CN102153607B - Water soluble camptothecin derivative and medicinal composition containing same - Google Patents
Water soluble camptothecin derivative and medicinal composition containing same Download PDFInfo
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- CN102153607B CN102153607B CN201010111584.1A CN201010111584A CN102153607B CN 102153607 B CN102153607 B CN 102153607B CN 201010111584 A CN201010111584 A CN 201010111584A CN 102153607 B CN102153607 B CN 102153607B
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- 0 B=C([C@@]1(*)C*=C)O[C@](C*)[C@]1O* Chemical compound B=C([C@@]1(*)C*=C)O[C@](C*)[C@]1O* 0.000 description 2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to a water soluble derivative of camptothecin and a preparation method thereof. The derivative has a structure shown in a formula (I). The derivative of the camptothecin has improved anticancer activity.
Description
Technical field
The present invention relates to field of medicaments, relate more specifically to anticarcinogen field, relate more specifically to the medicine based on camptothecine.
Background technology
Camptothecine (CPT) is a kind of cytotoxic alkaloid, its at first by Wall and colleagues thereof from a kind of primary in the plant of China---camplotheca acuminata (Camptotheca accuminata, Nyssaceae) isolate in leaf and bark and confirm (J.Am.Chem.Soc.88,3888,1966).The main cell target spot of CPT is topoisomerase I (topo I), and this enzyme participates in DNA replication dna process to be sheared by the transient single strand of two DNA, unwind and the relexation of the supercoil DNA be connected again.CPT, at the interface cohesion of covalency binary topo I-DNA mixture, forms stable ternary complex, and its prevention connects again, therefore causes the double-strand break and the DNA damage that copy mediation.Because CPT suppresses the necrocytosis of the S phase that can cause in cell cycle, CPT has become focus (Nature Review/Cancer, October 2006Vol.6, the pp789-802 of a further investigation in anticarcinogen exploitation; Bioorg.Med.Chem., 2004,12, pp1585-1604).
Natural CPT has a five ring structures be made up of the fused ring system of quinoline ring (ring A and B), tetramethyleneimine (ring C), α-pyridone (ring D) and a hexa-atomic lactonic ring (ring E).CPT only has an asymmetric center in 20-position, and demonstrates dextrorotation due to the S-configuration of tert-hydroxyl.At PH7 or more, this lactonic ring is hydrolyzed and obtains carboxylic acid derivative, this be one the hydrolytic process that promotes by the hydrogen bond on 20 (S)-OH and E-ring between carbonyl.The unstable (it can aggravate in physiological conditions, and in physiological conditions, this carboxylic acid derivative preferential (high 150 times) is attached to human serum protein) of E-ring hinders CPT as the main restriction of the clinical application of anti-cancer chemotherapeutic agents.This carboxylic acid derivative of CPT is not only biological inactive and toxicity is very high clinically.CPT is the water-soluble of its difference as another defect of drug molecule.Water insoluble or other the aquosity medium of suitable administered parenterally of natural CPT.For above-mentioned reasons, CPT is made its water-soluble carboxyl acid derivative less feasible.As can be seen here, improve lactone stability in vivo and water-soluble be the focus (Bioorg.Med.Chem., 2004,12, the pp1585-1604 that make great efforts based on the anticarcinogen research and development Chinese traditional medicine chemistry of CPT;
chem.Rev., 2009,109 (1), pp 213 – 235).
It is presently believed that the hydrolysis of E-cyclic lactone is by 20 (S)-between hydroxyl and adjacent carbonyl, interaction of hydrogen bond promotes.Earlier trials shows, by replacing this 20 (S)-hydroxyl with other groups of such as methyl or can obtaining E-cyclic lactone stable in physiological conditions with this 20 (S)-hydroxyl of protective group of such as ester.But because this 20 (S)-hydroxyl is most important for the pharmaceutical activity of camptothecine, this hydroxyl protection makes medicine be difficult to play antitumour activity in human body.
Prodrug strategies is that a good introducing ionizable functional groups is to improve the water miscible method of gained prodrugs.In this case, the CPT of insoluble in water is converted into water-soluble CPT prodrug by this prodrug strategies.Because this water-soluble CPT prodrug short period of time after feeding blood vessel spreads to whole body rapidly, these CPT prodrugs are exist with very low concentration when degrading, and this avoid CPT precipitation in the blood vessel.Obviously, this prodrug strategies can realize lactone stability, administration easily that is water-soluble and that develop for CPT anticarcinogen.
Trial for preparation CPT prodrug and CPT based compound has been reported, and wherein, the overwhelming majority introduces various protection functional group with the esterification of 20 (S)-hydroxyls, comprises oleophylic and ionizable functional group
(Chem.Rev., 2009,109 (1), pp 213 – 235).Ester prodrugs is be present in by one group to be called that the enzyme of esterase mediates in many animals (comprising people) blood to the conversion of natural CPT.The weakness of ester prodrugs is that ester chain is bad at people's vivo physiological conditions stability inferior, is too easily interrupted by esterase, and the clinical effectiveness of CPT ester prodrugs is undesirable (Chem.Rev., 2009,109 (1), pp 213 – 235).In addition, existing people prepares 20 (the S)-O-phosphoric acid of CPT or simple phosphonic acid ester to increase lactone stability water-soluble and in vivo.But through experimental verification, 20 (S)-O-phosphoric acid or simple phosphonic acid ester can not change into CPT in physiological conditions, and therefore they can not be used as CPT prodrug (Organic Lett., 2004,6 (3), pp321-324).20 (S)-O-phosphoric acid or the simple phosphate derivatives itself of CPT do not have antitumour activity.
Therefore, still need in prior art to find such CPT prodrug, it has suitable water-soluble, and has suitable enzymolysis activity in physiological conditions to discharge CPT activeconstituents.
Summary of the invention
An object of the present invention is to provide new CPT derivative, it has suitable lactonic ring stability and suitable water-soluble.
Another object of the present invention is to provide a kind of new CPT derivative, and it can discharge the CPT composition with antitumour activity in physiological conditions.
Another object of the present invention is to provide a kind of new CPT derivative, and it can discharge in physiological conditions and comprise the composition that CPT two kinds has antitumour activity, embodies synergistic effect.
Another object of the present invention is to provide a kind of method being prepared above-mentioned 20 (S)-O-Nucleotide CPT derivative by phosphoramidite chemistry.
Another object of the present invention is to provide a kind of method by phosphinate chemical preparation above-mentioned 20 (S)-O-Nucleotide CPT derivative.
Another object of the present invention is to provide a kind of method of some kind cancer for the treatment of of improvement.
