviral activity [Chiang.J.Li etc., TheJournalofBiologicalChemistry, 269:7051 (1994)] and anti-mycotic activity [FostelJ. etc., FEMSMicrobiologyLetters, 138:105 (1996)], therefore compound of the present invention can be used for preparing corresponding medicine.
As a third aspect of the present invention, compound of the present invention has anti-tumor activity, and fluorine replaces E ring camptothecin analogues, the application in the medicine of preparation treatment tumor disease.
They can be used for treating tumour, comprise the cancer that the positions such as esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, mammary gland, uterus, uterine endometrium, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin, eye, brain and central nervous system occur, and thyroid carcinoma, leukemia, suddenly king's evil, lymphoma and myelomatosis etc.
As a fourth aspect of the present invention, fluorine of the present invention replaces the application of E ring camptothecin analogues in the medicine for the preparation for the treatment of virus infection and fungi infestation.
The pharmacologically active of the compounds of this invention makes it may be used for preparing antitumor, antimycotic and antiviral, and therefore the present invention also comprises using these compounds and pharmaceutical salts thereof as the pharmaceutical composition of activeconstituents.This pharmaceutical composition can be solid form or liquid form.
Will be appreciated that, the any mixture of the racemic modification of compound of the present invention, diastereomer and these forms or its pharmaceutical salts also have the effect suppressing topoisomerase, there is anti-tumor activity, antiviral activity and anti-mycotic activity, can be used for preparing antitumor, antimycotic and antiviral.The present invention also comprises type I compound, comprise any mixture or its pharmaceutical salts of its racemic modification, diastereomer and its these forms, preparing the purposes in agents: medicine, the antitumor drug, antifungal drug and the antiviral aspect that suppress topoisomerase.
Beneficial effect of the present invention: the present invention has carried out further structural modification transformation to the crucial E ring of camptothecine, prepares the antitumor drug candidate of camptothecin that activity is more excellent, metabolic stability good, toxic side effect is less.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples only for illustration of the present invention but not for limiting scope of the present invention.
The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or the condition that manufacturer provides is carried out.
Embodiment 1,21-hydroxycamptothecine
1.00g camptothecine is suspended in the methyl alcohol of 50mL, stirred at ambient temperature is after 5 minutes, add 0.30g POTASSIUM BOROHYDRIDE, under room temperature, continue reaction 1h, now reaction solution clarification, boil off solvent and obtain light green solid, add 50mL water to make it to dissolve, then under ice-water bath, regulate PH to be acid with acetic acid, now separate out a large amount of solid, suction filtration is washed, and vacuum-drying obtains 0.99g faint yellow solid 21-hydroxycamptothecine (98.4%).
1HNMR(DMSO)，δ：
0.91(t，3H)，1.72(q，2H)，4.49-4.63(q，2H)，4.94(s，1H)，5.00(d，1H)，5.25(s，2H)，6.73(d，1H)，7.38(s，1H)，7.69(t，1H)，7.85(t，1H)，8.11(d，1H)，8.16(d，1H)，8.66(s，1H)。
The synthesis of embodiment 2,10-methoxyl group-21-hydroxycamptothecine
1.00g10-methoxycamptothecine is suspended in the methyl alcohol of 50mL, stirred at ambient temperature is after 5 minutes, add 0.30g POTASSIUM BOROHYDRIDE, under room temperature, continue reaction 1h, now reaction solution clarification, boil off solvent and obtain light green solid, add 50mL water to make it to dissolve, then under ice-water bath, regulate PH to be acid with acetic acid, now separate out a large amount of solid, suction filtration is washed, and vacuum-drying obtains 0.96g faint yellow solid 10-methoxyl group-21-hydroxycamptothecine (95.4%).
1HNMR(DMSO)，δ：
0.90(t，3H)，1.70(q，2H)，3.93(s，3H)，4.46-4.64(q，2H)，4.91(s，1H)，4.97(d，1H)，5.21(s，2H)，6.74(d，1H)，7.30(s，1H)，7.47(d，1H)，7.50(s，1H)，8.05(d，1H)，8.51(s，1H)。
The synthesis of embodiment 3,9-nitro-21-hydroxycamptothecine
1.00g9-nitrocamptothecin is suspended in the methyl alcohol of 50mL, stirred at ambient temperature is after 5 minutes, add 0.30g POTASSIUM BOROHYDRIDE, under room temperature, continue reaction 1h, now reaction solution clarification, boil off solvent and obtain light green solid, add 50mL water to make it to dissolve, then under ice-water bath, regulate PH to be acid with acetic acid, now separate out a large amount of solid, suction filtration is washed, and vacuum-drying obtains 0.95g faint yellow solid 21-hydroxycamptothecine (94.5%).
