CN102161680A - Phosphamide ester camptothecin derivative as well as preparation method, pharmaceutical composition and usage thereof - Google Patents
Phosphamide ester camptothecin derivative as well as preparation method, pharmaceutical composition and usage thereof Download PDFInfo
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Abstract
The invention relates to a phosphamide ester camptothecin derivative as well as a preparation method, a pharmaceutical composition and usage thereof. The phosphamide ester camptothecin derivative is shown in formula (1), has good water solubility and has low toxicity and high anticancer activity compared with other known water-soluble camptothecin derivatives. In the formula (1), X, R1, R2 and R3 are defined in specification.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to the anticarcinogen field, more specifically relate to the phosphoramidate camptothecin derivative that is used for the treatment of cancer, also relate to their preparation method, pharmaceutical composition and purposes.
Background technology
Natural camptothecine (CPT) has a five rings structure that is made of the condensed ring system of quinoline ring (A ring and B ring), tetramethyleneimine (C ring), α-pyridone (D ring) and a hexa-atomic lactonic ring (E ring).CPT only has an asymmetric center in the 20-position, and owing to the S-configuration of tert-hydroxyl shows dextrorotation.CPT is a kind of cytotoxic alkaloid, it is reported by Wall group at first, they are from a kind of former plant---camplotheca acuminata (Camptotheca accuminata that is born in China, Nyssaceae) isolate and prove conclusively out CPT in leaf and the bark, open up it and used the beginning (J.Am.Chem.Soc.88,3888,1966).The main cell target spot of CPT is topoisomerase I (topo I), and this enzyme participates in the dna replication dna process by shear, unwind the relexation with the supercoil DNA that is connected again of the instantaneous strand of two DNA.CPT forms stable ternary complex in the interface combination of covalency binary topo I-DNA mixture, and therefore the connection again of the DNA after its prevention is unwind causes duplicating the double-strand break and the dna damage of mediation.Because CPT suppresses can cause in the death of the S of cell cycle stages of cell, CPT has become focus (NatureReview/Cancer, October 2006 Vol.6, the pp789-802 of a further investigation in the anticarcinogen exploitation; Bioorg.Med.Chem., 2004,12, pp1585-1604).
Water insoluble or other the aquosity medium of suitable administration of CPT, pH=7 or more than, the lactonic ring of CPT (E-ring) is hydrolyzed the formation carboxylic acid derivative.The carboxylic acid derivative of CPT is water-soluble, but does not have required biological activity and toxicity is very high clinically.Being reflected under the physiological condition of hydrolysis of lactonic ring (E-ring) can be aggravated, and reason is under physiological condition, and the more natural camptothecine of this carboxylic acid derivative preferential (high 150 times) is attached to human serum protein (J.Med.Chem.1993,36,2580; Anal.Biochem.1993,212,285; Biochemistry, 1994,33,10325; Biochemistry, 1994,33,10325; Pharm.Sci.1995,84.518).The water-insoluble of CPT and these two restraining factors that are difficult to overcome of the clinical toxicity of its carboxylic acid derivative make natural camptothecine can not as anti-cancer chemotherapeutic agents clinical application (Nature Review/Cancer, October 2006 Vol.6, pp789-802).This shows, improve its lactone stability in vivo and chemical focus (Bioorg.Med.Chem., 2004,12, the pp1585-1604 that makes great efforts of anticarcinogen research and development Chinese traditional medicine of the water-soluble CPT of being based on by chemically modified CPT; Chem.Rev., 2009,109 (1), pp 213-235).
In open report in the past, under the certain bioactive prerequisite of maintenance, improve main A, the B, the C that are CPT of concentrating of water miscible successfully trial and introduce hydrophilic radical (Bioorg.Med.Chem., 2004,12, pp1585-1604 on encircling; Chem.Rev., 2009,109 (1), pp 213-235).Yet, compare with natural camptothecine, additional chemically modified group on this class condensed ring system is to a certain degree influencing CPT down and covalency binary topo I-DNA mixture forms stable ternary complex, thereby cause the biological activity of this analog derivative (for example standard chemotherapeutics topotecan Topotecan of anticancer growth) generally to be lower than CPT (Nature Review/Cancer, October 2006Vol.6, pp789-802; Bioorg.Med.Chem., 2004,12, pp1585-1604).In addition, the chemically modified on A, B, the C ring fails to alleviate the hydrolysis of E-cyclic lactone.It is generally acknowledged that the hydrolysis of E-cyclic lactone is to be subjected to promoted (Bioorg.Med.Chem., 2004,12, pp1585-1604 of interaction of hydrogen bond between 20 (S)-hydroxyls and the adjacent carbonyl; Chem.Rev., 2009,109 (1), pp 213-235).Early stage report shows; stability for the E-cyclic lactone ring that improves CPT; generally by become with for example alkyl or acyl group and 20 (S)-hydroxyl ether or ester make 20 (S)-hydroxyls can not and adjacent carbonyl between form hydrogen bond, thereby prevent the hydrolysis reaction of the E-cyclic lactone that quickens therefrom.But because this 20 (S)-hydroxyl is most important for the pharmaceutical activity of camptothecine, the CPT derivative that loses 20 (S)-hydroxyls is proved to be does not generally have antitumour activity (Organic Lett., 2004,6 (3), pp321-324; Bioorg.Med.Chem., 2004,12, pp1585-1604; Chem.Rev., 2009,109 (1), pp213-235).
From above elaboration as seen, the strategy of introducing water-soluble prodrug group (for example ionizable functional groups) on 20 (S)-hydroxyl group sites is one and can improves the method that gained prodrugs water-soluble (route of administration feasibility) can improve the stability (medicinal clinical safety) of CPT prodrug E-cyclic lactone in the blood circulation stage again.In this case, this prodrug strategy is converted into water-soluble CPT prodrug with water-fast CPT; Because this water-soluble CPT prodrug short period of time after feeding blood vessel spreads to whole body apace, these CPT prodrugs exist with very low concentration in degradation process, have avoided the precipitation of CPT in blood vessel like this.In addition, on 20 (S)-hydroxyl group sites, introduce the prodrug group of shielding, can avoid passing through hydrogen bond action and the hydrolysis reaction of promoted E-cyclic lactone between 20 (S)-hydroxyls and the adjacent carbonyl, thereby improve the stability of CPT prodrug E-cyclic lactone in the blood circulation stage, can alleviate by the CPT hydrolysis like this and generate the medicinal clinical safety problems such as hematotoxicity that carboxylic acid derivative causes.Obviously, the prodrug strategy of introducing the water-soluble prodrug group on 20 (S)-hydroxyl group sites is the pharmaceutical chemistry method that can realize convenient CPT anticarcinogen exploitations such as lactone stability, water-soluble, biological activity.
For the existing report of trial that comes modification CPT with chemical processes such as preparation CPT prodrug and CPT based compounds; wherein; most examples is to introduce (the Chem.Rev. of various protection functional groups (comprising oleophylic and ionizable functional group) with the approach of the esterification of 20 (S)-hydroxyls; 2009; 109 (1), pp213-235).Ester prodrugs transforms to natural CPT and is mediated by one group of enzyme that is called esterase, and this kind of enzyme extensively is present in animal (the comprising the people) blood.The weakness of ester prodrugs is ester chain poor stability under the intravital physiological condition of people, is easy to be interrupted by esterase the clinical effectiveness of CPT ester prodrugs undesirable (Chem.Rev., 2009,109 (1), pp 213-235).In addition, existing people prepare 20 (S)-O-phosphoric acid of CPT or simple phosphonic acid ester (Organic Lett., 2004,6 (3), pp321-324).20 (S) of disclosed CPT though-chemically modified of O-phosphoric acid or simple phosphonic acid ester can increase lactone stability water-soluble and in vivo, but through experimental verification, 20 (the S)-O-phosphoric acid of this class CPT or simple phosphate derivatives lack antitumour activity (Organic Lett., 2004,6 (3), pp321-324).20 (S)-O-phosphoric acid or simple phosphonic acid ester under physiological condition, can not change into CPT (Organic Lett., 2004,6 (3), pp321-324).
Therefore, a kind of new CPT derivative with suitable water-soluble and lactonic ring stability of invention is most important in the CPT anticarcinogen is researched and developed.