In order to realize these objects and consistent with object of the present invention, as embodiment of the present invention and wide in range description, the present invention relates to formula I or the acceptable salt of its pharmacology herein:
Wherein, M representation hydroxy or sulfydryl, A is ribose or ribodesose, or ribose derivates, and wherein, described part A is connected with phosphorus atom by a hydroxyl oxygen atom.
In optimal way of the present invention, described camptothecin derivative has the structure of formula II ',
Wherein, M representation hydroxy or sulfydryl, R1 represents the part of H, C1-C4 acyl group or activity of enzyme reaction,
R2, R3 can be identical or different, represent H, halogen, hydroxyl, alkoxyl group or activity of enzyme reaction part independently;
B is hydrogen, substituted or unsubstituted thymus pyrimidine, substituted or unsubstituted VITAMIN B4, substituted or unsubstituted cytosine(Cyt), substituted or unsubstituted guanine, substituted or unsubstituted uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 2-fluoroadenine, 2-chloroadenine, or
B is different from the heteroaryl of VITAMIN B4, thymus pyrimidine, cytosine(Cyt) or guanine or heteroalicyclyl and preferably has 1-3 monocycle and 1-3 N, O or S atom.
Preferably, the thymus pyrimidine that B is replaced by following group, VITAMIN B4, uridylic, cytosine(Cyt) or guanine: alkyl, aryl or heteroaryl or heteroalicyclyl, wherein said heteroaryl or heteroalicyclyl have 1-3 monocycle or condensed ring and 1-3 N, O or S atom.
In a preferred embodiment of the invention, M is hydroxyl.In following embodiment, unless stated otherwise, M is hydroxyl, and it represents with formula II:
In a kind of embodiment, R1 is acyl group, is more preferably ethanoyl.
More preferably, R1=R2=R3=H, B=H, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 3,4,7,8-imidazolidine [1,3] diazepine-8 alcohol, 2-fluoroadenine or 2-chloroadenine.
In another preferred embodiment, R1=R3=H, R2=OH, B=H, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5-azepine cytosine(Cyt).
In another preferred embodiment, R1=Ac, R2=R3=H, B=H, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5-azathymine, 2-chloroadenine, wherein, a hydrogen in amino is replaced by ethanoyl.
In another preferred embodiment, R1=Ac, R2=F, R3=H, B=2-chloroadenine, wherein, a hydrogen in amino is replaced by ethanoyl.
In another preferred embodiment, R1=Ac, R2=H, R3=OAc, B=2-fluoroadenine, wherein, a hydrogen in amino is replaced by ethanoyl.
In another preferred embodiment, R1=Ac, R3=H, R2=OAc, B=H, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5-azathymine, wherein, in amino, a hydrogen is replaced by ethanoyl.
The invention still further relates to the method being used for the treatment of mammiferous malignant tumour or cancer, comprise one or more the composition contained in above-mentioned formula I giving significant quantity.
Camptothecin derivative provided by the invention not only has be suitable for that administration and medicine send in vivo water-soluble, and improves the stability of camptothecine lactonic ring, reduces drug toxicity.
A part in other objects of the present invention and advantage will hereafter describe in detail, and a part will be become apparent by these explanations, or can know from enforcement of the present invention.
Accompanying drawing explanation
Fig. 1 .Dix-905 in H1693 cell than CPT better trigger cell kill response.
Fig. 2, due to synergistic effect, Dix-905 process creates kills cell ability byer force than CPT, floxuridine and etoposide in H1693 cell.
Fig. 3 .Dix-905 causes the necrocytosis according to time and dosage by Caspase activation (apoptosis pathway) in H1693.
The cell that Fig. 4 .Dix-905 causes in H146 kills response and is better than CPT.
What Fig. 5 .Dix-905 caused in H146 kill cell ability is better than CPT, floxuridine and etoposide.
Fig. 6 .Dix-905 causes the necrocytosis according to time and dosage by Caspase activation (apoptosis pathway) in H146.
What Fig. 7 .Dix-905 caused in HCT116 colon cell kill cell ability is better than CPT, floxuridine and etoposide.
The necrocytosis according to dosage of Fig. 8 .Dix-905 and CPT in HCT116 cell.
Embodiment
Definition
Term " ribose derivates " refers to the derivative containing ribose or ribodesose carbon skeleton, and the H on the H on one or more ring carbon atom or one or more hydroxyl is replaced by other groups.Other groups described here are selected from by thiazolinyl, alkynyl, alkoxyl group, cycloalkyl, cycloalkenyl group, acyl group, amido, acyloxy, amino, aminocarboxyl, alkoxycarbonyl amino, azido-, cyano group, halogen, hydroxyl, ketone group, thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclethio, thiol, alkylthio, aryl, aryloxy, heteroaryl, amino-sulfonyl, amino carbonyl amino, heteroaryloxy, heterocyclic radical, heterocyclic oxy group, hydroxylamino, alkoxy amino, nitro,-SO-alkyl,-SO-aryl,-SO-heteroaryl,-SO
2-alkyl ,-SO
2-aryl ,-SO
2the group of-heteroaryl, base and base analogue composition.
Unless stated otherwise, term " base " has general sense biologically, comprises purine and pyrimidine, such as VITAMIN B4, guanine, thymus pyrimidine, cytosine(Cyt) or uridylic.
Term " base analogue " refers to have 1-3 monocycle and 1-3 N, O or S atom, and its ring skeleton structure is different from VITAMIN B4, thymus pyrimidine, cytosine(Cyt) or guanine, wherein preferably monocycle or two fused ring heterocycle aromatic hydrocarbons.The mix example of aromatic hydrocarbons of monocycle comprises pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, furans, [1,2,4] oxadiazoles, [1,3,4] oxadiazoles, [1,2,4] thiadiazoles, [1,3,4] thiadiazoles, the example of two fused ring heterocycle aromatic hydrocarbons comprises indazole, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthlypyridine, quinoxaline, quinolizine, and the example of single assorted cycloalphatic hydrocarbon and two fused ring heterocycle fat hydrocarbon comprises complete hydride or the partial hydrogenation thing of the above-mentioned material enumerated.Term " nucleosides " refers to the glycoside compounds be formed by connecting by the first carbon atom of base and ribose or ribodesose, and it comprises ribonucleoside and dezyribonucleoside.
Nucleoside analog: refer to the nucleoside derivates that on the pentose moiety in nucleosides and/or the one or more carbon in base, on H, nitrogen, H or hydroxyl H is substituted, and there is the analogue of following base: this base is not VITAMIN B4, thymus pyrimidine, cytosine(Cyt) or guanine, but other the heteroaryl with 1-3 monocycle and 1-3 N, O or S atom or heteroalicyclyl.
Term " alkyl " refers to the unit price side chain or unbranched saturated hydrocarbon chain with 1-5 carbon atom, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.
