CN103288842A - Fluoro-substituted E cyclocamptothecin analogues and use thereof as drug - Google Patents
Fluoro-substituted E cyclocamptothecin analogues and use thereof as drug Download PDFInfo
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- CN103288842A CN103288842A CN201210043429XA CN201210043429A CN103288842A CN 103288842 A CN103288842 A CN 103288842A CN 201210043429X A CN201210043429X A CN 201210043429XA CN 201210043429 A CN201210043429 A CN 201210043429A CN 103288842 A CN103288842 A CN 103288842A
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Abstract
The invention relates to the technical field of medicines and in particular relates to fluoro-substituted E cyclocamptothecin analogues and use thereof as a drug. The structure of the compounds is shown in a formula I; and the compounds exist in forms of raceme, diastereoisomer as well as any mixture of the forms or medical salts thereof. The compounds disclosed by the invention have the effect of restraining the activity of the topoisomerase I and can be used for preparing anti-tumor drugs and also can be used for preparing drugs for preventing virus and fungal infection.
Description
Technical field
The present invention relates to medical technical field, relate to that fluorine replaces E ring camptothecin analogues and as the purposes of medicine, be specifically related to 21 deoxidation fluoric compounds of Cmptothecine E ring and as the purposes of medicine.
Background technology
Camptothecine (Camptothecin) is (J.Am.Chem.Soc.1966 such as Americanized scholar Wall in 1966,88,3888) a kind of alkaloid that from Chinese Nyssaceae plant camptotheca acuminata (Camtothecaacuminata), extracts, camptothecine is by indolizino [1,2-b] quinoline fragment and hexa-atomic-hydroxy-lactone condense the five rings rigid structure of composition, have-20 carbon of hydroxyl are asymmetric, it gives the MD characteristic.Its structure is as follows:
Camptothecine is to find the earliest, study at most, use the widest specificity topoisomerase I inhibitor (TopoI), also is the most classical TopoI specific inhibitor, and the various human tumor cell line is all shown good antineoplastic activity.Through structure activity study for many years, developed large quantities of camptothecin derivatives with using value, wherein irinotecan (Irinotecan, CPT-11) and topotecan (Topotecan, TPT) successively by FDA approval listing, Bei Nuo was ratified listing in 2004 by Korea S for health.
Studies show that in a large number that camptothecine compounds has efficiently, numerous advantages such as wide spectrum, selectivity are good, yet camptothecine still has shortcomings such as internal metabolism instability, water-soluble low, toxic action, species variation.Originally the investigator is prepared into carboxylate form with the open loop of camptothecine E ring and makes its raisings water-soluble, yet this change makes the active significantly reduction of camptothecine, and has caused its serious toxic side effect (CancerChemother.Rpt.1972,56,95).
Thereby be to improve camptothecine compounds stability enhanced activity in vivo, the investigator changes into prodrug with 20-position hydroxy ester, thereby so just can effectively stop the formation inhibition lactonic ring hydrolysis of 20 hydroxyls and adjacent carbonyl intramolecular hydrogen bond.1985, along with the discovery of camptothecine mechanism of action, it can specificly act on the DNA topoisomerase I, thereby had caused the second time upsurge of investigator to the camptothecine further investigation.1997, people such as OlivierLavergne proposed the brand-new camptothecin analogues with seven yuan of lactonic rings of beta-hydroxy of a class at WO97/00876, claim again high camptothecine (homocamptothecin, hCPT).It has not only strengthened anti-tumor activity, and have that species variation is little, toxic side effect is low, to the active advantages of higher of resistance antitumor cell, caused investigator's concern, present representational BN80915 (the diflomotecan) (ExpertOpin.Investig.Drugs.2009 that has, 18,69), BN80927 (CancerRes.2004,64,4942) etc., enter the II phase respectively, I phase clinical stage.2003, there is the investigator to synthesize alpha-hydroxy five-ring ketone again, have excellent anti-tumor activity and TopoI too and suppress active, and also representative compound enters clinical study (BioorgMedChemLett.2003,13,2731).
The camptothecin analogues of these E rings is than camptothecine, and internal metabolism stability improves really greatly, but part of compounds toxic side effect in various degree occurred in the clinical study stage, so that has influenced the further exploitation of such medicine.Therefore based on this kind reason, our seminar has carried out further structural modification transformation to the crucial E ring of camptothecine, in the hope of finding the antitumor drug candidate of active camptothecin more excellent, that metabolic stability good, toxic side effect is littler.Such novel compound of our research belongs to the novel compound of invention at home and abroad also without any report.