1HNMR(DMSO)，δ：
0.91(t，3H)，1.72(q，2H)，4.70-4.81(q，2H)，4.94(s，1H)，5.14(d，1H)，5.27(s，2H)，6.77(d，1H)，7.44(s，1H)，8.03(t，1H)，8.52(t，1H)，8.57(d，1H)，9.15(s，1H)。
The synthesis of embodiment 4,7-normal-butyl-21-hydroxycamptothecine
1.00g7-butyl camptothecine is suspended in the methyl alcohol of 50mL, stirred at ambient temperature is after 5 minutes, add 0.30g POTASSIUM BOROHYDRIDE, under room temperature, continue reaction 1h, now reaction solution clarification, boil off solvent and obtain light green solid, add 50mL water to make it to dissolve, then under ice-water bath, regulate PH to be acid with acetic acid, now separate out a large amount of solid, suction filtration is washed, and vacuum-drying obtains 1.0g faint yellow solid 7-butyl-21-hydroxycamptothecine (99.5%).
1H-NMR(DMSO)：
0.90(t，3H)，0.95(t，3H)，1.47-1.51(m，2H)，1.65-1.74(m，4H)，3.19(t，2H)，4.49-4.64(q，2H)，4.94(s，1H)，5.00(d，1H)，5.25(s，2H)，6.74(d，1H)，7.35(s，1H)，7.69(t，1H)，7.83(t，1Hz)，8.15(d，1H)，8.25(d，1H)。
Embodiment 5, (S, S)-21-fluorine camptothecine
The 21-hydroxycamptothecine of 0.3g is suspended in the anhydrous methylene chloride of 20mL, nitrogen protection, with dry ice acetone cooling reaction solution to-70 DEG C, after stirring 10min, the diethylin sulfur trifluoride (DAST) of 0.1mL is injected fast in solution, remove cooling, after room temperature reaction 40min, TLC analytical reaction are complete, now add the dchloromethane of 20mL, and then add 30mL 10% sodium bicarbonate aqueous solution, after stirring 15min, layering, aqueous phase methylene dichloride (20mL × 2) extracts, merge organic phase, anhydrous sodium sulfate drying, filter, boil off solvent, with silica gel chromatographic column (eluent: CH
2cl
2/ CH
3oH100: 1) separation obtains 80mg faint yellow solid (S, S)-21-fluorine camptothecine, [α]
d 20=+511 (c0.07, CH
2cl
2).
1H-NMR(DMSO)：
0.91(t，3H)，1.85(q，2H)，4.74-4.79(q，2H)，5.27(d，2H)，5.69(d，1H)，5.88(s，1H)，7.40(s，1H)，7.71(t，1H)，7.86(t，1H)，8.12(d，1H)，8.17(d，1H)，8.68(s，1H)。
Embodiment 6, (S, R)-21-fluorine camptothecine
According to the method for embodiment 5, be separated to obtain 70mg faint yellow solid (S, R)-21-fluorine camptothecine, [α]
d 20=+1275 (c0.05, CH
2cl
2).
1H-NMR(DMSO)：
1.02(t，3H)，1.78-2.17(dq)，4.69-4.79(q，2H)，5.28(s，2H)，5.67(d，1H)，5.90(s，1H)，7.34(s，1H)，7.71(t，1H)，7.86(t，1H)，8.12(d，1H)，8.17(d，1H)，8.68(s，1H)。
Embodiment 7, (R, S)-20,21-difluoro camptothecine
According to the method for embodiment 5, be separated to obtain 30mg faint yellow solid (R, S)-20,21-difluoro camptothecine, [α]
d 20=+201.1 (c0.056, CH
2cl
2).
1H-NMR(DMSO)：
1.08(t，3H)，1.98-2.58(dm，2H)，4.74-4.91(dq，2H)，5.31(s，2H)，6.05-6.16(dd，1H)，5.90(s，1H)，7.24(s，1H)，7.72(t，1H)，7.87(t，1H)，8.14(d，1H)，8.16(d，1H)，8.70(s，1H)。
Embodiment 8, (S, S)-9-nitro-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 9-nitro-21-hydroxycamptothecine, obtain 110mg faint yellow solid (S, S)-9-nitro-21-fluorine camptothecine, [α]
d 20=+437.1 (c0.07, DMF).
