CN1491947A - C10 ester carbonate substituted taxadane - Google Patents
C10 ester carbonate substituted taxadane Download PDFInfo
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- CN1491947A CN1491947A CNA011424087A CN01142408A CN1491947A CN 1491947 A CN1491947 A CN 1491947A CN A011424087 A CNA011424087 A CN A011424087A CN 01142408 A CN01142408 A CN 01142408A CN 1491947 A CN1491947 A CN 1491947A
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- pyridyl
- taxan
- thienyl
- furyl
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Abstract
The present invention provides taxane with C10 carbonate substituent, C7 hydroxy substituent and serial C2, C9 and C14 side chain substituents.
Description
Background of invention
The present invention relates to have new Taxan as the special purposes of antineoplastic agent.
Bearing taxanes in the terpenes comprises Baccatine III and taxol, all is the problem that people paid close attention at biology and chemical field.Taxol itself can be used as the chemotherapeutic of cancer, and has tumors inhibition activity widely.Taxol has 2 ' R, 3 ' S configuration and following structural formula:
Wherein, Ac is an ethanoyl.
People such as Colin are in U.S. Pat 4,814, reported in 470 have active obviously greater than a kind of specific paclitaxel analogs of taxol.One of these analogues are often referred to many Xi Taqi (docetaxel), have following structural formula:
Although taxol and many Xi Taqi are useful chemotherapeutics, their curative effect is limited, comprise the curative effect of limited cancer to particular type and when with the various dose administration to toxicity of patient etc.Therefore, need development to have better therapeutic and lower toxic other chemotherapeutic.
Therefore, one of purpose of the present invention be to provide a kind of aspect the curative effect of antineoplastic agent and the toxicity aspect than the taxol and the more desirable Taxan of Xi Taqi that manys.Usually, these Taxans have the carbonic ether substituting group in the C-10 position, have the C (2) of hydroxyl substituent and certain limit in the C-7 position, C (9), C (14), and C (13) side chain substituents.
Therefore, say concisely, the present invention relates to the Taxan composition, promptly relate to the pharmaceutical composition that contains Taxan and pharmaceutically acceptable carrier and the method for administration.
Other purpose of the present invention and feature will and indicate in the appearance of this paper back portions.
DESCRIPTION OF THE PREFERRED
In one embodiment of the invention, Taxan of the present invention is corresponding to structural formula (1):
Wherein:
R
2Be acyloxy;
R
7Be hydroxyl;
R
9Be ketone group, hydroxyl, or acyloxy;
R
10Be carbonic ether;
R
14Be hydrogen or hydroxyl;
X
3For replace or unsubstituted alkyl, thiazolinyl, alkynyl, phenyl or heterocyclic radical; Wherein alkyl comprises at least two carbon atoms
X
5For-COX
10,-COOX
10, or-CONHX
10
X
10Be alkyl, substituted hydrocarbon radical, or heterocycle;
Ac is an ethanoyl; And
R
7, R
9And R
10Independently have α or β three-dimensional chemical configuration.
In one embodiment, R
2Be ester group (R
2aC (O) O-), carbamate groups (R
2aR
2bNC (O) O-), carbonate group (R
2aOr thiocarbamate base (R OC (O) O-),
2aSC (O) O-), wherein, R
2aAnd R
2bBe hydrogen independently, alkyl, the alkyl of replacement or heterocyclic radical.In preferred embodiments, R
2Be ester group (R
2aC (O) O-), R
2aBe aryl or heteroaryl.In another preferred embodiment, R
2Be ester group (R
2aC (O) O-), R
2aFor replacing or unsubstituted phenyl furyl, thienyl, or pyridyl.R in a more preferred embodiment
2Be benzoyloxy.