Summary of the invention
The objective of the invention is to, provide a kind of fluorine to replace E ring camptothecin analogues and as the purposes of medicine, to overcome the above-mentioned shortcoming and defect of existing in prior technology.
The present invention carries out the rational structure transformation in conjunction with toxic side effect in the body that causes owing to E ring metabolic stability difference of camptothecine to its E ring.According to the structure activity study result before the camptothecine, we have kept 20 hydroxyls that its activity is played a crucial role, and the ester carbonyl group of previous hexa-atomic lactonic ring is removed, the substitute is fluorine atom, we utilize the biological characteristics of fluorine atom to carry out structure of modification at this, 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, with and any mixture or its pharmaceutical salts of these forms, structure such 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, rudimentary cyano group alkyl, 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, 4 to 7 yuan of heterocyclic radicals of [N=X] expression nitrogen atom N, N is an atom of heterocyclic group, and X represents to constitute all the other atoms of these heterocycle needs, and they are selected from O, S, CH
2, CH, NR
7And COR
10), replacement or unsubstituted rudimentary aralkyl, wherein substituting group is low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group, perhaps R
2And R
3Form 3 or 4 yuan chain 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, replacement or unsubstituted rudimentary aralkyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy, lower alkoxy low alkyl group, perhaps R
2And R
3Form 3 or 4 yuan chain together, wherein the unit of this chain is selected from CH, CH
2, O, S or NR
11
R
5Expression low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, low-grade halogenated alkyl, lower alkoxy low alkyl group or lower alkylthio low alkyl group.
Preferred R
5The expression low alkyl group;
R
6Expression hydrogen, hydroxyl, nitro, cyano group, halogen.
Preferred R
6Expression hydroxyl, halogen;
R
7, R
8Represent hydrogen, low alkyl group, rudimentary hydroxyalkyl, the rudimentary amido alkyl of low alkyl group, rudimentary amido alkyl, cycloalkyl, cycloalkyl low-grade alkyl, low-grade alkenyl, lower alkoxy low alkyl group, low-grade halogenated alkyl or replacement or unsubstituted rudimentary aralkyl independently, wherein substituting group is low alkyl group, halogen, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group;
R
9, R
10Expression hydrogen, low alkyl group, rudimentary hydroxyalkyl, amino, low-grade alkyl amino, the rudimentary amido alkyl of low alkyl group, rudimentary amido alkyl, cycloalkyl, cycloalkyl low-grade alkyl, low-grade alkenyl, lower alkoxy, lower alkoxy low alkyl group, low-grade halogenated alkyl and or replace or do not replace rudimentary aralkyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group;
R
11Expression hydrogen, low alkyl group, low-grade halogenated alkyl, aryl or the aryl that is replaced by following one or more groups: low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group;
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 represents to finish the chain of described heterocyclic radical needs and is 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 to contain the low alkyl group that 1 to 3 halogen atom replaces; Rudimentary aralkyl is the low alkyl group that is connected with aryl.
In this article, the term " rudimentary " relevant with alkyl, alkylthio and alkoxyl group refers to contain the straight or branched saturated fatty hydrocarbyl group of 1 to 6 carbon atom, for example, 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 contain the group of 2 to 6 carbon atoms and the one or more pairs of keys or triple bond, for example: vinyl, allyl group, isoolefine propyl group, pentenyl, hexenyl, propenyl, ethynyl, proyl and butynyl.The term cycloalkyl refers to contain the ring of 3 to 7 carbon, for example, and cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Term aryl refers to list, two or the tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, and each ring contains maximum 7 carbon atoms, for example, and phenyl, naphthyl, anthryl, xenyl or indenyl.Term halogen refers to chlorine, bromine, iodine or fluorine.Corresponding to the term low-grade halogenated alkyl; rudimentary cyano group alkyl; rudimentary 4-nitro alkyl; rudimentary amido alkyl; rudimentary diazanyl alkyl; the lower alkoxy low alkyl group; rudimentary azido-alkyl; rudimentary aralkyl; rudimentary hydroxyalkyl; the group of the rudimentary alkylsulfonyl alkyl of lower alkylthio low alkyl group and 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 alkylsulfonyl alkyl replace.Low-grade alkyl amino can contain one or two low alkyl group, for example represents NHCH
3, NHCH
2CH
3, N (CH
3)
2Or CH
3NCH
2CH
3Formula (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 have kept the parent configuration of camptothecine, i.e. S configuration, and 21 carbon atoms have R and two kinds of configurations of S.This compounds just has S like this, R and S, and two diastereomers of S, these two diastereomers can obviously differentiate on thin layer plate, what is interesting is S, and the compound anti tumor activity in vitro of S configuration obviously is better than S, the R configuration.In the process of synthetic this compounds, we have also obtained 20 and 21 structures that two fluorine replace simultaneously, and the external activity test result in early stage shows that this type of antitumor activity of compound is relatively poor.The present invention includes enantiomorph configuration, diastereomer and their various combinations of these compounds.