1H-NMR(DMSO)：
0.91(t，3H)，1.71(q，2H)，4.71-4.80(q，2H)，5.27(q，2H)，5.71(d，1H)，5.91(s，1H)，7.44(s，1H)，8.04(t，1H)，8.51(d，1H)，8.56(d，1H)，9.14(s，1H)。
Embodiment 9, (S, S)-7-ethyl-10-methoxyl group-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-ethyl-10-methoxyl group-21-hydroxycamptothecine, obtain 90mg faint yellow solid (S, S)-7-ethyl-10-methoxyl group-21-fluorine camptothecine, [α]
d 20=+383 (c0.086, CH
2cl
2).
1H-NMR(DMSO)：
0.90(t，3H)，1.32(t，3H)，1.71(q，2H)，3.25(q，2H)，3.98(s，3H)，4.75(s，2H)，5.28(d，2H)，5.68(d，1H)，5.88(s，1H)，7.31(s，1H)，7.49(s，1H)，7.52(d，1H)，8.07(d，1H)。
Embodiment 10, (S, S)-10-methoxyl group-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 10-methoxyl group-21-hydroxycamptothecine, obtain 70mg yellow solid (S, S)-10-methoxyl group-21-fluorine camptothecine, [α]
d 20=+854.1 (c0.056, CH
2cl
2).
1H-NMR(DMSO)：
0.91(t，3H)，1.70(q，2H)，3.95(s，3H)，4.70-4.77(q，2H)，5.22-5.29(q，2H)，5.69(d，1H)，5.85(s，1H)，7.34(s，1H)，7.50-7.52(m，2H)，8.06(dd，1H)，8.54(s，1H)。
Embodiment 11, (S, S)-10-benzyloxy-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 10-benzyloxy-21-hydroxycamptothecine, obtain 116mg faint yellow solid (S, S)-10-benzyloxy-21-fluorine camptothecine, [α]
d 20=+670.5 (c0.056, CH
2cl
2).
1H-NMR(DMSO)：
0.90(t，3H)，1.70(q，2H)，4.70-4.78(q，2H)，4.90(s，1H)，5.24(d，1H)，5.29(s，2H)，5.69(d，1H)，5.86(s，1H)，7.33(s，1H)，7.37(d，1H)，7.43(m，2H)，7.54-7.63(m，4H)，8.08(d，1H)，8.52(s，1H)。
Embodiment 12, (S, S)-10-hydroxyl-21-fluorine camptothecine
(S, S)-10-benzyloxy-21-fluorine camptothecine of 50mg is suspended in the ethanol of 15mL, adds the Pd-C of 10mg10%, pour hydrogen, react 12h under room temperature, core filters, boil off (S, S)-10-hydroxyl-21-fluorine camptothecine that solvent obtains 30mg, [α]
d 20=+224 (c0.09, DMF).
1H-NMR(DMSO)：
0.91(t，3H)，1.71(q，2H)，4.72(s，2H)，5.20(s，2H)，5.62(d，1H)，5.85(s，1H)，7.26(d，1H)，7.29(s，1H)，7.38-7.42(dd，1H)，8.01(d，1H)，8.42(s，1H)，10.29(s，1H)。
Embodiment 13, (S, S)-7-ethyl-10-benzyloxy-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-ethyl-10-benzyloxy-21-hydroxycamptothecine, obtain 145mg yellow solid (S, S)-7-ethyl-10-benzyloxy-21-fluorine camptothecine, [α]
d 20=+159.5 (c0.15, CH
2cl
2).
1H-NMR(DMSO)：
0.89(t，3H)，1.01(t，3H)，1.70(q，2H)，3.17(q，2H)，4.72-4.78(q，2H)，5.27(s，2H)，5.37(s，2H)，5.65(d，1H)，5.85(s，1H)，7.30(s，1H)，7.37(d，1H)，7.43(m，2H)，7.54-7.63(m，4H)，8.08(d，1H)。
Embodiment 14, (S, S)-7-ethyl-10-hydroxyl-21-fluorine camptothecine
According to the method for embodiment 12, replace (S with (S, S)-7-ethyl-10-benzyloxy-21-fluorine camptothecine, S)-10-benzyloxy-21-fluorine camptothecine, obtain (S, S)-7-ethyl-10-hydroxyl-21-fluorine camptothecine of 25mg, [α]
d 20=+422.4 (c0.083, DMF).