Term " alkoxyl group " refers to radicals R-O-, and wherein R refers to alkyl defined above, and this alkyl replaced by halogen, hydroxyl, amino alternatively.The example of alkoxyl group includes but not limited in methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, neo-pentyl oxygen base, trifluoromethoxy etc.
Term " aryl " refers to the aromatic carbocyclic group of 6 to 18 carbon atoms, and it has monocycle (such as, phenyl) or many rings (such as, xenyl) or many condensed ring (such as, naphthyl or anthryl).Preferred aryl comprises phenyl, naphthyl etc.
Term " heteroaryl " refers to the group derived from aromatic group (that is, completely undersaturated), and it has 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15 carbon atoms, and 1,2,3 or 4 annular atoms at least one ring is selected from the heteroatoms of oxygen, nitrogen and sulphur.Such heteroaryl groups can have monocycle (such as, pyridyl or furyl) or multiple condensed ring (such as, indolizine base (indolizinyl), benzothiazolyl or benzothienyl).The example of heteroaryl includes but not limited to: [1, 2, 4] oxadiazoles, [1, 3, 4] oxadiazoles, [1, 2, 4] thiadiazoles, [1, 3, 4] thiadiazoles, pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthlypyridine, quinoxaline, quinolizine, cinnolines (cinnoline), pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene, isoxazole, phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline etc., and containing heteroaryl compound as the N-oxide compound of pyridine-N-oxide derivative and N-alkoxy derivative.
Term " heteroalicyclyl " refers to that in wherein 1-5 ring, carbon atom is selected from the heteroatoms of nitrogen, sulphur, phosphorus and/or oxygen, saturated or the part unsaturated group of the unit price of the C3-C7 monocycle that a preferred 1-3 heteroatoms substitutes or 2-3 condensed ring, when it is condensed ring, has and be no more than 16 carbon atoms.Such as tetrahydrofuran base, morpholinyl, piperidyl, piperazinyl, dihydropyridine base etc.
Term " Nucleotide " refers to that 5 '-hydroxyl connects the nucleosides of phosphoric acid.
Term " polynucleotide " refers to that more than 2 nucleosides are by 5 '-3 ' order connected by phosphate bond, and its terminal 5 '-hydroxyl connects phosphoric acid.
Term " activity of enzyme reaction (enzymatically reactive) part " refers in vivo under physiological condition; the functional group of hydroxyl can be produced after enzymatic reaction; it is hydroxy-protective group normally, such as Nucleotide or poly-dinucleotides, acyl group, amide group.
" camptothecine prodrug " or " CPT prodrug " refers to the camptothecin derivative with biodegradable 20 (S)-hydroxy-protective groups.In physiological conditions, the blocking group of these biodegradable 20 (S)-hydroxyls is by the slowly cracking and discharge the camptothecine of pharmaceutical activity of specific enzyme.
The present invention is based on such strategy; with 20 (the S)-hydroxyls of specific protective group CPT; make E cyclic lactone have certain stability, and the prodrug obtained in physiological conditions can by enzymatic lysis (biodegradable), to discharge CPT composition.
The present invention relates to new water-soluble 20 (S)-O-Nucleotide CPT derivative and pharmacologically acceptable salts thereof, this CPT derivative has the chemical structure of formula I.
Wherein, M representation hydroxy or sulfydryl, A is nucleosides or its analogue.
In a kind of embodiment of the present invention, described 20 (S)-O-Nucleotide CPT derivative has the chemical structure of formula II '.
Wherein, M representation hydroxy or sulfydryl, wherein preferred hydroxyl; R1 represents H; C1-C4 acyl group, wherein preferred ethanoyl; The polynucleotide of optional replacement, wherein preferred poly-dinucleotides, or activity of enzyme reaction (particularly cleavable) part, such as-RCOOR ' and-NHCOR, wherein R and R ' is C1-C4 alkyl or alkenyl, such as C2 or C3 thiazolinyl;
R2, R3 can be identical or different, represent H, halogen, hydroxyl, alkoxyl group or by the hydroxyl having (particularly cleavable) group (as acetyl) of activity of enzyme reaction to protect independently;
B is thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 2-fluoroadenine, 2-chloroadenine, hydrogen, the thymus pyrimidine of optional replacement, the VITAMIN B4 of optional replacement, the cytosine(Cyt) of optional replacement or the guanine of optional replacement, here, substituting group for optional replacement is preferably alkyl, aryl, or heteroaryl or heteroalicyclyl, wherein, described heteroaryl or heteroalicyclyl preferably have 1-3 monocycle or 1-3 condensed ring and each ring have 1-3 N, O or S atom, or B is not VITAMIN B4, thymus pyrimidine, cytosine(Cyt) or guanine, but there is 1-3 monocycle and 1-3 N, the heteroaryl of O or S atom or heteroalicyclyl.In above-mentioned formula I and formula II, the amino in part A and hydroxyl can also protect by blocking group known in the art.Blocking group preferably for amino comprises ethanoyl, benzene (first) acyl group, isobutyryl, tertbutyloxycarbonyl, formyl radical, benzyl, p-methbxybenzyl-oxycarbonyl, trityl etc.Blocking group preferably for hydroxyl comprises ethanoyl, trifluoroacetyl group, valeryl, benzene (first) acyl group, alkyl-carbonyl, alkyl, methyl, methoxymethyl, benzyloxymethyl, benzyl, trimethyl silyl, t-Butyldimethylsilyl etc.Other suitable blocking groups well known by persons skilled in the art are disclosed in Greene, T., Wuts; P.G.M.; Protective Groups in Organic Synthesis, in Wiley (1999), its content disclosed is incorporated to herein with reform.Preferably comprise enzymic activity (particularly cleavable) part, such as acid amides, ester etc. for hydroxyl and amino blocking group.
In a preferred embodiment of the invention, in previously described formula I and formula II, nucleoside moiety represents FdUrd (floxuridine), thymidine, cytidine, guanosine, adenosine, 1 ', 2 '-ribodesose, Decitabine, azacitidine, gemcitabine, floxuridine, chlorine cut down and draw shore, CldAdo, spray Xi Tading, and wherein, 5 '-oxygen of these nucleoside analogs is covalently attached to phosphorus atom.In formula II, nucleoside moiety preferably has the array configuration of R2, R3 and the B listed in table 1.The nucleosides here listed or a part for nucleoside analog have been proved to be harmless in this medicine potent agent amount, such as thymidine, cytidine, guanosine, adenosine etc.; Another part uses clinically as cancer therapy drug, and such as floxuridine, chlorine cut down and draws shore, CldAdo, spray Xi Tading etc.
The present invention be more preferably in, there is in table 1 array configuration of listed R2, R3 and B.
As mode described in his-and-hers watches 1 further preferably, for the R1 in formula II ', be preferably H or ethanoyl.
Table 1.