The present invention also provides the preparation method of such novel camptothecin E ring analogues.Synthetic route is as follows:
With describe below and can prepare the formula I compound for the method that preferred compound of the present invention is given an example.
The different initial intermediate III that replace are to be obtained by camptothecine parent nucleus derivatize, can be 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 of then they being carried out 21 ester carbonyl groups obtains the dihydroxyl intermediate II, obtains our target compound at last under the effect of fluoro reagent.Be example with the camptothecine below, describe concrete synthesis step in detail:
1, for formula III compound, R
1, R
2, R
3, R
4When all being hydrogen, then initiator is the camptothecine parent nucleus just, and camptothecine is suspended in the specific solvent, adopts polarity or non-polar solvent such as methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF), acetic acid, toluene, benzene etc. usually, particular methanol or ethanol isopolarity solvent.The used reductive agent that reduces can be selected POTASSIUM BOROHYDRIDE, sodium borohydride, lithium aluminium hydride etc. for use, and our preferred especially POTASSIUM BOROHYDRIDE is as reductive agent at this.
2, intermediate II 21-hydroxycamptothecine is suspended in the suitable solvent, adopts polarity or non-polar solvent such as ethyl acetate, acetonitrile, tetrahydrofuran (THF), chloroform, methylene dichloride, toluene, benzene etc. usually, medium polar solvents such as preferred methylene dichloride or chloroform.Fluoro reagent can be selected 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 be in 0 ℃～-78 ℃ scopes, at this we preferred-50 ℃～-78 ℃.
Will be clear that and work as R
1, R
2, R
3, R
4When respectively replacement being arranged, adopting uses the same method also can obtain similar compounds, as: R
3When being methoxyl group, at first obtain 21-hydroxyl-10-Methoxycamptothecine; R
3, R
4Be 21-hydroxyl-10,11-difluoro camptothecine when all having F to replace; R
3, R
4Become ethylenedioxy, namely get 21-hydroxyl-10,11-ethylenedioxy camptothecine.Just can get the camptothecin analogues of corresponding E ring acetal then by above-mentioned route.
Some compound of the present invention can be prepared as the form of pharmaceutical salts according to ordinary method.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., and 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.
Formula I compound of the present invention has the effect that suppresses topoisomerase, and has anti-tumor activity.Prior art hints 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, with and any mixture or its pharmaceutical salts of these forms, the application in preparation topoisomerase I inhibitor.
Formula I compound of the present invention has the effect that suppresses topoisomerase, and has anti-tumor activity.Prior art hints 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 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 take place, and thyroid carcinoma, leukemia, king's evil, lymphoma and myelomatosis etc. suddenly.
As a fourth aspect of the present invention, fluorine of the present invention replaces E ring camptothecin analogues for the preparation of the application in the medicine for the treatment of virus infection and fungi infestation.
The pharmacologically active of The compounds of this invention makes it can be for the preparation of antitumor, antimycotic and antiviral, so the present invention also comprises with these compounds and pharmaceutical salts thereof the pharmaceutical composition as 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 that suppresses topoisomerase, have anti-tumor activity, antiviral activity and anti-mycotic activity, can be used for preparing antitumor, antimycotic and antiviral.The present invention also comprises formula I compound, comprise its racemic modification, diastereomer with and any mixture or its pharmaceutical salts of these forms, purposes aspect the following medicine of preparation: medicine, the antitumor drug, antifungal drug and the antiviral aspect that suppress topoisomerase.