1H-NMR(DMSO)：
0.90(t，3H)，1.04(t，3H)，1.71(q，2H)，3.07(q，2H)，4.74(s，2H)，5.25(s，2H)，5.67(d，1H)，5.87(s，1H，OH)，7.22(d，1H)，7.28(s，1H)，7.39(d，1H)，8.01(d，1H)，10.30(s，1H).
Embodiment 15, (S, S)-7-methyl-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-methyl-21-hydroxycamptothecine, obtain 130mg faint yellow solid (S, S)-7-methyl-21-fluorine camptothecine, [α]
d 20=+918 (c0.033, CH
2cl
2).
1H-NMR(DMSO)：
0.89(t，3H)，1.70(q，2H)，2.77(s，3H)，4.70-4.77(q，2H)，5.23-5.31(q，2H)，5.63(d，1H)，5.85(s，1H)，7.34(s，1H)，7.71(t，1H)，7.84(t，1H)，8.13(d，1H)，8.24(d，1H)。
Embodiment 16, (S, S)-7-ethyl-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-ethyl-21-hydroxycamptothecine, obtain 105mg yellow solid (S, S)-7-ethyl-21-fluorine camptothecine, [α]
d 20=+290.7 (c0.043, CH
2cl
2).
1H-NMR(DMSO)：
0.90(t，3H)，1.32(t，3H)，1.71(q，2H)，3.32(m，2H)，4.71-4.79(q，2H)，5.27-5.36(q，2H)，5.64-5.74(d，1H)，5.88(s，1H)，7.37(s，1H)，7.72(t，1H)，7.85(t，1H)，8.16(d，1H)，8.28(d，1H)。
Embodiment 17, (S, S)-7-propyl group-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-propyl group-21-hydroxycamptothecine, obtain 135mg faint yellow solid (S, S)-7-propyl group-21-fluorine camptothecine, [α]
d 20=+151.5 (c0.063, CH
2cl
2).
1H-NMR(DMSO)：
0.91(t，3H)，1.05(t，3H)，1.67-1.71(m，4H)，3.19(t，2H)，4.71-4.79(q，2H)，5.25-5.34(q，2H)，5.64-5.74(d，1H)，5.88(s，1H)，7.37(s，1H)，7.71(t，1H)，7.84(t，1H)，8.16(d，1H)，8.28(d，1H)。
Embodiment 18, (S, S)-7-butyl-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-butyl-21-hydroxycamptothecine, obtain 120mg faint yellow solid (S, S)-7-butyl-21-fluorine camptothecine, [α]
d 20=+236.5 (c0.056, CH
2cl
2).
1H-NMR(DMSO)：
0.90(t，3H)，0.95(t，3H)，1.47-1.53(m，2H)，1.65-1.74(m，4H)，3.30(t，2H)，4.71-4.79(q，2H)，5.25-5.33(q，2H)，5.64-5.74(d，1H)，5.88(s，1H)，7.37(s，1H)，7.72(t，1H)，7.84(t，1H)，8.16(d，1H)，8.26(d，1H)。
Embodiment 19, (S, S)-7-sec.-propyl-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-sec.-propyl-21-hydroxycamptothecine, obtain 90mg faint yellow solid (S, S)-7-sec.-propyl-21-fluorine camptothecine, [α]
d 20=+132.4 (c0.096, CH
2cl
2).
1H-NMR(DMSO)：
0.90(t，3H)，1.49(m，6H)，1.71(q，2H)，4.02(m，1H)，4.71-4.79(q，2H)，5.37-5.45(q，2H)，5.64-5.74(d，1H)，5.88(s，1H)，7.38(s，1H)，7.71(t，1H)，7.84(t，1H)，8.16(d，1H)，8.39(d，1H)。
Embodiment 20, (S, S)-7-(cyclopropyl-methyl fluoride)-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-(cyclopropyl-methylol)-21-hydroxycamptothecine, obtain 70mg faint yellow solid (S, S)-7-(cyclopropyl-methyl fluoride)-21-fluorine camptothecine, [α]
d 20=+739.5 (c0.07, CH
2cl
2).