Summary of the invention
An object of the present invention is to provide the new CPT derivative of a class, it has 20 new (S)-phosphoramidate chemically modified groups.The phosphoramidate CPT derivative that this class is new has suitable lactonic ring stability and suitable water-soluble, can be used for the treatment of cancer.
Another object of the present invention provides the chemical preparation process of the new phosphoramidate CPT derivative of this class.
A further object of the present invention provides a kind of improved treatment method for cancer.
In order to realize these purposes, on the one hand, the invention provides the compound of formula I or its pharmaceutically useful salt, solvate, hydrate:
Wherein:
X represents O, S, NH;
R
1, R
2Can be identical or different, represent H or alkyl independently, described alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group;
Perhaps R
1And R
2Form 5-10 unit nitrogen heterocyclic with the N atom that they connected, it is optional by halogen, hydroxyl, sulfydryl, alkyl, haloalkyl, amino, itrile group, nitro, alkoxyl group, alkylthio replacement;
R
3The group of representing H, alkyl or being fallen by enzymic hydrolysis under physiological condition, wherein said alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group.
In an embodiment of formula I compound, X represents O, specifically suc as formula shown in the II:
Wherein
R
1, R
2, R
3Suc as formula defining among the I.
In an embodiment of formula II compound, X represents O, R
3Represent H, specifically shown in formula III:
Wherein
R
1, R
2Suc as formula defining among the I.
In an embodiment of formula I compound, R
3The group that representative can be fallen by enzymic hydrolysis under physiological condition; the optional substituted acyl group of preferred representative; substituting group is selected from: halogen, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl are preferably selected from alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl.In a preferred embodiment, described optional substituted acyl group is optional substituted ethanoyl.In a preferred embodiment, the described group that can be fallen by enzymic hydrolysis under physiological condition is ethanoyl, ethylamino formyl radical ethanoyl, diethylamino formyl radical ethanoyl, diisopropylaminoethyl formyl radical ethanoyl.
In the embodiment of the compound of described in the above formula I, II, III, R
1And R
2Form 5-9 unit nitrogen heterocyclic with the N atom that they connected, it is optional by halogen, hydroxyl, sulfydryl, alkyl, haloalkyl, amino, itrile group, nitro, alkoxyl group, alkylthio replacement.In a preferred embodiment, R
1And R
2Form tetramethyleneimine with the N atom that they connected, morpholine, cis-2, the 6-thebaine, thiomorpholine, piperidines, 3-methoxyl group piperidines, piperazine, pipecoline, the 3-methyl piperidine, the 4-methyl piperidine, indoline, xylylenimine, perhydroisoindole, 5-bromine xylylenimine, 5-fluorine xylylenimine, 4-bromine xylylenimine, 4-fluorine xylylenimine, the amino xylylenimine of 5-, the amino xylylenimine of 4-, 5-hydroxyl xylylenimine, 4-hydroxyl xylylenimine, 5-nitro xylylenimine, 4-nitro xylylenimine, 5-trifluoromethyl xylylenimine, 5-cyano methyl xylylenimine, 4-cyano methyl xylylenimine, 5-trifluoromethyl xylylenimine, 4-trifluoromethyl xylylenimine.
In an embodiment of formula I compound, X represents NH, R
3Represent H or alkyl, preferably represent C
1-C
8Alkyl, more preferably C
1-C
6Alkyl, most preferable or ethyl.In a preferred embodiment, X represents NH, R
1And R
2In one be hydrogen, another and R
3Identical, represent alkyl, preferably represent C
1-C
8Alkyl, more preferably C
1-C
6Alkyl, most preferable or ethyl.
20 (S)-O-phosphoramidate camptothecin derivatives of described formula I are preferably selected from following compound:
Compound mentioned above (being also referred to as " 20 (S)-O-phosphoramidate camptothecin derivative ", " phosphoramidate CPT derivative " or " compound of the present invention " in context) not only has the curative effect of suitable treatment cancer, and has water-soluble that the administration of being suitable for and medicine send in vivo.And compound of the present invention has suitable camptothecine lactonic ring stability, thereby has appropriate drug toxicity.
On the other hand, the invention provides the compound of the present invention that is used for the treatment of cancer or its pharmaceutically useful salt, solvate, hydrate.
On the other hand, the invention provides the pharmaceutical composition that comprises at least a compound of the present invention or its pharmaceutically useful salt, solvate, hydrate and at least a pharmaceutically acceptable carrier.Also optional other anticarcinogens that comprises of this pharmaceutical composition.
On the other hand, the invention provides and be used for the treatment of mammiferous method for cancer, it comprises the compound of the present invention of administration treatment significant quantity or its pharmaceutically useful salt, solvate, hydrate and optional other anticarcinogens of using.
On the other hand, the invention provides compound of the present invention or its pharmaceutically useful salt, solvate, the purposes of hydrate (optional and other anticarcinogen combination) in the medicine of preparation treatment cancer.
Except as otherwise noted, used term has implication given below otherwise in the context of the present invention.Other terms that this paper does not specifically provide implication have its common in the art implication.
Term " halogen " is meant fluorine, chlorine, bromine, iodine, preferred fluorine, chlorine, bromine, more preferably fluorine and chlorine.
Term " hydroxyl " is meant group-OH.
Term " sulfydryl " is meant group-SH.
Term " amino " is meant group-NH
2
Term " cyano group " is meant group-C ≡ N.
Term " itrile group " is meant group-(CH
2)
m-C ≡ N, wherein m is 0,1,2 or 3, comprises cyano group, cyano methyl (CH
2-C ≡ N), cyano ethyl (CH
2-CH
2-C ≡ N), cyano group propyl group (CH
2-CH
2-CH
2-C ≡ N), cyano group butyl (CH
2-CH
2-CH
2-CH
2-C ≡ N).
Term " nitro " is meant group-NO
2
Term " alkyl " is meant the straight or branched saturated hydrocarbyl with 1-30 carbon atom, it preferably has 1-20 carbon atom, more preferably have 1-10 carbon atom, for example have 1-8 carbon atom, a 1-7 carbon atom, for example have 1,2,3,4,5,6 carbon atom.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, the 2-methyl butyl, neo-pentyl, the 1-ethyl propyl, hexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 1, the 2-dimethylbutyl, the 2-ethyl-butyl, heptyl, different heptyl, 3-methyl hexyl, the 3-ethyl-methyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl group, 1,4-dimethyl amyl group, 1,5-dimethyl amyl group, 2,2, the 4-tri-methyl-amyl, n-octyl, iso-octyl, nonyl, different nonyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl.
Term " alkoxyl group " is meant radicals R-O-, and wherein R is above defined alkyl.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, 1-methyl butoxy, 2-methyl butoxy, 3-methyl butoxy, neo-pentyl oxygen base, n-hexyl oxygen base, 4-methyl pentyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 1-methyl pentyloxy, 3,3-dimethyl butoxy, 2,2-dimethyl butoxy, 1,1-dimethyl butoxy, 1,2-dimethyl butoxy, 1,3-dimethyl butoxy, 2,3-dimethyl butoxy, 1,2-dimethyl butoxy, 2-ethyl butoxy, heptan the oxygen base, different heptan the oxygen base, 3-methyl hexyloxy, 3-ethyl methoxyl group, 2,2-dimethyl pentyloxy, 2,3-dimethyl pentyloxy, 1,4-dimethyl pentyloxy, 1,5-dimethyl pentyloxy, 2,2, the 4-trimethylpentyloxy, n-octyloxy, different octyloxy.
Term " alkylthio " is meant radicals R-S-, and wherein R is above defined alkyl.The example of alkylthio includes but not limited to methylthio group, ethylmercapto group, positive rosickyite base, the iprotiazem base, positive butylthio, uncle's butylthio, secondary butylthio, positive penta sulfenyl, 1-methyl butylthio, 2-methyl butylthio, 3-methyl butylthio, the neo-pentyl sulfenyl, the n-hexyl sulfenyl, 4-methylpent sulfenyl, 3-methylpent sulfenyl, 2-methylpent sulfenyl, 1-methylpent sulfenyl, 3,3-dimethyl butyrate sulfenyl, 2,2-dimethyl butyrate sulfenyl, 1,1-dimethyl butyrate sulfenyl, 1,2-dimethyl butyrate sulfenyl, 1,3-dimethyl butyrate sulfenyl, 2,3-dimethyl butyrate sulfenyl, 1,2-dimethyl butyrate sulfenyl, 2-ethyl butylthio, heptan sulfenyl, different heptan sulfenyl, the own sulfenyl of 3-methyl, 3-ethyl methylthio group, 2,2-dimethyl-penten sulfenyl, 2,3-dimethyl-penten sulfenyl, 1,4-dimethyl-penten sulfenyl, 1,5-dimethyl-penten sulfenyl, 2,2,4-trimethylammonium penta sulfenyl, positive hot sulfenyl, different hot sulfenyl.