Beneficial effect of the present invention: the present invention is that the crucial E ring to camptothecine has carried out further structural modification transformation, prepares the antitumor drug candidate of active camptothecin more excellent, that metabolic stability good, toxic side effect is littler.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples are only for explanation the present invention but not for limiting scope of the present invention.
The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition that manufacturer provides is carried out.
Embodiment 1,21-hydroxycamptothecine
The 1.00g camptothecine is suspended in the methyl alcohol of 50mL, stir after 5 minutes under the room temperature, add the 0.30g POTASSIUM BOROHYDRIDE, continue reaction 1h under the room temperature, reaction solution clarification this moment, boil off solvent and get the light green solid, add 50mL water and make it dissolving, it is acid regulating PH with acetic acid then under ice-water bath, separates out a large amount of solids this moment, the suction filtration washing, vacuum-drying gets 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)。
Synthesizing of embodiment 2,10-methoxyl group-21-hydroxycamptothecine
The 1.00g10-methoxycamptothecine is suspended in the methyl alcohol of 50mL, stir after 5 minutes under the room temperature, add the 0.30g POTASSIUM BOROHYDRIDE, continue reaction 1h under the room temperature, reaction solution clarification this moment, boil off solvent and get the light green solid, add 50mL water and make it dissolving, it is acid regulating PH with acetic acid then under ice-water bath, separates out a large amount of solids this moment, the suction filtration washing, vacuum-drying gets 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)。
Synthesizing of embodiment 3,9-nitro-21-hydroxycamptothecine
The 1.00g9-nitrocamptothecin is suspended in the methyl alcohol of 50mL, stir after 5 minutes under the room temperature, add the 0.30g POTASSIUM BOROHYDRIDE, continue reaction 1h under the room temperature, reaction solution clarification this moment, boil off solvent and get the light green solid, add 50mL water and make it dissolving, it is acid regulating PH with acetic acid then under ice-water bath, separates out a large amount of solids this moment, the suction filtration washing, vacuum-drying gets 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)。
Synthesizing of embodiment 4,7-normal-butyl-21-hydroxycamptothecine
1.00g7-butyl camptothecine is suspended in the methyl alcohol of 50mL, stir after 5 minutes under the room temperature, add the 0.30g POTASSIUM BOROHYDRIDE, continue reaction 1h under the room temperature, reaction solution clarification this moment, boil off solvent and get the light green solid, add 50mL water and make it dissolving, it is acid regulating PH with acetic acid then under ice-water bath, separates out a large amount of solids this moment, the suction filtration washing, vacuum-drying gets 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 extremely-70 ℃ of dry ice acetone cooling reaction solutions; after stirring 10min, inject the diethylin sulfur trifluoride (DAST) of 0.1mL in the solution fast, remove cooling; behind the room temperature reaction 40min; the TLC analytical reaction are complete, add the methylene dichloride dilution of 20mL this moment, and then add 10% the sodium bicarbonate aqueous solution of 30mL; after stirring 15min; layering, water merges organic phase with methylene dichloride (20mL * 2) extraction; anhydrous sodium sulfate drying; filter, boil off solvent, with silica gel chromatographic column (eluent: CH
2Cl
2/ CH
3OH100: 1) separate obtain the 80mg faint yellow solid (S, S)-21-fluorine camptothecine, [α]
D 20=+511 (c 0.07, 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, separate the 70mg faint yellow solid (S, R)-21-fluorine camptothecine, [α]
D 20=+1275 (c 0.05, 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, separate the 30mg faint yellow solid (R, S)-20,21-difluoro camptothecine, [α]
D 20=+201.1 (c 0.056, 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 the 21-hydroxycamptothecine with 9-nitro-21-hydroxycamptothecine, get the 110mg faint yellow solid (S, S)-9-nitro-21-fluorine camptothecine, [α]
D 20=+437.1 (c 0.07, 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 the 21-hydroxycamptothecine with 7-ethyl-10-methoxyl group-21-hydroxycamptothecine, get the 90mg faint yellow solid (S, S)-7-ethyl-10-methoxyl group-21-fluorine camptothecine, [α]