In preferred implementation described in table 1, the hydroxyl in part A and/or the H on amino can be unsubstituted, also can be replaced by acyl group, halogen, such as, are replaced by ethanoyl, chlorine, fluorine.Therefore, as the more specifically aspect of above-mentioned optimal way, formula II compound according to the present invention comprises following concrete material:
The camptothecin derivative of above-mentioned formula I and formula II can be used as the prodrug of camptothecine.Formula I and formula II prodrug can be called what the enzyme of phosphodiesterase mediated by one group to the conversion of corresponding camptothecine and the acid of 5 '-phosphoric acid nucleoside in Mammals.The present invention disclose formula I and be namely rapidly spread widely Whole Body in the short period of time of formula II compound after being administered into blood vessel, then by phosphodiesterase change into camptothecine and 5 '-phosphoric acid nucleoside acid (when B not for H time).
According to above-mentioned camptothecin derivative of the present invention, there is the stability of well water-soluble and camptothecine lactonic ring, its generation camptothecine of can degrading in physiological conditions.Derivative of the present invention avoids camptothecine precipitation in blood, not only reduces toxicity, and improves curative effect.
Of the present invention preferred in, when B is nucleoside analog, the second active compound can also be produced in physiological conditions according to CPT derivative of the present invention.There will be a known a lot of nucleoside analog there is anti-tumor activity and be used as carcinostatic agent clinically, include but not limited to floxuridine (floxuridine), Decitabine (decitabine), azacitidine (azacitidine), gemcitabine (gemcitabin), clofarabine (clofarabine), carat surrender shore (cladribine), pentostatin (pentostatin).All these Nucleotide all require to be phosphorylated just has antitumor drug effect (molecule mechanism mainly plays metabolic antagonist and DNA replication dna inhibitor) afterwards.Therefore, nucleotide structure is incorporated in CPT derivative of the present invention, likely improves the result for the treatment of of medicine.
The preparation of 20 (S)-O-Nucleotide camptothecin derivative of formula II of the present invention is preferably as being undertaken by phosphoramidite chemistry of describing in scheme 1.When M is sulfydryl, the synthesis of similar method can be adopted, just in the end use Beaucage reagent in single step reaction.
Scheme 1
In scheme 1, utilize CPT 20 (S)-O-phosphoramidite intermediate, mainly comprise the following steps:
(1) make CPT and amino phosphoryl chloride (phosphoramidic chloride) react, generate CPT 20 (S)-O-phosphoramidite intermediate;
(2) make CPT 20 (S)-O-phosphoramidite intermediate contact with formula III compound, generate 20 (S)-O-tris phosphite precursor;
Wherein, as hereinbefore defined, wherein, when existing amino in B, this amino is protected for R1, R3 and B;
(3) tris phosphite precursor is after oxidation and ammonia solution remove blocking group, obtains required product 20 (S)-O-Nucleotide camptothecin derivative.
Below a kind of universal method that scheme 1 is specifically implemented: under an inert atmosphere CPT (1 equivalent) is dissolved in anhydrous solvent (such as DMF or pyridine), stir and be cooled to 0-4 DEG C, DMAP (0.11 equivalent) is added in mixture, diisopropylethylamine (4 equivalent), and amino phosphoryl chloride (phosphoramidic chloride) (2 equivalent).Stir the mixture 1 hour, be then down to room temperature.After confirmation CPT completely consumed (about 2-12 hour), add a small amount of water to make mixture stopped reaction.Carry out separation and purification by extraction, be further purified with silica gel column chromatography alternatively.Then CPT20 (S)-O-phosphoramidite intermediate is dissolved in anhydrous solvent (as DMF); and at room temperature process 1-6 hour, until the consumption of phosphoramidite (phosphoramidite) intermediate is complete with the 5 '-OH nucleosides (1-3 equivalent) of 5-ethlythiotetrazole (1 equivalent) and suitably protection.Be used in iodine (2-10 equivalent) in moisture THF or superoxide (such as hydrogen peroxide, tertbutyl peroxide) reoxidizes 10 minutes, to obtain 20 (S)-O-phosphotriester precursor.After extracting and separating and optional silica gel column chromatography column purification, the process 20 (S)-O-phosphotriester a few hours (3-10h) at the temperature (30-60 DEG C) raised with ammoniacal liquor or methylamine/ethanol (> 10 equivalent).After evaporation of solvent, by the water-soluble thick product of purification by liquid extraction, be further purified and/or desalination with C-18 chromatography column, and lyophilize obtains flaxen solid phase prod.
For the preparation of 20 (S)-O-Nucleotide camptothecin derivative of formula II another method as in scheme 2 describe.
Scheme 2
The method is undertaken by phosphinate chemistry, and it utilizes CPT phosphinate intermediate, comprises the following steps:
(1) make the chloro-4H-1 of CPT and 2-, 3,2-benzo dioxy phosphorus heterocycle-4-reactive ketone, then reacts with TEAB again, generates CPT phosphonous acid monoesters intermediate;
(2) make CPT H-phosphonic acid ester intermediate and acyl chloride reaction, and then contact with formula III compound, generate CPT H-phosphonic acid diester precursor;
Wherein, as hereinbefore defined, wherein, when existing amino in B, this amino is protected for R1, R3 and B;
(3) be formula II compound by oxidation and deprotection by this phosphonic acid diester precursor conversion.
Below a kind of universal method that scheme 2 is specifically implemented: under an inert atmosphere CPT (1 equivalent) is dissolved in anhydrous solvent (such as DMF or pyridine); then 0-4 DEG C, the chloro-4H-1 of 2-of inert atmosphere protection is slowly joined; in the solution of 3,2-benzo dioxy phosphorus heterocycle-4-ketone (2-10 equivalent)/anhydrous pyridine.Stir the mixture 1 hour, be then cooled to room temperature.After confirmation CPT completely consumed (about 1-12 hour), poured into by reaction mixture in 1M TEAB (pH about 8.5), vigorous stirring, until no longer release CO2.The first abstraction purification of crude product CPT phosphinate, recycle silicon glue column chromatography, obtains spumescence product.Then, by 0.2M DBU supercarbonate/washed with dichloromethane, pure CPT phosphinate is changed into DBU salt.Then the DBU salt of H-phosphonic acid ester is dissolved in anhydrous pyridine, adds pivalyl chloride (3-5 equivalent) or Acetyl Chloride 98Min. (3-5 equivalent).After stirring at room temperature (1-10 hour), add nucleosides (2 equivalent), mixture is stirred 1-5 hour again, until all CPT H-phosphonic acid esters run out of.Then add and be dissolved in iodine (10 equivalent) in aqueous pyridine or superoxide (such as hydrogen peroxide, tertbutyl peroxide) and stir 10 minutes again.Optionally, with ammoniacal liquor or methylamine/ethanol (10 equivalent) at elevated temperatures (30-60 DEG C) process several hours.By the water-soluble thick product of purification by liquid extraction, with C-18 chromatography column be further purified, drying obtains flaxen solid 20 (S)-O-Nucleotide camptothecine product.