Term " thiazolinyl " is meant the straight or branched alkyl with 2-10 carbon atom that contains at least one two key (for example 1 or 2 two key), and it preferably has 2-8 carbon atom, more preferably has 2-6 carbon atom, for example has 2,3,4,5 carbon atoms.The example of thiazolinyl includes but not limited to vinyl, allyl group, but-1-ene base, but-2-ene base, penta-1-thiazolinyl, penta-2-thiazolinyl, penta-3-thiazolinyl, own-the 1-thiazolinyl, own-the 2-thiazolinyl, own-the 3-thiazolinyl, own-the 4-thiazolinyl.
Term " alkynyl " is meant the straight or branched alkyl with 2-10 carbon atom that comprises at least one three key (for example 1 or 2 three key), and it preferably has 2-8 carbon atom, more preferably has 2-6 carbon atom, for example has 2,3,4,5 carbon atoms.The example of alkynyl includes but not limited to ethynyl, propargyl, fourth-1-alkynyl, fourth-2-alkynyl, penta-1-alkynyl, penta-2-alkynyl, penta-3-alkynyl, own-the 1-alkynyl, own-the 2-alkynyl, own-the 3-alkynyl, own-the 4-alkynyl.
Term " aryl " is meant the aromatic carbon ring group with individual, preferred 6-10 the ring carbon atom of 6-18, and it can be monocycle (for example, phenyl), many ring (for example, xenyl) or condensed ring (for example, naphthyl or anthryl).Preferred aryl groups comprises phenyl, naphthyl etc.Most preferred aryl is a phenyl.
Term " heteroaryl " is meant and comprises 1,2,3 or 4 monocyclic, bicyclic or tricyclic aromatic series ring-type group that is selected from the 5-14 unit (for example 5-10 unit) of the ring hetero atom of sulphur, oxygen, phosphorus and/or nitrogen.The example of heteroaryl includes but not limited to [1,2,4]
Di azoly, [1,3,4]
Di azoly, [1,2,4] thiadiazolyl group, [1,3,4] thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, pseudoindoyl, indyl, indazolyl, purine radicals, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyl pyridyl, quinoxalinyl, quinolizinyl, cinnolines base (cinnolinyl), pteridyl, carbazyl, carbolinyl, phenanthridinyl, acridyl, phenanthroline base, isothiazolyl, phenazinyl, different
Azoles base, fen
Piperazine base, phenothiazinyl.Described heteroaryl can be the form of oxide compound, promptly sulphur, nitrogen, the phosphorus ring hetero atom can be oxidized.
Term " heterolipid cyclic group " is meant and comprises 1,2,3,4 or 5 saturated or undersaturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon group of part that is selected from the 3-16 unit (more preferably 3-14 unit, for example 3-10 unit, 3-9 unit, 3-6 unit) of the ring hetero atom of sulphur, oxygen, phosphorus and/or nitrogen.The example of heterolipid cyclic group includes but not limited to dihydrofuran base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl, morpholinyl, thio-morpholinyl, piperidyl, piperazinyl, dihydropyridine base, pyrrolidyl, pyrazolidyl, imidazolinyl, imidazolidyl, thiazolidyl, isothiazole alkyl, dihydroquinoline base, dihydro-isoquinoline base, tetrahydric quinoline group, tetrahydro isoquinolyl.Described heterolipid cyclic group can be the form of oxide compound, promptly sulphur, nitrogen, the phosphorus ring hetero atom can be oxidized.
Term " haloalkyl " is meant the above defined alkyl that is replaced by one or more halogens.The example of haloalkyl includes but not limited to trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, two brooethyls, methyl fluoride, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls, 2-bromotrifluoromethane, 2-chloroethyl, 2-fluoro ethyl, 2,2-two bromotrifluoromethanes.
Term " 5-10 unit nitrogen heterocyclic " and " the first nitrogen heterocyclic of 5-9 " be meant respectively except with R
1And R
2Also optionally beyond the nitrogen-atoms that connects contain monocycle or the bicyclic nitrogen heterocyclic ring that 1,2,3 or 4 total that is selected from the ring hetero atom of sulphur, nitrogen, phosphorus and/or oxygen has 5-10 or 5-9 annular atoms, optional by halogen, hydroxyl, sulfydryl, alkyl, haloalkyl, amino, itrile group, nitro, alkoxyl group, alkylthio replacement.Example includes but not limited to tetramethyleneimine, morpholine, cis-2, the 6-thebaine, thiomorpholine, piperidines, 3-methoxyl group piperidines, piperazine, pipecoline, the 3-methyl piperidine, the 4-methyl piperidine, indoline, xylylenimine, perhydroisoindole, 5-bromine xylylenimine, 5-fluorine xylylenimine, 4-bromine xylylenimine, 4-fluorine xylylenimine, the amino xylylenimine of 5-, the amino xylylenimine of 4-, 5-hydroxyl xylylenimine, 4-hydroxyl xylylenimine, 5-nitro xylylenimine, 4-nitro xylylenimine, 5-trifluoromethyl xylylenimine, 5-cyano methyl xylylenimine, 4-cyano methyl xylylenimine, 5-trifluoromethyl xylylenimine, 4-trifluoromethyl xylylenimine.
Term " group that can be fallen by enzymic hydrolysis under physiological condition " is meant the group that can be fallen by the hydrolysis reaction cracking by intravital one or more enzymes of Mammals (for example people), for example optional substituted acyl group.
Term " acyl group " be meant R '-C (O)-, wherein R ' is hydrogen or above defined alkyl.Preferably, R ' is hydrogen or C
1-C
6Alkyl is more preferably hydrogen or C
1, C
2, C
3, C
4, C
5Alkyl.The example of acyl group includes but not limited to formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, positive pentanoyl, valeryl, pentanoyl, isovaleryl, capryloyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecane acyl group, octadecanoyl, nonadecane acyl group, eicosane acyl group.
Term " optional substituted acyl group " is meant optional by one or more halogen, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, optional above defined acyl groups that replaced by the substituting group of the formamyl of 1 or 2 alkyl replacement of being selected from.
Term " alkoxy carbonyl " be meant radicals R-O-C (O)-, wherein R is above defined alkyl, preferred R is C
1-C
6Alkyl.Its example includes but not limited to methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, n-pentyloxy carbonyl, neopentyl oxygen carbonyl, pentyloxy carbonyl, isopentyloxy carbonyl, carbonyl octyloxy, ninth of the ten Heavenly Stems oxygen base carbonyl, last of the ten Heavenly stems oxygen base carbonyl.
Term " the optional formamyl that is replaced by 1 or 2 alkyl " is meant optional by 1 or 2 above defined alkyl (preferred C
1-C
6Alkyl) formamyl of Qu Daiing, its example includes but not limited to the methylamino formyl radical; formyl-dimethylamino; the ethylamino formyl radical; the diethylamino formyl radical; the n-propyl formamyl; the di formamyl; the sec.-propyl formamyl; the diisopropylaminoethyl formyl radical; the normal-butyl formamyl; the di-n-butyl formamyl; the isobutylamino formyl radical; the diisobutyl formamyl; the n-pentyl formamyl; two n-pentyl formamyls; the neo-pentyl formamyl; the di neo-pentyl formamyl; the isopentyl formamyl; the diisoamyl formamyl; the n-octyl formamyl; the di-n-octyl formamyl; the n-nonyl formamyl; two n-nonyl formamyls; the decyl formamyl; the didecyl formamyl.
Term " CPT prodrug " is meant the camptothecin derivative that has biodegradable 20 (S)-hydroxy-protective groups.Under physiological condition, the blocking group of these biodegradable 20 (S)-hydroxyls is by the slowly cracking and discharge the camptothecine of pharmaceutical activity of specific enzyme.
Term " Mammals " includes but not limited to primate, particularly people; Rodent comprises mouse, rat and hamster; Domestic animal, for example rabbit, horse, ox, dog, cat etc.In some embodiments, described Mammals is the people.