R in one embodiment of the invention
9During for ketone group, R in other embodiment
9Can have α or β three-dimensional chemical configuration, preferred β three-dimensional chemical configuration, and can be, for example α-or beta-hydroxy or α-or β-acyloxy.For example, work as R
9During for acyloxy, it can be ester group (R
9aC (O) O-), carbamate groups (R
9aR
9bNC (O) O-), carbonate group (R
9aOr thiocarbamate base (R OC (O) O-),
9aSC (O) O-), wherein, R
9aAnd R
9bBe hydrogen independently, alkyl, the alkyl of replacement or heterocyclic radical.If R
9Be ester group (R
9aC (O) O-), R
9aBe to replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted aryl, or replacement or unsubstituted assorted virtue exist.And more preferably R
9Be ester group (R
9aC (O) O-), R
9aFor replacing or unsubstituted phenyl, replace or unsubstituted furyl, replace or unsubstituted thienyl, or replacement or unsubstituted pyridine base.R in one embodiment
9Be ester group (R
9aC (O) O-), R wherein
9aBe methyl, ethyl, propyl group (straight chain, side chain or ring-type), butyl (straight chain, side chain or ring-type), amyl group (straight chain, side chain or ring-type), or hexyl (straight chain, side chain or ring-type).In another embodiment, R
9Be ester group (R
9aC (O) O-), R wherein
9aBe the methyl that replaces, the ethyl of replacement, the propyl group of replacement (straight chain, side chain or ring-type), the butyl (straight chain of replacement; side chain or ring-type), the amyl group of replacement (straight chain, side chain or ring-type), or the hexyl (straight chain, side chain or ring-type) that replaces; wherein substituting group is selected from heterocyclic radical, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy; hydroxyl, the hydroxyl of protection, carbonyl, acyloxy; nitro, amino, amido, sulfydryl; ketal group, acetal radical, ester group and ether, but do not comprise the phosphorated group.
In one embodiment, R
10Be R
10aOCOO-, wherein R
10aFor (i) replaces or unsubstituted C
1To C
8Alkyl (straight chain, side chain or ring-type), methyl for example, ethyl, propyl group, butyl, amyl group, or hexyl; (ii) replace or unsubstituted C
2To C
8Thiazolinyl (straight chain, side chain or ring-type), vinyl for example, propenyl, butenyl, pentenyl, or hexenyl; (iii) replace or unsubstituted C
2To C
8Alkynyl (straight or branched), ethynyl for example, proyl, butynyl, pentynyl, or hexin base; (iv) replace or unsubstituted phenyl; Or (v) replace or unsubstituted heteroaryl for example furyl, thienyl or pyridyl.Substituting group can be alkyl or other local and the alkyl that replaces define consistent any heteroatomic substituting group that contains herein.In preferred embodiments, R
10aBe methyl, ethyl, straight chain, side chain or cyclopropyl, straight chain, side chain or cyclobutyl, straight chain, side chain or cyclopentyl, straight chain, side chain or cyclohexyl, straight chain, side chain or cyclopropenyl radical, isobutenyl, furyl, or thienyl.In another preferred embodiment, R
10aBe the ethyl that replaces, the propyl group of replacement (straight chain, side chain or ring-type), the propenyl of replacement (straight or branched); the butenyl that replaces, the furyl of replacement or the thienyl of replacement, wherein substituting group is to be selected from one group that following group is formed, heterocyclic radical; alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy; hydroxyl, the hydroxyl of protection, carbonyl, acyloxy; nitro, amino, amido, sulfydryl; ketal group, acetal radical, ester group and ether, but do not comprise the phosphorated group.
X
3Substituent example comprises and replacing or unsubstituted C
2-C
8Alkyl replaces or unsubstituted C
2-C
8Thiazolinyl replaces or unsubstituted C
2-C
8Alkynyl contains replacement or unsubstituted heteroaryl and the replacement or the unsubstituted phenyl of 5 or 6 annular atomses.Preferred X
3Substituent example comprises and replacing or unsubstituted ethyl, propyl group, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutyl-, furyl, thienyl and pyridyl.