D 20=+383 (c 0.086, 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 the 21-hydroxycamptothecine with 10-methoxyl group-21-hydroxycamptothecine, get the 70mg yellow solid (S, S)-10-methoxyl group-21-fluorine camptothecine, [α]
D 20=+854.1 (c 0.056, 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 the 21-hydroxycamptothecine with 10-benzyloxy-21-hydroxycamptothecine, get the 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
With 50mg (S, S)-10-benzyloxy-21-fluorine camptothecine is suspended in the ethanol of 15mL, adds the Pd-C of 10mg10%, pours hydrogen, reacts 12h under the room temperature, core filters, boil off solvent obtain 30mg (S, S)-10-hydroxyl-21-fluorine camptothecine, [α]
D 20=+224 (c 0.09, 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 the 21-hydroxycamptothecine with 7-ethyl-10-benzyloxy-21-hydroxycamptothecine, get the 145mg yellow solid (S, S)-7-ethyl-10-benzyloxy-21-fluorine camptothecine, [α]
D 20=+159.5 (c 0.15, 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, with (S, S)-7-ethyl-10-benzyloxy-21-fluorine camptothecine replace (S, S)-10-benzyloxy-21-fluorine camptothecine, get 25mg (S, S)-7-ethyl-10-hydroxyl-21-fluorine camptothecine, [α]
D 20=+422.4 (c 0.083, 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 the 21-hydroxycamptothecine with 7-methyl-21-hydroxycamptothecine, get the 130mg faint yellow solid (S, S)-7-methyl-21-fluorine camptothecine, [α]
D 20=+918 (c 0.033, 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 the 21-hydroxycamptothecine with 7-ethyl-21-hydroxycamptothecine, get the 105mg yellow solid (S, S)-7-ethyl-21-fluorine camptothecine, [α]
D 20=+290.7 (c 0.043, 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 the 21-hydroxycamptothecine with 7-propyl group-21-hydroxycamptothecine, get the 135mg faint yellow solid (S, S)-7-propyl group-21-fluorine camptothecine, [α]
D 20=+151.5 (c 0.063, 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 the 21-hydroxycamptothecine with 7-butyl-21-hydroxycamptothecine, get the 120mg faint yellow solid (S, S)-7-butyl-21-fluorine camptothecine, [α]
D 20=+236.5 (c 0.056, 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 the 21-hydroxycamptothecine with 7-sec.-propyl-21-hydroxycamptothecine, get the 90mg faint yellow solid (S, S)-7-sec.-propyl-21-fluorine camptothecine, [α]
D 20=+132.4 (c 0.096, 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 the 21-hydroxycamptothecine with 7-(cyclopropyl-methylol)-21-hydroxycamptothecine, get the 70mg faint yellow solid (S, S)-7-(cyclopropyl-methyl fluoride)-21-fluorine camptothecine, [α]
D 20=+739.5 (c 0.07, 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 the 21-hydroxycamptothecine with 7-cyclobutyl-21-hydroxycamptothecine, get the 70mg faint yellow solid (S, S)-7-cyclobutyl-21-fluorine camptothecine, [α]
D 20=+683.1 (c 0.043, 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 the 21-hydroxycamptothecine with 7-cyclopentyl-21-hydroxycamptothecine, get the 70mg faint yellow solid (S, S)-7-cyclopentyl-21-fluorine camptothecine, [α]
D 20=+304.6 (c 0.043, 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 the 21-hydroxycamptothecine with 7-cyclohexyl-21-hydroxycamptothecine, get the 70mg faint yellow solid (S, S)-7-cyclohexyl-21-fluorine camptothecine, [α]
D 20=+325.4 (c 0.086, 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
Compound of the present invention has been carried out the tumor cell proliferation inhibition test, and test method adopts conventional mtt assay (as Lv Qiujun chief editor " developmental pharmacology research method ", 2007:242-243).
Cell strain is selected 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) for use, and is frozen and go down to posterity by Shanghai Institute of Pharmaceutical Industry pharmacological evaluation chamber.Nutrient solution is that RPMI1640+15%NBS+ is two anti-.
MTT solution preparation: take by weighing the MTT0.5 gram, be dissolved in the phosphoric acid buffer (PBS) of 100ml or do not have in the phenol red substratum,, put 4 ℃ and keep in Dark Place to remove the bacterium in the solution with 0.22 μ m membrane filtration.
Sample liquid preparation: after DMSO (Merck) dissolving, adding PBS (-) is made into solution or the uniform suspension of 100 μ g/mL, use PBS (-) dilution of DMSO then, 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.
Antitumor drug topotecan (TPT) and the irinotecan (IRT) of listing are made into reference substance solution with same condition.