On the other hand, the present invention also provides the method for preparation 20 (S)-O-phosphoramidate camptothecin derivatives, and it is preferably undertaken by the phosphoramidite chemistry as shown in fig. 1.
Shown in Fig. 1 (A), the method for described preparation 20 (S)-O-phosphoramidate camptothecin derivative may further comprise the steps:
(1) makes PCl
3With formula R
4The nitrogen azole active substance reaction of H, the inferior phosphoryl triamide intermediate of production IV:
Formula IV
R wherein
4Be
Or
Deng;
(2) the inferior phosphoryl triamide intermediate of formula IV and CPT are reacted,
The CPT 20 (S) of production V-O-phosphoramidite intermediate:
R wherein
4As hereinbefore defined;
(3) CPT 20 (the S)-O-phosphoramidite intermediate of formula V and the amine of formula VI are reacted,
R wherein
1, R
2As hereinbefore defined,
The phosphoramidite intermediate of production VII:
R wherein
1, R
2As hereinbefore defined;
(4) the phosphoramidite intermediate of formula VII is handled with oxygenant or vulcanizing agent, is obtained the compound of formula I:
Wherein X, R
1, R
2As hereinbefore defined, R
3Represent H or alkyl, described alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group;
With, randomly
(5) make wherein X, R
1, R
2As hereinbefore defined and R
3Represent the compound reaction of formula I compound and the formula IX of H,
Wherein R ' represents hydrogen or alkyl, and described alkyl is optional to be replaced by one or more halogens, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl; Y is Cl or Br;
Generate wherein R
3Representative can for example be chosen wantonly the formula I compound of substituted acyl group by the group that enzymic hydrolysis is fallen under physiological condition.
More specifically, this method can followingly be carried out: take by weighing an amount of (for example 1-10 equivalent) formula R
4The nitrogen azole active substance of H is dissolved in organic solvent for example among pyridine, acetonitrile, DMF, the DMSO, ice bath is cooled to-10～10 ℃, add an amount of (for example 0.5-4 equivalent) phosphorus trichloride, remove ice bath, stir an amount of (for example 1 equivalent) CPT that the back adds above-mentioned organic solvent dissolution under the room temperature, stirring reaction is complete, and CPT transforms amine such as the diethylamine solution of an amount of (for example 1-16 equivalent) formula VI of the above-mentioned organic solvent diluting of back adding fully, stirring reaction; After reacting completely, add an amount of oxygenant or vulcanizing agent, after reaction finished, the reaction solution evaporated under reduced pressure was crossed silicagel column.Collect effluent, evaporated under reduced pressure, solid is dissolved in the less water, crosses the C18 reversed-phase column, collects effluent, and freeze-drying gets target compound.Randomly, products therefrom (for example 1 equivalent) is dissolved in for example pyridine of organic solvent, acetonitrile, DMF, DMSO, the carboxylic acid halides reagent of an amount of (for example 1-5 equivalent) the formula IX of adding is Acetyl Chloride 98Min. for example, stirring at room for example 2-12 hour, get target compound, target compound can obtain through conventional method of purification, as reaction mixture pressure reducing and steaming solvent, adds an amount of water, add organic solvent such as ether, extraction such as methylene dichloride or trichloromethane, collect water, the pressure reducing and steaming water adds methyl alcohol or dissolve with ethanol solid, dry method is crossed silicagel column, collect effluent, boil off solvent, obtain pure substance with the mixed solvent recrystallization of methyl alcohol and ether or acetone.
Perhaps, shown in Fig. 1 (B), may further comprise the steps:
(1) makes PCl
3Amine reaction with formula VI:
R wherein
1, R
2As hereinbefore defined,
The phosphoramidite intermediate of production VIII:
R wherein
1, R
2As hereinbefore defined,
(2) make phosphoramidite intermediate and the CPT of formula VIII
CPT
At formula R
4The effect of the nitrogen azole active substance of H is reaction down, the phosphoramidite intermediate of production VII:
Formula VII
R wherein
1, R
2, R
4As hereinbefore defined,
(3) the phosphoramidite intermediate of formula VII is handled with oxygenant or vulcanizing agent, obtain formula I compound:
Formula I
Wherein X, R
1, R
2As hereinbefore defined, R
3Represent H or alkyl, described alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group;
With, randomly
(4) make wherein X, R
1, R
2As hereinbefore defined and R
3Represent the compound reaction of formula I compound and the formula IX of H,
Wherein R ' represents hydrogen or alkyl, and described alkyl is optional to be replaced by one or more halogens, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl; Y is Cl or Br;
Generate wherein R
3Representative can for example be chosen wantonly the formula I compound of substituted acyl group by the group that enzymic hydrolysis is fallen under physiological condition.
More specifically, this method can followingly be carried out: the amine that takes by weighing an amount of (for example 1-20 equivalent) formula VI for example diethylamine dissolves in organic solvent for example in ether, normal hexane, the benzene, the ice bath cooling; Will an amount of (for example 1-6 equivalent) phosphorus trichloride organic solvent for example the drips of solution in ether, normal hexane, the benzene be added in the amine aqueous solution that obtains previously, drip off the recession ice bath, be warming up to 20-80 ℃ of restir after the stirring, reaction finishes, filter, the filtrate solvent evaporated, for example pyridine, acetonitrile, DMF, DMSO dissolve resistates with an amount of organic solvent, add organic solvent for example pyridine, acetonitrile, DMF, DMSO dissolved CPT (for example 1 equivalent) then, after the stirring with organic solvent for example pyridine, acetonitrile, DMF, DMSO dissolved formula R
4The solution of the nitrogen azole active substance of H splashes in the mixed solution, and stirring is spent the night.Add oxygenant or vulcanizing agent, after the stirring, generate target product.Can it be separated through conventional aftertreatment, for example with reaction solution pressure reducing and steaming partial solvent, cross the strongly basic anion exchange resin post, collect effluent, evaporated under reduced pressure gets pale brown look solid; After solid dissolved with methylene dichloride or trichloromethane, water extracted several times, combining water layer, and the evaporated under reduced pressure water layer gets solid; Solid is separated out solid with acetone or methyl alcohol and methylene dichloride mixing solutions recrystallization, filters, and solid drying gets target compound.Randomly, products therefrom (for example 1 equivalent) is dissolved in for example pyridine of organic solvent, acetonitrile, DMF, DMSO, the carboxylic acid halides reagent of an amount of (for example 1-5 equivalent) the formula IX of adding is Acetyl Chloride 98Min. for example, stirring at room for example 2-12 hour, get target compound, target compound can obtain through conventional method of purification, as reaction mixture pressure reducing and steaming solvent, adds an amount of water, add organic solvent such as ether, extraction such as methylene dichloride or trichloromethane, collect water, the pressure reducing and steaming water adds methyl alcohol or dissolve with ethanol solid, dry method is crossed silicagel column, collect effluent, boil off solvent, obtain pure substance with the mixed solvent recrystallization of methyl alcohol and ether or acetone.
If desired, aforesaid method can comprise that also the compound with the free form of gained changes into the step of its pharmaceutically useful salt, solvate, hydrate.
In aforesaid method, used organic solvent there is not particular restriction, as long as its solubilizing reaction thing and reaction do not had detrimentally affect to a certain extent.Its example includes but not limited to pyridine, acetonitrile, DMF, DMSO, methylene dichloride, trichloromethane, acetone, ether, normal hexane, benzene or its combination.
In aforesaid method, used oxygenant is a conventional oxidant known in the art, is preferably selected from moisture or water-free I
2/ THF, moisture or water-free I
2/ pyridine, moisture or water-free H
2O
2, moisture or water-free tertbutyl peroxide.Under the aqueous situation of oxygenant, in a step hydrolysis, oxidation take place in the end, generate the target product that X wherein represents O; Under the water-free situation of oxygenant, generate the target product that X wherein represents NH.Used vulcanizing agent is a conventional vulcanizing agent known in the art, is preferably selected from S
4, S
8, Beaucage reagent etc.
In aforesaid method, churning time is not crucial, as long as can react fully, for example 0.1 hour to a few hours, for example 0.1-16 hour, and for example 0.1-8 hour, 0.1-2 hour, 0.3-2 hour, 0.1-1 hour or 2-16 hour.