X
5Substituent example comprises-COX
10,-COOX
10, or-CONHX
10, wherein, X
10For replacing or unsubstituted alkyl thiazolinyl, phenyl or heteroaryl, preferred X
5Substituent example comprises-COX
10,-COOX
10, or-CONHX
10, wherein, X
10For (i) replaces or unsubstituted C
1-C
8Alkyl for example replaces or unsubstituted methyl ethyl, propyl group (straight chain, side chain or ring-type), butyl (straight chain, side chain or ring-type), amyl group (straight chain, side chain or ring-type), or hexyl (straight chain, side chain or ring-type); (ii) replace or unsubstituted C
2-C
8Thiazolinyl (straight chain, side chain or ring-type) for example replaces or unsubstituted vinyl propenyl (straight chain, side chain or ring-type), butenyl (straight chain, side chain or ring-type), pentenyl (straight chain, side chain or ring-type), or hexenyl (straight chain, side chain or ring-type); (iii) replace or unsubstituted C
2-C
8Alkynyl (straight or branched) for example replaces or unsubstituted ethynyl proyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or hexin base (straight or branched); (iv) replace or unsubstituted phenyl; Or (v) replace or unsubstituted heteroaryl for example furyl, thienyl or pyridyl.Wherein, wherein substituting group is selected from heterocyclic radical, alkoxyl group, and alkene oxygen base, alkynyloxy group, aryloxy, hydroxyl, the hydroxyl of protection, carbonyl, acyloxy, nitro, amino, amido, sulfydryl, ketal group, acetal radical, ester group and ether, but do not comprise the phosphorated group.
In preferred embodiments, Taxan of the present invention is corresponding to following structural formula (2):
Wherein,
R
7Be hydroxyl;
R
10Be carbonic ether;
X
3For replace or unsubstituted alkyl, thiazolinyl, alkynyl, or heterocyclic radical, wherein alkyl comprises at least two carbon atoms;
X
5For-COX
10,-COOX
10, or-CONHX
10And
X
10Be alkyl, substituted hydrocarbon radical, or heterocycle.
For example, in embodiment preferred corresponding to the Taxan of structure (2), R
10Be R
10aOCOO-, wherein R
10aBe replacement or unsubstituted methyl, ethyl, propyl group, butyl, amyl group or hexyl, more preferably replacement or not substituent methyl, ethyl or propyl group also more preferably replace or unsubstituted methyl, ethyl, preferred especially unsubstituted methyl or ethyl are worked as R
10aWhen being selected from above-mentioned these groups, X in one embodiment
3Be selected from replacement or unsubstituted alkyl, thiazolinyl, phenyl or heterocyclic radical more preferably replace or unsubstituted thiazolinyl, and phenyl or heterocyclic radical also more preferably replace or unsubstituted phenyl or heterocyclic radical, and preferred especially heterocyclic radical is furyl for example, thienyl or pyridyl; Work as R
10aAnd X
3When being selected from above-mentioned these groups, X in one embodiment
5Be selected from-COX
10, X wherein
10Be phenyl, alkyl or heterocyclic radical, more preferably phenyl is selectable, works as R
10aAnd X
3When being selected from above-mentioned these groups, X in one embodiment
5Be selected from-COX
10, X wherein
10Be phenyl, alkyl or heterocyclic radical, more preferably phenyl, or X
5For-COOX
10, X wherein
10Be alkyl, the preferred tertiary butyl, in a more preferred embodiment, and corresponding to the Taxan of structure (2), (i) X wherein
5For-COOX
10, X wherein
10Be the tertiary butyl, or X
5For-COX
10, X wherein
10Be phenyl, (ii) X
3Be to replace or unsubstituted cycloalkyl, thiazolinyl, phenyl or heterocyclic radical more preferably replace or unsubstituted isobutenyl, phenyl, furyl, thienyl or pyridyl, and (iii) R
10aBe unsubstituted methyl, ethyl or propyl group, more preferably methyl or ethyl.