For the preparation of 20 (S) of the present invention-O-Nucleotide camptothecin derivative another preferred general method as in scheme 3 describe be undertaken by solid state chemistry, it utilizes 20 (S)-O-phosphoramidite precursor.
Scheme 3
The method is undertaken by phosphoramidite chemistry, and it utilizes CPT phosphoramidite intermediate, comprises the following steps:
(1) by formula III compound with alkali-sensitive linking agent (such as succsinic acid (salt/ester) is fixed on a kind of solid carrier (upholder) (such as, CPG, polystyrene),
Wherein, R1 be H, R2, R3 and B as hereinbefore defined,
(2) make CPT and amino phosphoryl chloride (phosphoramidic chloride) react, generate CPT 20 (S)-O-phosphoramidite intermediate;
(3) make this amino phosphoryl chloride and the formula III compound be fixed on the support react, generate 20 (S)-O-tris phosphite precursor;
(4) by oxidation and deprotection by this tris phosphite precursor conversion for making II compound.
In a kind of embodiment of scheme 3, by nucleosides alkali-sensitive linking agent (such as succsinic acid (salt/ester) with standard strategy (R.T.Pon, in Methods inMolecular Biology volume 20, Edited by S.Agrawal, 1993) a kind of solid-state carrier (upholder) is fixed to (such as, CPG, polystyrene) on.The synthesis of CPT 20 (S)-O-phosphoramidite intermediate is described in scheme 1.In that have inert atmosphere protection to one, that the above-mentioned nucleosides (1-3 equivalent) being incorporated into solid support is housed container (such as flask), be added in 20 (S)-O-phosphoramidite intermediate (1 equivalent) in anhydrous solvent (such as methylene dichloride) and 5-ethlythiotetrazole.Jiggle except desolventizing after 10-60 minute, the enough solvent washs of solid support, to remove all solvable reagent.Then, this solid support uses iodine solution (such as, 0.02M, in pyridine/water/THF) to process 5 minutes again, fully washs and drying with acetonitrile.20 (S)-O-phosphotriester intermediate that this solid is supported heats (28%, 50 DEG C, 5h) together with ammoniacal liquor again.Collect the aqueous solution obtained, be evaporated to dry, obtain crude product, with the pure/desalination further of C-18 chromatography column, 20 (the S)-O-Nucleotide camptothecine product obtaining formula I.
In addition, for the preparation of 20 (S) of the present invention-O-Nucleotide camptothecin derivative another preferred general method as in scheme 4 describe be undertaken by solid state chemistry.
Scheme 4
The method is undertaken by utilizing CPT H-phosphonic acid ester intermediate, comprises the following steps:
(1) by formula III compound with alkali-sensitive linking agent (such as succsinic acid (salt/ester) is fixed on a kind of solid carrier (upholder) (such as, CPG, polystyrene),
Wherein, R1 be H, R2, R3 and B as hereinbefore defined,
(2) make the chloro-4H-1 of CPT and 2-, 3,2-benzo dioxy phosphorus heterocycle-4-reactive ketone, then reacts with TEAB again, generates CPT phosphonous acid monoesters intermediate;
(3) make CPT phosphonous acid monoesters intermediate and acyl chloride reaction, and then contact with the III compound being fixed on described carrier, generate CPT phosphonous acid diester precursors;
(4) by oxidation and deprotection this CPT phosphonous acid diester precursors is converted into and makes II compound.
In a kind of embodiment of scheme 4, by nucleosides alkali-sensitive linking agent (such as succsinic acid (salt/ester) with standard strategy (R.T.Pon, in Methods inMolecular Biology volume 20, Edited by S.Agrawal, 1993) above fix on a kind of solid-state carrier (upholder) (such as polystyrene).The synthesis of CPT H-phosphonic acid ester intermediate is described in scheme 2.Under inert atmosphere protection, CPT H-phosphonate monoester (1 equivalent) and pivalyl chloride (3-5 equivalent) pre-mixing in flask in anhydrous solvent (such as pyridine) will be dissolved in.The above-mentioned Nucleotide being incorporated into upholder is added in this flask.Jiggle except desolventizing after 10-20 minute, the enough solvent washs of solid support, to remove all solvable reagent.Then, this solid support uses iodine solution (such as, 0.02M, at pyridine/water/THF) to process 5 minutes again, fully washs and drying with acetonitrile.20 (S)-O-phosphodiester intermediate that this solid is supported heats (28%, 50 DEG C, 5h) together with ammoniacal liquor again.Collect obtained aqueous solution, and be evaporated to dry, obtain crude product, with the pure/desalination further of C-18 chromatography column, 20 (the S)-O-Nucleotide camptothecine product obtaining formula I.
In the scheme 1-4 of above-mentioned 20 (the S)-O-Nucleotide camptothecin derivative being used for preparing formula I, any nucleoside analog obtaining 5 '-hydroxyl all can be used as Nucleotide starting raw material.Nucleosides preferred for the present invention has formula III structure, include but not limited to thymidine, cytidine, guanosine, adenosine, 1 ', 2 '-ribodesose, FdUrd (floxuridine), Decitabine, azacitidine, gemcitabine, floxuridine, chlorine cut down and draw shore, CldAdo, spray Xi Tading.Except 5 '-hydroxyl, the amino of above-mentioned formula III nucleosides or other hydroxyls by with suitable blocking group protect, for the starting raw material in scheme 1-4.
In formula III, should be appreciated that, amino and hydroxyl can comprise blocking group known in the art.Blocking group preferably for amino comprises ethanoyl, benzene (first) acyl group, isobutyryl, tertbutyloxycarbonyl, formyl radical, benzyl, p-methbxybenzyl-oxycarbonyl, trityl etc.Blocking group preferably for hydroxyl comprises ethanoyl, trifluoroacetyl group, valeryl, benzene (first) acyl carbonyl, alkyl, methyl, methoxymethyl, benzyloxymethyl, benzyl, trimethyl silyl, t-Butyldimethylsilyl etc.Other suitable blocking groups well known by persons skilled in the art are disclosed in Greene, T., Wuts; P.G.M.; Rrotective Groups in Organic Synthesis, in Wiley (1999), its content disclosed is incorporated to herein with reform.Preferably comprise enzymic activity (particularly cleavable) part, such as acid amides, ester etc. for hydroxyl and amino blocking group.