Formula I compound of the present invention can be used for the treatment of cancer (being also referred to as " malignant tumour ") effectively, comprises the low differentiation of being in of form of ownership, moderate differentiation and the cancer of height differentiation phase.When compound of the present invention being offerd medicine, the compound of the present invention of significant quantity or the preparation that contains one or more compounds of the present invention are applied to described individuality to this treatment of needs individual.As used herein, " significant quantity " is meant the amount that can produce the compound of the present invention of desirable effect.For example, with regard to treatment cancer/malignant tumour, significant quantity is a kind of like this consumption, it suppresses, slows down the development of cancer, perhaps kill cancer cell or tumour cell, and/or for example make the resolution of symptoms of malignant tumour and/or alleviate, for example reduce tumor size or size, or eliminate tumour fully.The significant quantity of compound of the present invention (dosage) is preferably per kilogram of body weight 0.1-100mg compound of the present invention.More preferably, significant quantity (dosage) is one or more the compound of the present invention of per kilogram of body weight 0.1-40mg.If it is necessary and feasible that doctor or animal doctor think, significant quantity can be outside above-mentioned scope.When compound of the present invention was used with the form of its pharmaceutically useful salt, solvate, hydrate, described significant quantity was meant the amount of free cpds.
Compound of the present invention or pharmaceutical composition can be used for treating various cancers, include but not limited to for example leukemia of solid tumors such as lung cancer, mammary cancer, colorectal carcinoma, the rectum cancer, 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 neoplastic hematologic disorder.Preferred solid tumor includes but not limited to colorectal carcinoma and the rectum cancer, mammary cancer, lung cancer, especially small cell lung cancer.
Compound of the present invention can be used in combination with one or more other anticarcinogens.Other anticarcinogens described in the context comprise: 1) estrogenic agents, for example tamoxifen, raloxifene, idoxifene; 2) androgen receptor modifier, for example finasteride, Nilutamide, flutamide, bicalutamide; 3) retinoid receptor conditioning agent, for example bexarotene, vitamin A acid, 13-cis-vitamin A acid, 9-cis-vitamin A acid; 4) cell toxicant material comprises alkylating agent, tumour necrosis factor, Antitubulin, topoisomerase enzyme inhibitor, for example ifosfamide, carboplatin, ranomustine, fotemustine, oxaliplatin, mitoxantrone, taxol, topotecan; 5) antiproliferative, for example trimetrexate, fludarabine, capecitabine; 6) isopentene group protein transferase inhibitor, 7) the HMG-CoA reductase inhibitor, 8) hiv protease inhibitor and 9) reverse transcriptase inhibitors etc.
Compound of the present invention also can be used as the inhibitor of topoisomerase I.Compound of the present invention can give with the significant quantity of inhibitory enzyme topoisomerase I.Described significant quantity is generally per kilogram of body weight 0.1-100mg weekly, excellent about 0.1-40mg.
In addition, compound of the present invention can also be as antiviral (for example anti-HIV) agent and antiparasitic.
Compound of the present invention can be made pharmaceutically useful acid salt with mineral acid (for example using hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid and nitric acid) or organic acid (for example acetate, tartrate, fumaric acid, succsinic acid, citric acid, methylsulfonic acid, right-toluene sulfonic acide and stearic acid).Pharmaceutically unacceptable acid salt can be used as the intermediate of preparation and purifying compound or pharmaceutically acceptable salt thereof of the present invention.
Compound of the present invention or its pharmaceutically useful salt can with itself form as medicine or with the form of pharmaceutical composition as medicine.Except compound of the present invention and pharmaceutically acceptable carrier, pharmaceutical composition of the present invention can also further comprise not damaging its expectation function and/or replenishing the active substance that improves this expectation function of other.
Compound of the present invention and pharmaceutical composition can be with any administrations, for example adopt oral, intranasal, parenteral, vein, intradermal injection, subcutaneous injection or topical with the form of liquid or solid.
For the purpose of parenteral administration, activeconstituents can be placed solution or suspension.Solution and suspension can also comprise following composition: the sterile diluent that is used to inject, for example water for injection; The liposome particles suspended matter wherein comprises stable active drug at the particulate center, and this particle has predetermined pH value and shielded interior environment; The liposome particles suspended matter, wherein active drug hangs over any film of particulate appearance or two films outward; Salt brine solution, expressed oil, polyoxyethylene glycol, glycerine, propylene glycol or other synthetics; Antiseptic-germicide, for example benzylalcohol or methyl p-hydroxybenzoate; Antioxidant, for example xitix or sodium bisulfite; Sequestrant, for example ethylenediamine tetraacetic acid (EDTA); Buffer reagent, for example acetate (salt), citric acid (salt) and the material that is used for adjustment of tonicity, for example sodium-chlor or glucose.The preparation of parenteral administration can be contained in the bottle of ampoule, disposable syringe or the multidose made by glass or plastics.
Oral compositions comprises inert diluent or edible carrier usually.They can be installed in the gelatine capsule or be pressed into tablet.For oral administration, compound of the present invention can be become tablet, pill, capsule, lozenge, elixir, suspensoid, syrup, film, chewable tablet etc.These tablets, pill, capsule etc. can comprise following composition: tackiness agent, for example Microcrystalline Cellulose, tragacanth gum or gelatin; Vehicle, for example starch or lactose; Disintegrating agent, for example alginic acid, Primogel, W-Gum etc.; Lubricant, for example Magnesium Stearate or Sterote; Glidant, for example silica gel; And sweeting agent, for example sucrose or asccharin, perhaps correctives, for example spearmint oil, wintergreen oil or the agent (orange flavoring) of orange flavor.Capsule can also comprise for example fatty oil of liquid carrier except that mentioned component.Other formulations can comprise other multiple material, for example coatings of regulating the formulation physical aspect.For example, pill and tablet can coat with sugar, shellac or other enterosoluble substance.Syrup removes the active ingredient beyond the region of objective existence can comprise sucrose as sweeting agent and some sanitass, dyestuff, tinting material and correctives.The material that is used for pharmaceutical compositions should be pharmaceutically useful.It is acceptable that term " pharmaceutically acceptable " is meant for people's medical science or veterinary science, is nontoxic in amount ranges.
Description of drawings
Fig. 1 is two kinds of schemes of the compound of preparation formula I, wherein X, R
1, R
2, R
3, R
4, R ', Y as hereinbefore defined.
Fig. 2 is the synthetic route chart of compound H M910.
Fig. 3 is the synthetic route chart of compound H M912.
Fig. 4 is the synthetic route chart of compound H M922.
Fig. 5 is the synthetic route chart of compound H M926.
Fig. 6 has shown that compound H M910 causes the necrocytosis according to dosage in H446 (small cell lung cancer) cell." CPT " group is to handle H446 (small cell lung cancer) cell 48 hours with CPT (being dissolved among the DMSO) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " HM910 " group is to handle H446 (small cell lung cancer) cell 48 hours with HM910 (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate.
Fig. 7 has shown that compound H M910 causes the necrocytosis according to dosage in MDAMB231 (mammary cancer) cell." CPT " group is to handle MDAMB231 (mammary cancer) cell 48 hours with CPT (being dissolved among the DMSO) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " HM910 " group is to handle MDAMB231 (mammary cancer) cell 48 hours with HM910 (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate.
Fig. 8 has shown that compound H M910 causes the necrocytosis according to dosage in HCT116 (colorectal carcinoma) cell." CPT " group is to handle HCT116 (colorectal carcinoma) cell 48 hours with CPT (being dissolved among the DMSO) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " HM910 " group is to handle HCT116 (colorectal carcinoma) cell with HM910 (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate.
Fig. 9 has shown that compound H M912 causes the necrocytosis according to dosage in H446 (small cell lung cancer) cell." CPT " group is to handle H446 (small cell lung cancer) cell 48 hours with CPT (being dissolved among the DMSO) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " HM912 " group is to handle H446 (small cell lung cancer) cell 48 hours with HM912 (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " etoposide " group is with etoposide (Etoposide in X-coordinate, another name: etoposide is dissolved in the salt solution) handled H446 (small cell lung cancer) cell 48 hours by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles).
Figure 10 has shown that compound H M912 causes the necrocytosis according to dosage in HCT116 (colorectal carcinoma) cell." CPT " group is to handle HCT116 (colorectal carcinoma) cell 48 hours with CPT (being dissolved among the DMSO) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " HM912 " group is to handle HCT116 (colorectal carcinoma) cell 48 hours with HM912 (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " etoposide " group is to handle HCT116 (colorectal carcinoma) cell 48 hours with etoposide (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate.