In preferred embodiment corresponding to the Taxan of structure (1) or (2), R wherein
10Be R
10aOCOO-, R
10aFor replacing or unsubstituted ethyl or propyl group, more preferably unsubstituted ethyl or propyl group are worked as R
10aWhen being selected from these above-mentioned groups, X in one embodiment
3Be selected from replacement or unsubstituted cycloalkyl, phenyl or heterocyclic radical more preferably replace or unsubstituted cycloalkyl phenyl, furyl, thienyl or pyridyl; Work as R
10aAnd X
3When being selected from above-mentioned these groups, X in one embodiment
5Be selected from-COOX
10, X wherein
10Be the tertiary butyl, tert-pentyl, isobutyl-, sec.-propyl or replacement or unsubstituted ring alkyl, R
2, R
9And R
14Such as structure (1) and (2) definition, preferably be respectively benzoyloxy, ketone group, and hydrogen.In a more preferred embodiment, corresponding to the Taxan of structure (2), (i) X wherein
5For-COOX
10, X wherein
10Be the tertiary butyl, tert-pentyl, isobutyl-, sec.-propyl or replacement or unsubstituted ring alkyl, the more preferably tertiary butyl, (ii) X
3Be to replace or unsubstituted cycloalkyl phenyl, furyl, thienyl or pyridyl, more preferably unsubstituted cycloalkyl, phenyl, furyl, thienyl or pyridyl, and (iii) R
10aBe unsubstituted ethyl or propyl group, in the scheme of each replacement in this embodiment, when Taxan has structure (1), each R
7And R
10Can have the β three-dimensional chemical configuration, each R
7And R
10Can have the α three-dimensional chemical configuration, work as R
10Has the β three-dimensional chemical configuration, R
7Have the α three-dimensional chemical configuration, or work as R
10Has the α three-dimensional chemical configuration, R
7Has the β three-dimensional chemical configuration.
In preferred embodiment corresponding to the Taxan of structure (1) or (2), R wherein
10Be R
10aOCOO-, wherein R
10aBe methyl.In this embodiment, X
3Be preferably cycloalkyl, isobutenyl, or heterocyclic radical, more preferably heterocyclic radical, more preferably furyl also, thienyl or pyridyl; X
5Be preferably benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl.In the interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, R
14Be hydrogen.In another interchangeable scheme of this embodiment, X
3Be heterocyclic radical; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, and R
14Be hydrogen; In another interchangeable scheme of this embodiment, X
3Be heterocyclic radical; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, and R
14Be hydroxyl; In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be hydroxyl, and R
14Be hydroxyl.In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be hydroxyl, and R
14Be hydrogen.In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be acyloxy, and R
14Be hydroxyl.In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be acyloxy, and R
14Be hydrogen.In each interchangeable embodiment, when Taxan has structure 1, each R
7And R
10Can have the α three-dimensional chemical configuration, each R
7And R
10Can have the α three-dimensional chemical configuration, work as R
10Has the β three-dimensional chemical configuration, R
7Have the α three-dimensional chemical configuration, or work as R
10Has the α three-dimensional chemical configuration, R
7Has the β three-dimensional chemical configuration.
Equally, in the preferred embodiment of Taxan corresponding to structure 1 or 2, R wherein
10Be R
10aOCOO-, wherein R
10aBe ethyl.In this embodiment, X
3Be preferably cycloalkyl, isobutyl phenenyl, substituted-phenyl is p-nitrophenyl for example, or heterocyclic radical, more preferably heterocyclic radical, more preferably furyl also, thienyl or pyridyl; X
5Be preferably benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl.In an interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, R
14Be hydrogen.In another interchangeable scheme of this embodiment, X
3Be heterocyclic radical; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, and R
14Be hydrogen; In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, more preferably tertbutyloxycarbonyl also, R
2Be benzoyl, R
9Be ketone group, and R
14Be hydroxyl; In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be hydroxyl, and R
14Be hydroxyl; In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be hydroxyl, and R
14Be hydrogen.In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be acyloxy, and R
14Be hydroxyl.In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, more preferably tertbutyloxycarbonyl also, R
2Be benzoyl, R
9Be acyloxy, and R
14Be hydrogen.In each interchangeable embodiment, when Taxan has structure 1, each R
7And R
10Can have the α three-dimensional chemical configuration, each R
7And R
10Can have the α three-dimensional chemical configuration, work as R
10Has the β three-dimensional chemical configuration, R
7Have the α three-dimensional chemical configuration, or work as R
10Has the α three-dimensional chemical configuration, R
7Has the β three-dimensional chemical configuration.