Formula I of the present invention is used for the treatment of cancer effectively, includes but not limited to, malignant tumour and other forms of cancer.As used herein, term " malignant tumour " is intended to comprise that being in of form of ownership is less differentiated, moderate differentiation and the human cancer of height differentiation phase, sarcoma and melanoma.When being offerd medicine by compound of the present invention to the patient of this treatment of needs, this compound of significant quantity or the preparation containing one or more the compounds of this invention are applied to patient.As used herein, " significant quantity " the compounds of this invention refers to so a kind of consumption, it suppresses, slows down the development of cancer, or kill cancer cells or tumour cell, and/or the disappearing and/or alleviate of the cancer of such as malignant tumour, such as reduce volume or the size of tumour, or eliminate tumour completely.
Compound of the present invention or preparation of the present invention can be used for treating kinds of tumors and/or cancer, include but not limited to the lung cancer of people, mammary cancer, colorectal carcinoma, prostate cancer, melanoma, carcinoma of the pancreas, cancer of the stomach, liver cancer, the cancer of the brain, kidney, uterus carcinoma, cervical cancer, ovarian cancer, urethral carcinoma, gastrointestinal cancer, and long other solid knurls outside blood vessel, and such as leukemic neoplastic hematologic disorder.Other solid knurl includes but not limited to colorectal carcinoma and the rectum cancer.Compound of the present invention also can be used as the inhibitor of topoisomerase I.A part of camptothecin analogues in the present invention can make pharmaceutical salts with mineral acid (such as using hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid and nitric acid).These camptothecin analogues can also make pharmaceutical salts with organic acid (such as acetic acid, tartrate, fumaric acid, succsinic acid, citric acid, methylsulfonic acid, p-toluene sulfonic acide and stearic acid).Can also with other acid as the intermediate preparing the compounds of this invention or its pharmaceutical salts.
The invention still further relates to methods for the treatment of, it comprises the compounds of this invention giving pharmacy effective dose.Such as, this compound can suffer from cancer and/or leukemic patient.Compound of the present invention can also as antiviral (such as AntiHIV1 RT activity) agent and antiparasitic.Pharmacy effective dose (dosage) is preferably the compound of a kind of formula I of per kilogram of body weight 0.1-100mg.More preferably, the compound of pharmacy effective dose (dosage) one or more the formula I that is per kilogram of body weight 0.1-40mg.Generally speaking, pharmacy effective dose or dosage comprise a kind of effective display leukemia of compound and/or antitumor) amount of performance.Scope of the present invention also comprises containing the pharmaceutical composition of at least one compound of the present invention as activeconstituents, comprising based on pharmaceutical salts of the present invention and pharmaceutical carrier or thinner.
Compound of the present invention can give with the dosage of an effective inhibitory enzyme topoisomerase I.This consumption generally at per kilogram of body weight 0.1-100mg weekly, excellent about 0.1-40mg.
Compound of the present invention can also give with a kind of form containing the pharmaceutical composition of this compound and pharmaceutical carrier or thinner.Not damaging its expectation function and/or supplementing the active substance improving this expectation function of other can also be comprised further in composition.Can with any administration according to compound/active substance of the present invention, such as adopt oral, intranasal, without stomach, vein, intradermal injection, subcutaneous injection or topical with the form of liquid or solid.
In order to the object of parenteral routes, activeconstituents can be placed in solution or suspension.Solution and suspension can also comprise composition below: such as, for the sterile diluent injected, water; Liposome particles suspended substance, wherein comprises stable active drug at the center of particle, and this particle has predetermined pH value and shielded environment; Liposome particles suspended substance, wherein hangs over the appearance of particle or any film of two film outside active drug; Salt brine solution, expressed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetics; Antiseptic-germicide, such as benzylalcohol or methyl p-hydroxybenzoate; Antioxidant, such as xitix or sodium bisulfite; Sequestrant, such as ethylenediamine tetraacetic acid (EDTA); Buffer reagent, such as acetic acid (salt), citric acid (salt) and for regulating the medicament of tonus, such as sodium-chlor or glucose.The preparation of administered parenterally can be contained in the bottle of ampoule, disposable syringe or the multidose be made up of glass or plastics.
The another kind of administering mode of the compounds of this invention is oral.Oral compositions comprises inert diluent or edible carrier usually.They can be installed in gelatine capsule or be pressed into tablet.In order to oral administration, aforesaid compound can be combined with vehicle and with tablet, lozenge, capsule, elixir, suspension agent, syrup, eye disc, masticatory etc.
These tablets, pill, capsule etc. can comprise composition below: binding agent, such as Microcrystalline Cellulose, tragacanth gum or gelatin; Vehicle, such as starch or lactose; Disintegrating agent, such as alginic acid, Primogel, W-Gum etc.; Lubricant, such as Magnesium Stearate or Sterote; Glidant, silica gel; And sweeting agent, such as sucrose or asccharin or flavour agent, such as spearmint oil, wintergreen oil, or orange taste agent (orange flavoring).When dose unit is with capsule form, it also can comprise the liquid carrier of such as fatty oil in addition to the above ingredients.Other dosage unit forms can comprise other many kinds of substances of adjust dosages unit physical aspect, such as coating.Such pill and tablet can be coated by sugar, shellac or other enteric agents.Syrup can comprise sucrose in addition to the active compound as sweeting agent and some sanitass, dyes and dyestuffs and flavour agent.Material for the preparation of these different pharmaceutical compositions should be that pharmacy is acceptable or animal doctor is pure, and is nontoxic in amount ranges.
Term " 20 (S)-O-Nucleotide camptothecin derivative " in the above description refers to the compound of general formula I of the present invention.
The explanation of embodiment above can disclose general feature of the present invention fully, so that other people are easily embody rule by existing knowledge and adjust and/or adaptations to these embodiments, these all do not depart from scope of the present invention, and therefore these adjust and revise the equivalent replacement that be considered as embodiment disclosed in the present invention.Will also be understood that expression or technical term are for illustrative purposes herein simultaneously, instead of for limiting its implication.
The following examples exemplify explanation the present invention further, but are not construed as limiting the invention.