Figure 11 has shown that HM922 and HM926 cause the necrocytosis according to dosage in H446 (small cell lung cancer) cell." CPT " group is to handle H446 (small cell lung cancer) cell 48 hours with CPT (being dissolved among the DMSO) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " etoposide " group is to handle H446 (small cell lung cancer) cell 48 hours with etoposide (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " HM922 " group is to handle H446 (small cell lung cancer) cell 48 hours with HM922 (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate; " HM926 " group is to handle H446 (small cell lung cancer) cell 48 hours with HM926 (being dissolved in the salt solution) by corresponding 4 concentration gradients (being respectively 0,0.1,1.0,10 micromoles) in X-coordinate.
Embodiment
The following examples further illustrate the present invention, but are construed as limiting the invention never in any form.
Synthetic and the anticancer evaluation of embodiment 1:HM910
(a) HM910's is synthetic
Synthetic route chart as shown in Figure 2.
Diethylamine 2.5mL is dissolved in the 30mL ether, adds the diethyl ether solution 5mL of 0.3mL phosphorus trichloride, and stirring under the reactant room temperature suitably heated up and stirred in 1 hour is no more than 5 hours.Filter, after filtrate decompression concentrates, in residue, add the 15mL pyridine, add 20mL pyridine dissolved CPT 600mg, tetrazole 240mg more successively, stirred overnight at room temperature.In reactant, add 4mL water, stir that the evaporated under reduced pressure solvent gets solid after 0.5 hour; Solid 15mL dissolve with methanol, the iodine pyridine solution of adding 1mL 0.4mol/L stirred 0.5 hour, and reaction solution pressure reducing and steaming methyl alcohol, solid add entry 40 * 3mL after dissolving with the 60mL methylene dichloride, extracts 3 times, combining water layer, the reduction vaporization water layer gets solid; The solid acetone recrystallization gets target compound 0.39g, and is water-soluble＞10mg/mL, yield: 46.8%.
1H?NMR(500MHz，CDCl
3)：δ8.385(s，1H)，8.202-8.185(d，1H)，7.949-7.933(d，1H)，7.844-7.815(t，1H)，7.683-7.651(m，2H)，5.550-5.516(d，1H)，5.319-5.269(m，3H)，2.862-2.836(m，4H)，2.172-2.100(m，1H)，2.067-1.995(m，1H)，1.172-1.143(t，6H)，0.909-0.880(t，3H)；
13C?NMR(125MHz，CDCl
3)：δ169.000，156.489，151.529，147.783，147.541，144.449，130.035，129.589，128.626，127.397，127.039，126.906，118.630，97.542，75.765，65.641，48.840，40.508，32.850，32.789，9.803，6.655；
31P?NMR(202MHz，CDCl
3)：δ1.577；[M+1]484。
(b) anticancer evaluation
In order to measure the ability of formula I compound kill cancer cell, we utilize the CellTiter-Glo test kit of Promega company, have carried out the cytoactive analysis with allogenic cell not.This test kit is by enzymatic luciferase test ATP level.The viable cell that has eubolism speed and produce normal level ATP has high luciferase substrate turnover, and it needs ATP to carry out enzymatic reaction and sends fluorescent signal.On the contrary, dead cell will provide low fluorescent signal result, because their metabolic function disappears.The fluorescent signal that sends will be caught by photometer.
For carrying out activation analysis, small cell lung cancer cell (ATCC catalog number (Cat.No.) H446), breast cancer cell (ATCC catalog number (Cat.No.) MDAMB231) or colon cancer cell (ATCC catalog number (Cat.No.) HCT116) are seeded in 96 orifice plates, handled 24,48,72 hours with formula I representation compound and other cancer therapy drugs.At each time point, with cell and CellTiter-Glo reagent mix 1 hour and write down fluorescent signal.
For Caspase activation, cell through separately reagent after different time points is handled, similarly analyze with the Caspase-Glo3/7 test kit of Promega.The mechanism that Caspase 3/7Glow analyzes is to utilize the Caspase3/7 substrate that merges with the Luciferase substrate, its Caspase that can be activated 3/7 cracking.The Luciferase substrate that discharges passes through enzyme reaction again and sends fluorescent signal.Opposite with activation analysis, the restricted step of this analysis is the Caspase activation.Have the dead cell that activates Casapsed and have the high fluorescent signal reading that is recorded in the photometer.
The antitumour activity of compound H M910 is as shown in Fig. 6-8 and table 1-3.
Table 1: use the CPT of respective concentration and the survival rate that HM910 handles back H446 (small cell lung cancer) cell
Can see that water miscible HM910 causes the necrocytosis according to dosage in H446 (small cell lung cancer) cell, its effect is better than CPT.
Table 2: use the CPT of respective concentration and the survival rate that HM910 handles back MDAMB231 (mammary cancer) cell
Can see that water miscible HM910 causes the necrocytosis according to dosage in MDAMB231 (mammary cancer) cell, its effect and CPT are suitable.
Table 3: use the CPT of respective concentration and the survival rate that HM910 handles back HCT116 (colorectal carcinoma) cell
Can see that water miscible HM910 causes the necrocytosis according to dosage in HCT116 (colorectal carcinoma) cell, its effect and CPT are suitable.
(c) toxicological evaluation
Test group (HM910): select 12 of Healthy female Balb/c nude mices (Shanghai Slac Experimental Animal Co., Ltd., SPF level).Wherein 8 female nude mices are used for administration, and weekly twice, give HM910 two weeks continuously, dosage is 10mg/kg, 30mg/kg.Tried thing and passed through intravenous administration by the administration volume of 0.2mL/20g.
Control group (topotecan): select 12 of Healthy female Balb/c nude mices (Shanghai Slac Experimental Animal Co., Ltd., SPF level).Wherein 8 female nude mices are used for administration, and weekly twice, give topotecan two weeks continuously, dosage is 10mg/kg.Tried thing and passed through intravenous administration by the administration volume of 0.2mL/20g.
All animals are carried out twice cage limit observation every day, whether have situations such as morbidity, death, infringement to occur to determine it, and whether sufficient for food and water supply.All animals of experimental session carry out twice detailed clinical observation every day; Experimental session writes down the administration same day and tests the body weight of the last day.Animal to all survivals when experiment finishes carries out euthanasia.
Test-results: twice weekly, after continuous two all intravenous injections give test group HM910 30mg/kg, all animal subjects are all survived to the experiment end, the toxic reaction relevant with being tried thing do not occur, and the animal subject body weight have increased by 6.64% gradually in experimentation.
After twice, continuous two all intravenous injections gave control group topotecan 10mg/kg weekly, all animal subjects were all survived to the experiment end, but redness appears in control group injection place, and the animal subject body weight has become thin 10.06% gradually in experimentation.
In sum, female nude mice toxic reaction do not occur after twice, continuous two all veins give HM910 30mg/kg weekly, and its maximum tolerated dose is greater than 30mg/kg.The maximum tolerated dose of control group (topotecan) is less than 10mg/kg.
Synthetic and the anticancer evaluation of embodiment 2:HM912
(a) HM912's is synthetic
Synthetic route chart as shown in Figure 3.
Diisopropylamine 3.2mL is dissolved in the 30mL ether, adds the diethyl ether solution 5mL of 0.3mL phosphorus trichloride, and stirring under the reactant room temperature suitably heated up and stirred in 1 hour is no more than 5 hours.Normal temperature filters, and after filtrate concentrates, adds the 15mL pyridine in residue, adds 20mL pyridine dissolved CPT 600mg, tetrazole 240mg successively, and stirred overnight at room temperature.In reactant, add 4mL water, after stirring, concentrating, get solid; Solid 15mL dissolve with methanol, the iodine pyridine solution of adding 1mL 0.4mol/L, after the stirring, reaction solution pressure reducing and steaming methyl alcohol, solid add entry 40 * 3mL after dissolving with the 60mL methylene dichloride, extract combining water layer, the most of water of pressure reducing and steaming, C 3 times
18Reversed-phase column is purified, and gets faint yellow solid 0.3g, and is water-soluble＞10mg/mL, yield: 30.2%.