Equally, in the preferred embodiment of Taxan corresponding to structure 1 or 2, R wherein
10Be R
10aOCOO-, wherein R
10aBe propyl group.In this embodiment, X
3Be preferably cycloalkyl, isobutyl phenenyl, substituted-phenyl is p-nitrophenyl for example, or heterocyclic radical, more preferably heterocyclic radical, more preferably furyl also, thienyl or pyridyl; X
5Be preferably benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, in an interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, R
14Be hydrogen.In another interchangeable scheme of this embodiment, X
3Be heterocyclic radical; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, and R
14Be hydrogen; In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be ketone group, and R
14Be hydroxyl; In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be hydroxyl, and R
14Be hydroxyl; In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be hydroxyl, and R
14Be hydrogen.In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be acyloxy, and R
14Be hydroxyl.In another interchangeable scheme of this embodiment, X
3Be heterocycle; X
5Be benzoyl, carbalkoxy, or heterocyclic radical carbonyl, more preferably benzoyl, tertbutyloxycarbonyl, or uncle's penta oxygen carbonyl, also more preferably tertbutyloxycarbonyl; R
2Be benzoyl, R
9Be acyloxy, and R
14Be hydrogen.In each interchangeable embodiment, when Taxan has structure 1, each R
7And R
10Can have the β three-dimensional chemical configuration, each R
7And R
10Can have the α three-dimensional chemical configuration, work as R
10Has the β three-dimensional chemical configuration, R
7Have the α three-dimensional chemical configuration, or work as R
10Has the α three-dimensional chemical configuration, R
7Has the β three-dimensional chemical configuration.
Taxan with general formula 1 can obtain by following method; promptly handle beta-lactam and be formed on the C-13 position and have β-substituent compound of amido ester and (see Holton United States Patent (USP) U.S.Pat 5 for details with having the substituent alkoxide of the Fourth Ring parent nucleus of Taxan and C-13 metal oxide; 466; 834), then remove the protecting group of hydroxyl.Beta-lactam has following structural formula (3):
P wherein
2Be hydroxyl protecting group, X
3And X
5Define as the front, and alkoxide has structural formula (4):
Wherein M is metal or ammonium, P
7Be hydroxyl protecting group, and R
10Define as the front.
Alkoxide can be prepared by following method by 10-deacetylate Baccatine III, and promptly selectivity forms the carbonic ether of C (10) hydroxyl, then protects C (7) hydroxyl (as people such as Holton in more full method described in the PCT patent application WO99/09021.) then handle with the metal amide.The acylating agent that is used for C (10) the hydroxyl selectively acylating to Taxan comprises two methylcarbonates, Ue-5908, tert-Butyl dicarbonate, two dimethyl benzyls etc.Although the acidylate of the C of Taxan (10) oh group will be carried out under enough speed concerning many acylating agents, it is found that when in reaction mixture, containing Lewis acid and will improve speed of reaction.Preferred Lewis acid comprises zinc chloride, tin chloride, cerous compounds, cuprous chloride, lanthanum trichloride, dysprosium trichloride, and ytterbium trichloride.Preferred especially zinc chloride or cerous compounds when acylating agent is two carbonic ethers.
In C (2), derivative that C (9) and C (14) position have interchangeable substituent 10-deacetylate Baccatine III and preparation method thereof is known in the prior art.Have the acyloxy substituting group in C (2) position and be not that the Taxan of benzoyloxy can be prepared as follows, for example, at United States Patent (USP) U.S.5, described in 728,725, or people such as Kingston is at United States Patent (USP) U.S.6, described in 002,023 as people such as Holton.Have acyloxy or hydroxyl substituent in C (9) position and replace the Taxan of carbonyl to be prepared as follows, for example, at United States Patent (USP) U.S.6, described in 011,056, or people such as Gunawardana is at United States Patent (USP) U.S.5, described in 352,806 as people such as Holton.The Taxan that has the β hydroxyl substituent in C (14) position can be by the 14-hydroxyl-10-deacetylate Baccatine III preparation of natural generation.