The synthesis of embodiment 1:Dix-905 and anticancer evaluations
Formula I of the present invention comprises the Compound D ix-905 with structure below
The synthesis of (a) Dix-905
By CPT (174mg under nitrogen protection; 1 equivalent) be dissolved in anhydrous solvent (10ml DMF); stir and be cooled to 0-4 DEG C; DMAP (6.7mg is added in mixture; 0.11 equivalent), diisopropylethylamine (258mg; 2 equivalents) and 2-cyanoethyl N, N-di-isopropyl chloro phosphoramidite (236mg, 2 equivalents).Mixture stirs 1 hour, is then chilled to room temperature.After confirmation completely consumed CPT (about 4 hours), add a small amount of water (1ml) with stopped reaction.Evaporation removing reaction solvent, resistates is resuspended in methylene dichloride (10ml), with ice-cold 10% sodium carbonate solution, saline water extraction, then uses dried over sodium sulfate.Evaporated under reduced pressure methylene dichloride, obtains the thick CPT phosphoramidite intermediate of white.Need not be further purified; this CPT 20 (S)-O-phosphoramidite intermediate is dissolved in anhydrous THF (5ml) again; with 5-ethlythiotetrazole (1 equivalent) and the floxuridine (432mg with the protection of 3 '-ethanoyl; 3 equivalents) at room temperature process 6 hours, until be completely consumed phosphoramidite intermediate.Be oxidized 10 minutes with the iodine be dissolved in moisture THF (5 equivalent), obtain 20 (S)-O-phosphotriester precursor.After evaporating reaction solvent, mixture is being dissolved in methylene dichloride (10ml), and with 5% sodium carbonate and salt water washing.Residue dodges post through silica gel, obtains white foam 20 (S)-O-phosphotriester.Then, with methylamine/ethanol (being greater than 10 equivalents) this 20 (S)-O-phosphotriester of room temperature treatment 15 hours.After boiling off solvent, water-soluble crude product is resuspended in water (5ml), and extracts by ethyl acetate (3x 2ml), with C8 chromatography column be further purified, desalination, freezing, to obtain flaxen solid.TLC and NMR shows the purity of CPT 20 (S)-Nucleotide higher than 90%.ES-MS (anionic textiles pattern): C29H25FN4O11P (655), find 655.1H-NMR(d-DMSO,300Hz):δ8.1-7.9(m,3H),7.9-7.3(m,6H),6.7(s,1H),5.8(m,1H),4.9-4.5(m,2H),4.5-4.1(m,5H),3.6-3.4(m,2H),2.4-2.0(m,4H),0.9(m,3H)ppm.
(b) anticancer evaluations
Kill the ability of cancer cells to measure Compound D ix-905 (also becoming compound 905), we utilize the CellTiter-Glo test kit of Promega company, have carried out cell activation assay with not allogenic cell.This test kit is by enzymatic luciferase test ATP level.Have eubolism speed and the viable cell producing normal level ATP has high luciferase substrate turnover, it needs ATP carry out enzymatic reaction and send fluorescent signal.On the contrary, dead cell will provide low fluorescent signal result, because their metabolic function disappears.The fluorescent signal sent will be caught by photometer.
For carrying out activation analysis, small cell lung cancer cell is seeded in 96 orifice plates, with compound 905 and other cancer therapy drug process 24,48,72 hours.At each time point, cell and CellTiter-Glo reagent mix 1 hour are recorded fluorescent signal.
In order to Caspase activation, cell through respective reagent after different time points process, carry out similar analysis with the Caspase-Glo3/7 test kit of Promega.The mechanism that Caspase3/7Glow analyzes utilizes with the Caspase3/7 substrate of Luciferase substrate fusion, and it can by Caspase 3/7 cracking activated.The Luciferase substrate of release sends fluorescent signal through enzyme reaction again.Contrary with activation analysis, the restricted step of this analysis is Caspase activation.Dead cell with activation Casapsed has the high fluorescent signal reading be recorded in photometer.
C the antitumour activity of () Dix-905 is summarised in Fig. 1-8.
Fig. 1 .Dix-905 in H1693 cell than CPT better trigger cell kill response.
Fig. 2, due to synergistic effect, Dix-905 process creates kills cell ability byer force than CPT, floxuridine and etoposide in H1693 cell.
Fig. 3 .Dix-905 causes the necrocytosis according to time and dosage by Caspase activation (apoptosis pathway) in H1693.
The cell that Fig. 4 .Dix-905 causes in H146 kills response and is better than CPT.
What Fig. 5 .Dix-905 caused in H146 kill cell ability is better than CPT, floxuridine and etoposide.
Fig. 6 .Dix-905 causes the necrocytosis according to time and dosage by Caspase activation (apoptosis pathway) in H146.
What Fig. 7 .Dix-905 caused in HCT116 colon cell kill cell ability is better than CPT, floxuridine and etoposide.
The necrocytosis according to dosage of Fig. 8 .Dix-905 and CPT in HCT116 cell.
The explanation of embodiment above can disclose general feature of the present invention fully, so that other people are easily embody rule by existing knowledge and adjust and/or adaptations to these embodiments, these all do not depart from scope of the present invention, and therefore these adjust and revise the equivalent replacement that be considered as embodiment disclosed in the present invention.Should also be understood that expression or technical term are for illustrative purposes herein simultaneously, instead of for limiting its implication.
Claims (17)
1. a water soluble camptothecin derivatives, has structure or its pharmacy acceptable salt of formula II,
Wherein, R1 represents H or C1-C4 acyl group;
R2, R3 can be identical or different, represent H, halogen, hydroxyl or alkoxyl group independently; Described alkoxyl group refers to radicals R-O-, and wherein R refers to have the unit price side chain of 1-5 carbon atom or the alkyl of unbranched saturated hydrocarbon chain;
B is hydrogen, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 2-fluoroadenine, 2-chloroadenine or 3,4,7,8-imidazolidine [1,3] diazepine-8-alcohol.
2. camptothecin derivative according to claim 1, wherein, R1 is C1-C4 acyl group.
3. camptothecin derivative according to claim 1, wherein, R1 is ethanoyl.
4. camptothecin derivative according to claim 1, wherein, R1=R3=H, R2=OH, B=H, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic or 5-azepine cytosine(Cyt).
5. camptothecin derivative according to claim 1, wherein, R1=Ac; R2=R3=H; B=H, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5-azathymine or 2-chloroadenine, wherein, a hydrogen in amino is replaced by ethanoyl.
6. camptothecin derivative according to claim 1, wherein, R1=Ac, R2=F, R3=H, B=2-chloroadenine, wherein, a hydrogen in amino is replaced by ethanoyl.
7. camptothecin derivative according to claim 1, wherein, R1=Ac, R2=H, R3=OAc, B=2-fluoroadenine, wherein, a hydrogen in amino is replaced by ethanoyl.
8. camptothecin derivative according to claim 1, wherein, R1=Ac, R3=H, R2=OAc, B=H, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5-azathymine, wherein, in amino, a hydrogen is replaced by ethanoyl.