Mtt assay: it is 4-6 * 10 that the every hole of 96 orifice plates adds concentration
4The cell suspension 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and the 570nmOD value is surveyed with the full-automatic microplate reader of MK-2 in the dissolving back.Calculation of half inhibitory concentration IC
50
Test-results sees Table 1 and table 2, and wherein, sample refers to the high camptothecine compounds (for example embodiment 4 is the high camptothecine of 7-(4-nitrophenyl) vinyl) for preparing among the 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 that compound of the present invention has good antineoplastic activity, and a plurality of compounds are higher than the marketed drug topotecan, so The compounds of this invention and its esters can be for the preparation of antitumor drugs.
More than show and described 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; that describes in above-described embodiment and the 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.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (5)
1. fluorine replaces E ring camptothecin analogues, comprises its racemic modification, diastereomeric form, with and any mixture or its pharmaceutical salts of these forms, structure is 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, low-grade alkenyl, cyano group, rudimentary cyano group alkyl, 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, 4 to 7 yuan of heterocyclic radicals of [N=X] expression nitrogen atom N, N is an atom of heterocyclic group, and X represents to constitute all the other atoms of these heterocycle needs, and they are selected from O, S, CH
2, CH, NR
7And COR
10), replacement or unsubstituted rudimentary aralkyl, wherein substituting group is low alkyl group, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group, perhaps R
2And R
3Form 3 or 4 yuan chain together, wherein the unit of this chain is selected from CH, CH
2, O, S or NR
11R
5Expression low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, low-grade halogenated alkyl, lower alkoxy low alkyl group or lower alkylthio low alkyl group;
R
6Expression hydrogen, hydroxyl, nitro, cyano group, halogen;
R
7, R
8Represent hydrogen, low alkyl group, rudimentary hydroxyalkyl, the rudimentary amido alkyl of low alkyl group, rudimentary amido alkyl, cycloalkyl, cycloalkyl low-grade alkyl, low-grade alkenyl, lower alkoxy low alkyl group, low-grade halogenated alkyl or replacement or unsubstituted rudimentary aralkyl independently, wherein substituting group is low alkyl group, halogen, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group;
R
9, R
10Expression hydrogen, low alkyl group, rudimentary hydroxyalkyl, amino, low-grade alkyl amino, the rudimentary amido alkyl of low alkyl group, rudimentary amido alkyl, cycloalkyl, cycloalkyl low-grade alkyl, low-grade alkenyl, lower alkoxy, lower alkoxy low alkyl group, low-grade halogenated alkyl and or replace or do not replace rudimentary aralkyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group;
R
11Expression hydrogen, low alkyl group, low-grade halogenated alkyl, aryl or the aryl that is replaced by following one or more groups: low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or lower alkoxy low alkyl group;
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 represents to finish the chain of described heterocyclic radical needs and is 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 to contain the low alkyl group that 1 to 3 halogen atom replaces; Rudimentary aralkyl is the low alkyl group that is connected with aryl.
2. according to the described compound of claim 1, it is characterized in that described R
5Be ethyl, described R
6Be hydroxyl, fluorine atom.
3. according to the described compound of claim 1, it is characterized in that described 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.
4. the arbitrary compound in the claim 1 to 3 is selected from its racemic modification, diastereomeric form, with and any mixture or its pharmaceutical salts of these forms, the application in preparation topoisomerase I inhibitor.
5. the arbitrary compound in the claim 1 to 3, the application in the medicine of preparation treatment tumor disease.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111533753A (en) * | 2020-04-28 | 2020-08-14 | 中国人民解放军海军军医大学 | Carbamate fluoro camptothecin compound and application thereof |
| CN112500412A (en) * | 2020-12-14 | 2021-03-16 | 中国人民解放军空军军医大学 | Penamine A alkaloid structure simplification compound and application 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 |
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| WO1997016454A1 (en) * | 1995-11-02 | 1997-05-09 | Glaxo Wellcome Inc. | Method for preparing camptothecin derivatives |
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| CN111533753A (en) * | 2020-04-28 | 2020-08-14 | 中国人民解放军海军军医大学 | Carbamate fluoro camptothecin compound and application thereof |
| CN112500412A (en) * | 2020-12-14 | 2021-03-16 | 中国人民解放军空军军医大学 | Penamine A alkaloid structure simplification compound and application thereof |
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