The method of preparation and fractionation beta-lactam starting raw material is usually known.For example, beta-lactam can be according to Holton at United States Patent (USP) U.S.5,430, the preparation of method in 160, the beta-lactam mixture of enantiomers that obtains can by use lipase or for example Patel in United States Patent (USP) U.S.5,879,929 and Patel at United States Patent (USP) U.S.5, enzyme stereo selective hydrolysis described in 567,614 and splitting, or for example use that the liver homogenate described in the PCT application No.00/41204 splits.In preferred embodiments, the beta-lactam of beta-lactam for being replaced by furans at C (4) can prepare by the method shown in the following reaction scheme:
Wherein Ac is an ethanoyl, NEt
3Be triethylamine, CAN is the high cerium of ammonium nitrate, and p-TsOH is a tosic acid.Beef liver splits and can followingly carry out, for example, and by enantiomorph beta-lactam mixture and beef liver suspension (for example be prepared as follows, add 20g refrigerated beef liver in agitator, then add the damping fluid of pH8, making cumulative volume is 1 liter) mixing are split.
Formula formula 1 compound of the present invention comprises aspect the human tumor growth it being effectively suppressing Mammals, preferably the form administration of the pharmaceutical composition that combines with at least a pharmacy or pharmacology acceptable carrier with the The compounds of this invention that comprises antitumor significant quantity.Carrier also is that prior art is known, as vehicle, and vehicle, auxiliary, adjuvant or thinner are inert pharmaceutically, denseness that can be suitable or form form composition and do not reduce any material of the curative effect of antineoplastic compound.Carrier is " acceptable on pharmacy or the pharmacology ", as long as can not cause during to Mammals or people's administration badly when it, hypersensitive or other reaction that things turn out contrary to one's wishes suits.
The pharmaceutical composition that contains antineoplastic compound of the present invention can be by the method preparation of any routine.Suitable preparation depends on selected route of administration.The preparation that composition of the present invention can be made the suiting measures to different conditions of any route of administration depends on selected route of administration.Composition of the present invention can be made the preparation of any route of administration, as long as target tissue is fit to this approach.Suitable route of administration includes, but not limited to oral, parenteral (for example, intravenous, endarterial, subcutaneous, rectum, subcutaneous, intramuscular, in the socket of the eye, in the capsule, intravertebral, endoperitoneal or intrasternal), partial (nose, through skin, intraocular), intravesical, in the sheath, in the intestines, lung, in the lymph, in the chamber, vagina, transurethral, intradermal, ear, intramammary, cheek, normal position, endotracheal, in the damage, through skin, through endoscope, in the mucous membrane, the hypogloeeis and intestines in administration.
The pharmaceutically acceptable carrier that is used for composition of the present invention is well-known to those skilled in the art, and is selected according to more following factors: the concrete antineoplastic compound that uses, its concentration, the bioavailability of stability and target; With the disease that this composition will be treated, imbalance or situation; Individuality, its age, body size and total condition; Approach with administration.Suitable carrier can be determined easily by those of ordinary skills.(see, for example, J.G.Nairn,
Reminciton ' s Pharmaceutical ScienceIn (A.Gennaro volume), Mack publishing company, Easton, Pa., (1985), the 1492-1517 page or leaf, its content is hereby incorporated by reference).
Said composition is preferably made tablet, powder, pill, capsule, gel capsule, Caplet, gelifying agent, the agent of little fat body, granule, solution, suspensoid, emulsion, syrup, elixir lozenge, drageeing, lozenge, or the formulation of other any Orally-administrable.Being used to prepare the technology of oral dosage form and composition such as following reference among the present invention describes:
Modern pharmacy 7 (
7Modern Pharmaceutics), the 9th and 10 chapter (Banker ﹠amp; Rhodes compiles 1979); People such as Lieberman, pharmaceutical dosage form: tablet (
Pharmaceutical Dosage Forms: Tablets) (1981); And Ansel, the pharmaceutical dosage form introduction (
Introduction to Pharmaceutical Dosage Forms) the 2nd edition (1976).
Liquid preparations for oral administration of the present invention is included in the compound of the present invention of the antitumor significant quantity in the pharmaceutically acceptable carrier.The appropriate carrier of solid dosage comprises sugar, and starch and other conventional substances comprise lactose, talcum powder, sucrose, gelatin, carboxymethyl cellulose, agar mannitol, sorbyl alcohol, calcium phosphate, lime carbonate, yellow soda ash, kaolin, alginic acid, gum arabic, W-Gum, yam starch, soluble saccharin, magnesiumcarbonate, tragacanth gum, Microcrystalline Cellulose, silicon dioxide colloid, cross-linked carboxymethyl cellulose sodium, talcum powder, Magnesium Stearate, and stearic acid.In addition, above-mentioned solid dosage can not have afterbirth, or according to the known technology afterbirth, promptly can delay disintegration and absorption.