1H?NMR(400MHz，MeOD)：δ8.533(s，1H)，8.133-8.112(d，1H)，8.007-7.987(d，1H)，7.827-7.789(t，1H)，7.758(s，1H)，7.662-7.625(t，2H)，5.604-5.563(d，1H)，5.417-5.376(d，1H)，5.150(s，2H)，3.460-3.398(m，2H)，2.192-2.077(m，2H)，1.295-1.279(d，12H)，1.033-0.998(t，3H)；
13C?NMR(100MHz，MeOD)：δ171.600，159.255，153.833，151.311，149.843，147.188，132.949，131.730，130.702，130.232，129.856，129.734，129.016，120.289，100.393，78.609，78.528，67.720，51.477，34.715，19.429，8.375；
31P?NMR(161MHz，MeOD)：δ2.161；[M+1]512。
(b) anticancer evaluation
Utilize the method described in the embodiment 1 (b) to test the antitumour activity of compound H M912, test-results is as shown in Fig. 9-10 and table 4-5.
Table 4: with CPT, the HM912 of respective concentration, the survival rate that etoposide is handled back H446 (small cell lung cancer) cell
Can see that water miscible HM912 causes the necrocytosis according to dosage in H446 (small cell lung cancer) cell, its effect is better than CPT, also is better than etoposide (in clinical use, the cell target spot is topo II).
Table 5: with CPT, the HM912 of respective concentration, the survival rate that etoposide is handled back HCT116 (colorectal carcinoma) cell
Can see that water miscible HM912 causes the necrocytosis according to dosage in HCT116 (colorectal carcinoma) cell, its effect is better than CPT, also is better than etoposide (in clinical use, the cell target spot is topo II).
Synthetic and the anticancer evaluation of embodiment 3:HM922
Synthetic route chart as shown in Figure 4.
Pyrrolidine 2.1mL is dissolved in the 30mL ether, adds the diethyl ether solution 5mL of 0.3mL phosphorus trichloride, and stirring under the reactant room temperature suitably heated up and stirred in 1 hour is no more than 5 hours.Normal temperature filters, and after filtrate concentrates, adds the 15mL pyridine in residue, adds 20mL pyridine dissolved CPT 600mg, tetrazole 240mg successively, and stirred overnight at room temperature.In reactant, add 4mL water, after stirring, concentrating, get solid; Solid 15mL dissolve with methanol, the iodine pyridine solution of adding 1mL 0.4mol/L is after the stirring, reaction solution pressure reducing and steaming methyl alcohol, solid adds entry 40 * 3mL after dissolving with the 60mL methylene dichloride, extracts 3 times, combining water layer, the most of water of pressure reducing and steaming, the C18 reversed-phase column is purified, and gets faint yellow solid 0.26g, water-soluble＞10mg/mL, yield: 30.7%.
1H?NMR(400MHz，MeOD)：δ8.601(s，1H)，8.188-8.166(d，1H)，8.063-7.043(d，1H)，7.873-7.835(t，1H)，7.783(s，1H)，7.712-7.675(t，1H)，5.631-5.589(d，1H)，5.441-5.399(d，1H)，5.295(s，2H)，3.327-3.223(t，4H)，2.210-2.075(m，2H)，2.017-1.966(t，4H)，1.042-1.005(t，3H)；
13C?NMR(100MHz，MeOD)：δ170.158，157.776，152.381，149.579，148.365，145.736，131.443，130.223，129.288，128.719，128.398，128.194，127.512，118.853，98.767，77.075-76.995，66.208，49.995，45.109，33.238-33.157，23.654，6.775；
31P?NMR(162MHz，MeOD)：δ2.488；[M+1]482。
Utilize the method described in the embodiment 1 (b) to test the antitumour activity of compound H M922, test-results is as shown in Figure 11 and table 6 hereinafter.
Synthetic and the anticancer evaluation of embodiment 4:HM926
Synthetic route chart as shown in Figure 5.
Morpholine 2.1mL is dissolved in the 30mL ether, adds the diethyl ether solution 5mL of 0.3mL phosphorus trichloride, and stirring under the reactant room temperature suitably heated up and stirred in 1 hour is no more than 5 hours.Normal temperature filters, and after filtrate concentrates, adds the 15mL pyridine in residue, adds 20mL pyridine dissolved CPT 600mg, tetrazole 240mg successively, and stirred overnight at room temperature.In reactant, add 4mL water, after stirring, concentrating, get solid; Solid 15mL dissolve with methanol, the iodine pyridine solution of adding 1mL 0.4mol/L, after the stirring, reaction solution pressure reducing and steaming methyl alcohol, solid add entry 40 * 3mL after dissolving with the 60mL methylene dichloride, extract combining water layer, the most of water of pressure reducing and steaming, C 3 times
18Reversed-phase column is purified, and gets faint yellow solid 0.26g, and is water-soluble＞10mg/mL, yield: 30.7%.
1H?NMR(400MHz，MeOD)：δ8.555(s，1H)，8.145-8.123(d，1H)，8.022-8.002(d，1H)，7.841-7.803(t，1H)，7.737(s，1H)，7.677-7.640(t，1H)，5.612-5.570(d，1H)，5.427-5.385(d，1H)，5.224(s，2H)，3.835-3.812(t，4H)，3.201-3.177(t，4H)，2.213-2.063(m，2H)，1.034-0.998(t，3H)；
13C?NMR(100MHz，MeOD)：δ170.222，157.703，152.275，149.517，148.284，145.728，131.486，130.250，129.263，128.641，128.360，128.200，127.529，118.849，98.672，77.062，66.187，63.493，49.983，43.135，33.092，6.793；
31P?NMR(162MHz，MeOD)：δ2.439；[M+1]498。
Utilize the method described in the embodiment 1 (b) to test the antitumour activity of compound H M926, test-results is as shown in Figure 11 and table 6.
Table 6: the survival rate of handling back H446 (small cell lung cancer) cell with CPT, etoposide, HM922, the HM926 of respective concentration
Can see that water miscible HM922, HM926 cause the necrocytosis according to dosage in H446 (small cell lung cancer) cell, its effect is better than CPT, also is better than etoposide (in clinical use, the cell target spot is topo II).
According to the universal synthesis method shown in Fig. 1 with suitable feedstock production following compound.Work as R
1, R
2In when containing amino or hydroxyl, in building-up process, with amino or hydroxyl protecting group it is protected earlier, synthesize and slough protecting group when finishing again.Those skilled in the art know how to select, add and slough conventional amino or hydroxyl protecting group, for example can be referring to Theodora W.Green, Peter G.M.Wuts:Protective Groups in Organic Synthesis, the 3rd edition, John Wiley ﹠amp; Sons (1999).
Utilize the method described in the embodiment 1 (b) to test the antitumour activity of the compound of embodiment 5-39, utilize the method described in the embodiment 1 (c) to test the maximum tolerated dose of the compound of embodiment 2-39.The test-results that obtains and water-soluble and stable being summarised in the following table 7 of all embodiment compounds.
Table 7: the biological activity of embodiment compound and control compound, physical properties
The explanation of the embodiment of front can disclose general feature of the present invention fully, so that other people are easily concrete application by existing knowledge these embodiments are adjusted and/or adaptations, these all do not depart from scope of the present invention, so these adjustment and revise the replacement that is equal to be considered as embodiment disclosed in the present invention.
Claims (19)
1. the compound of formula I or its pharmaceutically useful salt, solvate, hydrate:
Wherein:
X represents O, S, NH;
R
1, R
2Can be identical or different, represent H or alkyl independently, described alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group;
Perhaps R
1And R
2Form 5-10 unit nitrogen heterocyclic with the N atom that they connected, it is optional by halogen, hydroxyl, sulfydryl, alkyl, haloalkyl, amino, itrile group, nitro, alkoxyl group, alkylthio replacement;
R
3The group of representing H, alkyl or being fallen by enzymic hydrolysis under physiological condition, wherein said alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group.
2. compound according to claim 1 or its pharmaceutically useful salt, solvate, hydrate, wherein X represents O, shown in II:
R wherein
1, R
2And R
3As defined in claim 1.
3. compound according to claim 2 or its pharmaceutically useful salt, solvate, hydrate, wherein R
3Represent H, shown in formula III:
R wherein
1And R
2As defined in claim 1.
4. compound according to claim 1 or its pharmaceutically useful salt, solvate, hydrate, wherein R
3The group that representative can be fallen by enzymic hydrolysis under physiological condition; the optional substituted acyl group of preferred representative; substituting group is selected from: halogen, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl are preferably selected from alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl.