1H-NMR(DMSO)：
0.55-0.59(m，1H)，0.70-0.75(m，3H)，0.87(t，3H)，1.64-1.73(m，3H)，4.71-4.79(q，2H)，5.24-5.48(dt，2H)，5.64-5.73(d，1H)，5.88(s，1H)，6.04-6.16(dq，1H)，7.40(s，1H)，7.72(t，1H)，7.88(t，1H)，8.20(d，1H)，8.30(d，1H)。
Embodiment 21, (S, S)-7-cyclobutyl-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-cyclobutyl-21-hydroxycamptothecine, obtain 70mg faint yellow solid (S, S)-7-cyclobutyl-21-fluorine camptothecine, [α]
d 20=+683.1 (c0.043, DMF).
1H-NMR(DMSO)：
0.89(t，3H)，1.70(q，2H)，1.89-1.92(m，1H)，2.16-2.17(m，1H)，2.53-2.57(m，2H)，2.63-2.67(m，2H)，4.38(m，1H)，4.70-4.78(q，2H)，5.43(s，2H)，5.63-5.75(d，1H)，5.88(s，1H)，7.36(s，1H)，7.67(t，1H)，7.82(t，1H)，8.13(d，1H)，8.18(d，1H)。
Embodiment 22, (S, S)-7-cyclopentyl-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-cyclopentyl-21-hydroxycamptothecine, obtain 70mg faint yellow solid (S, S)-7-cyclopentyl-21-fluorine camptothecine, [α]
d 20=+304.6 (c0.043, DMF).
1H-NMR(DMSO)：
0.90(t，3H)，1.68(q，2H)，1.83(m，2H)，1.98(m，4H)，2.18(m，2H)，3.94(m，1H)，4.70-4.79(q，2H)，5.33-5.63(q，2H)，5.65-5.75(d，1H)，5.88(s，1H)，7.37(s，1H)，7.69(t，1H)，7.83(t，1H)，8.16(d，1H)，8.36(d，1H)。
Embodiment 23, (S, S)-7-cyclohexyl-21-fluorine camptothecine
According to the method for embodiment 5, replace 21-hydroxycamptothecine with 7-cyclohexyl-21-hydroxycamptothecine, obtain 70mg faint yellow solid (S, S)-7-cyclohexyl-21-fluorine camptothecine, [α]
d 20=+325.4 (c0.086, DMF).
1H-NMR(DMSO)：
0.89(t，3H)，1.46(m，2H)，1.60(m，2H)，1.70(q，2H)，1.81(m，2H)，1.90(m，4H)，3.69(m，1H)，4.71-4.79(q，2H)，5.42(s，2H)，5.63-5.74(d，1H)，5.88(s，1H)，7.37(s，1H)，7.72(t，1H)，7.84(t，1H)，8.15(d，1H)，8.40(d，1H)。
The anti-tumor activity test of embodiment 24, the compounds of this invention
Carried out Cytostatic to tumor cell test to compound of the present invention, test method adopts conventional mtt assay (as Lv Qiujun chief editor " developmental pharmacology research method ", 2007:242-243).
Cell strain selects A549 (human lung carcinoma cell), MDA-MB-435 (human breast cancer cell), SK-BR-3 (human breast cancer cell), HCT116 (people's colon-cancer cell), frozen and go down to posterity by Shanghai Institute of Pharmaceutical Industry's pharmacological evaluation room.Nutrient solution is that RPMI1640+15%NBS+ is dual anti-.
MTT solution preparation: take MTT0.5 gram, be dissolved in 100ml phosphoric acid buffer (PBS) or without in phenol red substratum, with 0.22 μm of membrane filtration to remove the bacterium in solution, put 4 DEG C and keep in Dark Place.
Sample liquid is prepared: after dissolving with DMSO (Merck), add PBS (-) and be made into the solution of 100 μ g/mL or uniform suspension, then use the PBS (-) of DMSO to dilute, ultimate density is respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL, 0.001 μ g/mL, 0.0001 μ g/mL.
The antitumor drug topotecan (TPT) of listing and irinotecan (IRT) are made into reference substance solution with same condition.
Mtt assay: it is 4-6 × 10 that the 96 every holes of orifice plate add concentration
4the cell suspension 100 μ l of individual/ml, puts 37 DEG C, 5%CO
2in incubator.After 24h, add sample liquid, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO
2effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, and add lysate after effect 4h, 100 μ l/ holes, put in incubator, surveys 570nmOD value after dissolving by the full-automatic microplate reader of MK-2.Calculation of half inhibitory concentration IC
50.