Antineoplastic compound of the present invention also can preferably be made the preparation of parenterai administration, promptly make transvenous, the injection of endoperitoneal or intrasternal approach.The composition of the present invention that is used for parenterai administration is included in the compound of the present invention of the antitumor significant quantity of pharmaceutically acceptable carrier.The suitable dosage forms of parenterai administration comprises solution, suspension, dispersion, the formulation of emulsion or other any suitable parenterai administration.The technology and the composition that are used to prepare the parenterai administration formulation are that prior art is known.
The appropriate carrier that is used to prepare the liquid dosage form of oral or parenterai administration comprises water-free, the acceptable polar solvent of pharmacy, for example oils, alcohols, amides, ester class, ethers, ketone, hydro carbons and their mixture, also comprise water, salt brine solution, glucose solution (being DW5), electrolyte solution, or other is aqueous, the acceptable liquid of pharmacy.
Suitable is water-free, and the acceptable polar solvent of pharmacy (for example includes, but not limited to alcohols, α-glycerol methylal, β-glycerol methylal, 1, the 3-methyltrimethylene glycol has the fat or the aromatic alcohol of 2-30 carbon atom, for example methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, hexanol, octanol, amylene hydrate, phenylcarbinol, glycerol (glycerine), ethylene glycol, hexylene glycol, the tetrahydro-furfuryl alcohol, lauryl alcohol, hexadecanol, or stearyl-alcohol, the fatty acid ester of Fatty Alcohol(C12-C14 and C12-C18), for example polyalkylene glycol is (for example, polypropylene glycol, polyoxyethylene glycol) anhydro sorbitol, sucrose and cholesterol); Acid amides (for example, N,N-DIMETHYLACETAMIDE (DMA), benzyl benzoyl ester DMA, dimethyl formamide, N-(beta-hydroxyethyl)-lactic amide, N,N-dimethylacetamide, 2-Pyrrolidone, 1-Methyl-2-Pyrrolidone, or Polyvinylpyrolidone (PVP)); Ester class (for example, 1-Methyl-2-Pyrrolidone, 2-Pyrrolidone, acetic ester is monoacetin for example, glyceryl diacetate, and triacetin, the for example sad or oil of cognac of fat or aromatic ester, oleic acid alkyl ester, peruscabin, jasmal, methyl-sulphoxide (DMSO), glyceryl ester be citric acid or tartrate list for example, two or Witepsol W-S 55, ethyl benzoate, ethyl acetate, ethyl-carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, the PEG ester of fatty acid derived, glyceryl monostearate, glyceryl ester are for example single, two, or Witepsol W-S 55, fatty acid ester is Isopropyl myristate for example, and the PEG ester of fatty acid derived is PEG-hydroxy oleate ester for example, with the PEG-hydroxy stearic acid ester, N-Methyl pyrrolidone, pluronic 60, oleic acid polyoxyethylene sorbitol polyester be poly-(oxyethyl group) for example
30-60Sorbyl alcohol gathers (oleic acid ester)
2-4, poly-(oxygen ethene)
15-20Monoleate, poly-(oxygen ethene)
15-20Single 12-hydroxy stearic acid ester and poly-(oxygen ethene)
15-20Single ricinoleate ester, Sorbitan ethoxylate, for example single oleic acid Sorbitan ethoxylate, single palmitinic acid Sorbitan ethoxylate
The mono laurate Sorbitan ethoxylate, Stearinsaeure Sorbitan ethoxylate, and Polysorbate 20,40,60 or 80 (originate from ICI Americas, Wilmington, DE), Polyvinylpyrolidone (PVP), the fatty acid ester that alkene oxygen base is modified, for example poly-hydroxyl oxygen base 40 hydrogenated castor oils and the ethylating Viscotrol C of polyoxy (for example, Cremophor EL solution or Cremophor RH 40 solution), the fatty acid ester of carbohydrate (be monose condenses (for example, pentose such as ribose, ribulose, pectinose, wood sugar, lyxose, and xylulose, hexose such as glucose, fructose, semi-lactosi, seminose and sorbose, triose, tetrose, heptose and hot candy), disaccharides (for example, sucrose, maltose, lactose and trehalose) or oligose or they and C