5. compound according to claim 4 or its pharmaceutically useful salt, solvate, hydrate; the wherein said group that can be fallen by enzymic hydrolysis under physiological condition is optional substituted ethanoyl; substituting group is selected from: halogen, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl are preferably selected from alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl.
6. compound according to claim 5 or its pharmaceutically useful salt, solvate, hydrate, the wherein said group that can be fallen by enzymic hydrolysis under physiological condition are ethanoyl, ethylamino formyl radical ethanoyl, diethylamino formyl radical ethanoyl, diisopropylaminoethyl formyl radical ethanoyl.
7. according to each described compound among the claim 1-6 or its pharmaceutically useful salt, solvate, hydrate, wherein R
1And R
2Form 5-10 unit nitrogen heterocyclic with the N atom that they connected, the first nitrogen heterocyclic of preferred 5-9, it is optional by halogen, hydroxyl, sulfydryl, alkyl, haloalkyl, amino, itrile group, nitro, alkoxyl group, alkylthio replacement.
8. compound according to claim 7 or its pharmaceutically useful salt, solvate, hydrate, wherein R
1And R
2Form tetramethyleneimine with the N atom that they connected, morpholine, cis-2, the 6-thebaine, thiomorpholine, piperidines, 3-methoxyl group piperidines, piperazine, pipecoline, the 3-methyl piperidine, the 4-methyl piperidine, indoline, xylylenimine, perhydroisoindole, 5-bromine xylylenimine, 5-fluorine xylylenimine, 4-bromine xylylenimine, 4-fluorine xylylenimine, the amino xylylenimine of 5-, the amino xylylenimine of 4-, 5-hydroxyl xylylenimine, 4-hydroxyl xylylenimine, 5-nitro xylylenimine, 4-nitro xylylenimine, 5-trifluoromethyl xylylenimine, 5-cyano methyl xylylenimine, 4-cyano methyl xylylenimine, 5-trifluoromethyl xylylenimine, 4-trifluoromethyl xylylenimine.
9. compound according to claim 1 or its pharmaceutically useful salt, solvate, hydrate, wherein X represents NH, R
3Represent H or alkyl.
10. compound according to claim 9 or its pharmaceutically useful salt, solvate, hydrate, wherein X represents NH, R
1And R
2In one be hydrogen, another and R
3Identical, represent alkyl, preferably represent C
1-C
8Alkyl, more preferably C
1-C
6Alkyl, most preferable or ethyl.
11. compound according to claim 1 or its pharmaceutically useful salt, solvate, hydrate, wherein said compound is selected from:
12. prepare the method for each described compound among the claim 1-11 or its pharmaceutically useful salt, solvate, hydrate, this method may further comprise the steps:
(1) makes PC1
3With formula R
4The nitrogen azole active substance reaction of H, the inferior phosphoryl triamide intermediate of production IV:
R wherein
4Be
Or
Deng;
(2) the inferior phosphoryl triamide intermediate of formula IV and CPT are reacted,
The CPT 20 (S) of production V-O-phosphoramidite intermediate:
R wherein
4As hereinbefore defined;
(3) CPT 20 (the S)-O-phosphoramidite intermediate of formula V and the amine of formula VI are reacted,
R wherein
1, R
2As each defines among the claim 1-11,
The phosphoramidite intermediate of production VII:
R wherein
1, R
2As each defines among the claim 1-11;
(4) the phosphoramidite intermediate of formula VII is handled with oxygenant or vulcanizing agent, is obtained the compound of formula I:
Wherein X, R
1, R
2As each defines among the claim 1-11, R
3Represent H or alkyl, described alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group;
(5) randomly, make wherein X, R
1, R
2As each defines and R among the claim 1-11
3Represent the compound reaction of formula I compound and the formula IX of H,
Wherein R ' represents hydrogen or alkyl, and described alkyl is optional to be replaced by one or more halogens, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl; Y is Cl or Br;
Generate wherein R
3Representative can for example be chosen wantonly the formula I compound of substituted acyl group by the group that enzymic hydrolysis is fallen under physiological condition;
With,
(6) randomly, the formula I compound with the free form of gained changes into its pharmaceutically useful salt, solvate, hydrate;
Perhaps, this method may further comprise the steps:
(1) makes PC1
3Amine reaction with formula VI:
R wherein
1, R
2As each defines among the claim 1-11,
The phosphoramidite intermediate of production VIII:
R wherein
1, R
2As each defines among the claim 1-11,
(2) make phosphoramidite intermediate and the CPT of formula VIII
At formula R
4The effect of the nitrogen azole active substance of H is reaction down, the phosphoramidite intermediate of production VII:
R wherein
1, R
2As each defines among the claim 1-11, R
4As hereinbefore defined,
(3) the phosphoramidite intermediate of formula VII is handled with oxygenant or vulcanizing agent, obtain formula I compound:
Wherein X, R
1, R
2As each defines among the claim 1-11, R
3Represent H or alkyl, described alkyl is optional to be replaced by halogen, hydroxyl, sulfydryl, amino, cyano group, nitro, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl or heterolipid cyclic group;
(4) randomly, make wherein X, R
1, R
2As each defines and R among the claim 1-11
3Represent the compound reaction of formula I compound and the formula IX of H,
Wherein R ' represents hydrogen or alkyl, and described alkyl is optional to be replaced by one or more halogens, hydroxyl, sulfydryl, alkoxyl group, alkylthio, thiazolinyl, alkynyl, aryl, heteroaryl, heterolipid cyclic group, alkoxy carbonyl, the optional formamyl that is replaced by 1 or 2 alkyl; Y is Cl or Br;
Generate wherein R
3Representative can for example be chosen wantonly the formula I compound of substituted acyl group by the group that enzymic hydrolysis is fallen under physiological condition;
With
(5) randomly, the formula I compound with the free form of gained changes into its pharmaceutically useful salt, solvate, hydrate.
13. method according to claim 12, wherein said oxygenant are selected from moisture or water-free I
2/ THF, moisture or water-free I
2/ pyridine, moisture or water-free H
2O
2, moisture or water-free tertbutyl peroxide.
14. method according to claim 12, wherein said vulcanizing agent is selected from S
4, S
8, Beaucage reagent.
15. as each described compound among the claim 1-11 of medicine or its pharmaceutically useful salt, solvate, hydrate.
16. a pharmaceutical composition, it comprises each described compound or its pharmaceutically useful salt, solvate, hydrate and at least a pharmaceutically acceptable carrier among at least a claim 1-11.
17. pharmaceutical composition according to claim 16, it also comprises other anticarcinogens.
18. each described compound or its pharmaceutically useful salt among the claim 1-11, solvate, hydrate (optional with other anticarcinogen combination) are used for the treatment of purposes in the medicine of cancer in preparation, wherein said cancer is preferably selected from lung cancer, mammary cancer, colorectal carcinoma, the rectum cancer, 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, more preferably be selected from mammary cancer, colorectal carcinoma, the rectum cancer, lung cancer, particularly small cell lung cancer.
19. treat mammiferous method for cancer, it comprises each described compound or its pharmaceutically useful salt, solvate, hydrate and optional other anticarcinogens of using among the claim 1-11 of administration treatment significant quantity.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62195394A (en) * | 1986-02-24 | 1987-08-28 | Yakult Honsha Co Ltd | Novel camptothecin derivative and production thereof |
| JPS62195393A (en) * | 1986-02-21 | 1987-08-28 | Yakult Honsha Co Ltd | Novel camptothecin derivative and production thereof |
| CA2379660A1 (en) * | 1999-08-03 | 2001-02-08 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
| CN101628919A (en) * | 2009-08-20 | 2010-01-20 | 浙江大学 | Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof |
-
2011
- 2011-02-24 CN CN2011100452984A patent/CN102161680A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62195393A (en) * | 1986-02-21 | 1987-08-28 | Yakult Honsha Co Ltd | Novel camptothecin derivative and production thereof |
| JPS62195394A (en) * | 1986-02-24 | 1987-08-28 | Yakult Honsha Co Ltd | Novel camptothecin derivative and production thereof |
| CA2379660A1 (en) * | 1999-08-03 | 2001-02-08 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
| CN101628919A (en) * | 2009-08-20 | 2010-01-20 | 浙江大学 | Camptothecin, self-emulsifying medicine precursor of derivative thereof and application thereof |
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