9. camptothecin derivative according to claim 1, it is one of compound in following table:
10., for the preparation of a method for compound described in claim 1, comprise the following steps:
(1) make CPT and amino phosphoryl chloride react, generate CPT 20 (S)-O-phosphoramidite intermediate;
(2) make CPT 20 (S)-O-phosphoramidite intermediate contact with formula III compound, generate 20 (S)-O-tris phosphite precursor;
Wherein, R1 represents H or C1-C4 acyl group;
R2, R3 can be identical or different, represent H, halogen, hydroxyl or alkoxyl group independently; Described alkoxyl group refers to radicals R-O-, and wherein R refers to have the unit price side chain of 1-5 carbon atom or the alkyl of unbranched saturated hydrocarbon chain;
B is hydrogen, thymus pyrimidine, cytosine(Cyt), uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 2-fluoroadenine, 2-chloroadenine or 3,4,7,8-imidazolidine [1,3] diazepine-8-alcohol;
Wherein, when existing amino in B, this amino is protected;
(3) tris phosphite precursor is after oxidation and ammonia solution remove blocking group, obtains required product 20 (S)-O-Nucleotide camptothecin derivative.
11. 1 kinds, for the preparation of the method for compound described in claim 1, comprise the following steps:
(1) make the chloro-4H-1 of CPT and 2-, 3,2-benzo dioxy phosphorus heterocycle-4-reactive ketone, then reacts with TEAB again, generates CPT phosphonous acid monoesters intermediate;
(2) make CPT H-phosphonic acid ester intermediate and acyl chloride reaction, and then contact with formula III compound, generate CPT H-phosphonic acid diester precursor;
Wherein, R1 represents H, C1-C4 acyl group,
R2, R3 can be identical or different, represent H, halogen, hydroxyl, alkoxyl group independently; Described alkoxyl group refers to radicals R-O-, and wherein R refers to have the unit price side chain of 1-5 carbon atom or the alkyl of unbranched saturated hydrocarbon chain;
B is hydrogen, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 2-fluoroadenine, 2-chloroadenine or 3,4,7,8-imidazolidine [1,3] diazepine-8-alcohol;
Wherein, when existing amino in B, this amino is protected;
(3) be formula II compound by oxidation and deprotection by this phosphonic acid diester precursor conversion.
12. 1 kinds, for the preparation of the method for compound described in claim 1, comprise the following steps:
(1) the alkali-sensitive linking agent of formula III compound is fixed on a kind of solid carrier,
Wherein, R1 is H; R2, R3 can be identical or different, represent H, halogen, hydroxyl, alkoxyl group independently; Described alkoxyl group refers to radicals R-O-, and wherein R refers to have the unit price side chain of 1-5 carbon atom or the alkyl of unbranched saturated hydrocarbon chain;
B is hydrogen, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 2-fluoroadenine, 2-chloroadenine or 3,4,7,8-imidazolidine [1,3] diazepine-8-alcohol;
(2) make CPT and amino phosphoryl chloride react, generate CPT 20 (S)-O-phosphoramidite intermediate;
(3) make this amino phosphoryl chloride and the formula III compound be fixed on the support react, generate 20 (S)-O-tris phosphite precursor;
(4) be formula II compound by oxidation and deprotection by this tris phosphite precursor conversion.
13. 1 kinds, for the preparation of the method for compound described in claim 1, comprise the following steps:
(1) the alkali-sensitive linking agent of formula III compound is fixed on a kind of solid carrier,
Wherein, R1 is H;
R2, R3 can be identical or different, represent H, halogen, hydroxyl, alkoxyl group independently; Described alkoxyl group refers to radicals R-O-, and wherein R refers to have the unit price side chain of 1-5 carbon atom or the alkyl of unbranched saturated hydrocarbon chain;
B is hydrogen, thymus pyrimidine, VITAMIN B4, cytosine(Cyt), guanine, uridylic, 5 FU 5 fluorouracil, 5-azepine cytosine(Cyt), 2-fluoroadenine, 2-chloroadenine or 3,4,7,8-imidazolidine [1,3] diazepine-8-alcohol;
(2) make the chloro-4H-1 of CPT and 2-, 3,2-benzo dioxy phosphorus heterocycle-4-reactive ketone, then reacts with TEAB again, generates CPT phosphonous acid monoesters intermediate;
(3) make CPT phosphonous acid monoesters intermediate and acyl chloride reaction, and then contact with the III compound being fixed on described carrier, generate CPT phosphonous acid diester precursors;
(4) by oxidation and deprotection, this CPT phosphonous acid diester precursors is converted into formula II compound.
14. 1 kinds of pharmaceutical compositions, it comprises at least one in the camptothecin derivative described in any one of claim 1 to 9 and at least one pharmaceutical carrier or thinner.
Pharmaceutical composition described in 15. claims 14 is for the preparation of the purposes in the medicine of Therapeutic cancer, and wherein said cancer is solid tumor or neoplastic hematologic disorder.
16. purposes according to claim 15, wherein said cancer is lung cancer, mammary cancer, colorectal carcinoma, prostate cancer, melanoma, carcinoma of the pancreas, cancer of the stomach, liver cancer, the cancer of the brain, kidney, uterus carcinoma, cervical cancer, ovarian cancer, urethral carcinoma, gastrointestinal cancer, leukemia or small cell lung cancer.
17. purposes according to claim 15 or 16, wherein said cancer is small cell lung cancer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998014459A1 (en) * | 1996-09-30 | 1998-04-09 | Bayer Aktiengesellschaft | Glycoconjugates from modified camptothecin derivates (20-o-linkage) |
| CN1357000A (en) * | 1998-08-07 | 2002-07-03 | 堪萨斯州立大学 | Water soluble prodrugs of hindered alcohols or phenols |
| CN1534036A (en) * | 2003-03-28 | 2004-10-06 | 贵州省生物研究所 | Derivative of camptothecin kind analogue and its preparation method |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0714955B2 (en) * | 1987-03-26 | 1995-02-22 | 株式会社ヤクルト本社 | Novel camptothecin derivative |
-
2010
- 2010-02-11 CN CN201010111584.1A patent/CN102153607B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998014459A1 (en) * | 1996-09-30 | 1998-04-09 | Bayer Aktiengesellschaft | Glycoconjugates from modified camptothecin derivates (20-o-linkage) |
| CN1357000A (en) * | 1998-08-07 | 2002-07-03 | 堪萨斯州立大学 | Water soluble prodrugs of hindered alcohols or phenols |
| CN1534036A (en) * | 2003-03-28 | 2004-10-06 | 贵州省生物研究所 | Derivative of camptothecin kind analogue and its preparation method |
Non-Patent Citations (4)
| Title |
|---|
| 孙雪,等.几种喜树碱-糖缀合物的合成.《中国海洋大学学报》.2007,第37卷第141-146页. * |
| 李庆勇,等.相转移催化法合成喜树碱糖苷及其对Topo I抑制活性.《药学学报》.2005,第40卷(第12期),第1116-1121页. * |
| 穆海川,等.喜树碱的结构修饰与构效关系.《中国药业》.2006,第15卷(第6期),第1-3页. * |
| 赵育,等.几种喜树碱-糖缀合物的合成及其抗肿瘤活性研究.《中国海洋大学学报》.2007,第37卷(第5期),第733-739页. * |
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