Test-results is in table 1 and table 2, and wherein, sample refers to the hCPT compounds (such as embodiment 4 i.e. 7-(4-nitrophenyl) vinyl hCPT) prepared in corresponding embodiment.
Table 1, test compounds are to the half-inhibition concentration IC of tumour cell
50(unit: μ g/ml)
Table 2, test compounds are to the half-inhibition concentration IC of tumour cell
50(unit: μ g/ml)
Above experimental result shows, compound of the present invention has good anti-tumor activity, and multiple compound is higher than marketed drug topotecan, and therefore the compounds of this invention and its esters may be used for preparing antitumor drug.
More than show and describe ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (5)
1. fluorine replaces E ring camptothecin analogues, and structure is as shown in general formula I:
Wherein:
R
1, R
2, R
3, R
4represent following groups independently: hydrogen, hydroxyl, amino, low-grade alkyl amino, low alkyl group, halogen, low-grade halogenated alkyl, lower alkoxy, cyano group, nitro, amide group, diazanyl, azido-,
R
5represent low alkyl group, low-grade halogenated alkyl;
R
6represent hydrogen, hydroxyl, nitro, cyano group, halogen,
So-called low alkyl group is for containing 1 to 6 carbon atom straight chain or branched-chain alkyl; Lower alkoxy is for containing 1 to 6 carbon atom straight chain or branched alkoxy; Low-grade halogenated alkyl is the low alkyl group replaced containing 1 to 3 halogen atom.
2. compound according to claim 1, is characterized in that, described R
5for ethyl, described R
6for hydroxyl, fluorine atom.
3. compound according to claim 1, it is characterized in that, described formula I is selected from:
(S, S)-21-fluorine camptothecine,
(S, R)-21-fluorine camptothecine,
(R, S)-20,21-difluoro camptothecine,
(S, S)-9-nitro-21-fluorine camptothecine,
(S, S)-7-ethyl-10-methoxyl group-21-fluorine camptothecine,
(S, S)-10-methoxyl group-21-fluorine camptothecine,
(S, S)-10-benzyloxy-21-fluorine camptothecine,
(S, S)-10-hydroxyl-21-fluorine camptothecine,
(S, S)-7-ethyl-10-benzyloxy-21-fluorine camptothecine,
(S, S)-7-ethyl-10-hydroxyl-21-fluorine camptothecine,
(S, S)-7-methyl-21-fluorine camptothecine,
(S, S)-7-ethyl-21-fluorine camptothecine,
(S, S)-7-propyl group-21-fluorine camptothecine,
(S, S)-7-normal-butyl-21-fluorine camptothecine,
(S, S)-7-sec.-propyl-21-fluorine camptothecine,
(S, S)-7-(cyclopropyl-methyl fluoride)-21-fluorine camptothecine,
(S, S)-7-cyclobutyl-21-fluorine camptothecine,
(S, S)-7-cyclopentyl-21-fluorine camptothecine,
(S, S)-7-cyclohexyl-21-fluorine camptothecine.
4. the compound described in any one of claims 1 to 3 is preparing the purposes in topoisomerase I inhibitor.
5. the purposes of the compound described in any one of claims 1 to 3 in the medicine of preparation treatment tumor disease.
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| WO1997016454A1 (en) * | 1995-11-02 | 1997-05-09 | Glaxo Wellcome Inc. | Method for preparing camptothecin derivatives |
| CN1301701A (en) * | 1999-11-18 | 2001-07-04 | 阿迪尔公司 | Camptothecine like compound, its preparing method and medicinal composition containing them |
| CN102250103A (en) * | 2011-05-19 | 2011-11-23 | 南京大学 | Synthesis method of SN38 or intermediate thereof |
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| WO1997016454A1 (en) * | 1995-11-02 | 1997-05-09 | Glaxo Wellcome Inc. | Method for preparing camptothecin derivatives |
| CN1301701A (en) * | 1999-11-18 | 2001-07-04 | 阿迪尔公司 | Camptothecine like compound, its preparing method and medicinal composition containing them |
| CN102250103A (en) * | 2011-05-19 | 2011-11-23 | 南京大学 | Synthesis method of SN38 or intermediate thereof |
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| Fluorine in Medicinal Chemistry;Hans-Joachim Bohm,等;《chembiochem》;20040503;第5卷(第5期);全文 * |
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