4-C
22Lipid acid (for example, saturated fatty acid such as sad, lauric acid, myristic acid, palmitinic acid, and stearic acid, and unsaturated fatty acids such as physetoleic acid, oleic acid, elaidic acid, erucic acid, and linolic acid) mixture), or steroid ester); Alkyl with 2-30 carbon atom, aryl, or cyclic ethers (for example, ether, tetrahydrofuran (THF), isosorbide dimethyl ether, the single ethyl ether of DIETHYLENE GLYCOL); Glycofurol (tetrahydrofurfuryl alcohol polyglycol ether); Ketone (for example, acetone, methylethylketone, methyl iso-butyl ketone (MIBK)) with 3-30 carbon atom; Aliphatics with 4-30 carbon atom, cycloaliphatic or aromatic hydrocarbon based (for example, benzene, hexanaphthene, methylene dichloride, dioxolane, hexane, n-decane, n-dodecane, normal hexane, tetramethylene sulfone, tetramethylene sulfone, tetramethylene sulfoxide, toluene, methyl-sulphoxide (DM50), or tetramethylene sulfoxide); Mineral, plant, animal, the oils in natural or synthetic source is (for example, mineral oil such as aliphatics or cerul hydro carbons, aromatic hydrocarbon, blended aliphatics and aromatic hydrocarbon are the hydro carbons on basis, and Refined Paraffin Wax oil, vegetables oil such as Toenol 1140, tung oil tree oil, Thistle oil, soybean oil, Viscotrol C, Oleum Gossypii semen, Peanut oil, rapeseed oil, Oleum Cocois, plam oil, sweet oil, Semen Maydis oil, Fructus Maydis oil, sesame oil and peanut oil and glyceryl ester are for example single, two, Witepsol W-S 55, animal oil is fish oil for example, marine animal oil, Sperm whale oil, cod-Oils,glyceridic,cod-liver, haliver oil, squalene, squalane, and shark liver oil, the ethylating Viscotrol C of oleic oils and polyoxy); Has 1-30 carbon atom and the selectable substituent alkyl or aryl halogenide that surpasses a halogen atom; Methylene dichloride; Monoethanolamine; Petroleum spirit, trolamine (trolamine); ω-3 polyunsaturated fatty acids (for example, alpha-linolenic acid, timnodonic acid, clupanodonic acid, or docosahexenoic acid); The macrogol ester of 12-oxystearic acid and polyethylene glycol (Solutol HS-15 originates from BASF, Ludwigshafen, Germany); The polyoxyethylene glycerol; Sodium laurate; Sodium oleate, or anhydro sorbitol monooleate.
Other is used for pharmacy acceptable solvent of the present invention is well-known to those skilled in the art, and defines in the book below: chemotherapy source register (
The Chemotherapy Source Book) (Williams﹠amp; Wilkens publishes), the pharmaceutical excipient handbook (
The Handbook of Pharmaceutical Excipients), (American Pharmaceutical Association (American Pharmaceutical Association), Washington, D.C. and Great Britain pharmaceutical society (The Pharmaceutical Society of GreatBritain), London, Britain, 1968), modern pharmacy (
Modern Pharmaceutics), (people such as G.Banker, the 3rd edition) (Marcel Dekker, company, New York, New York, 1995),
Therapeutic pharmacology Learn basis (The Pharmacological Bas is of Therapeutics)(Goodman ﹠amp; ' Gilman, McGraw Hill publishes), pharmaceutical formulation (
Pharmaceutical Dosaae Forms), people such as (, compile) H.Lieberman (Marcel Dekker, Inc., New York New York, New York, 1980),
Remington ' s Pharmaceutical Sciences(A.Gennaro compiles, the 19th edition) (Mack publishes, Easton, PA, 1995), American Pharmacopeia 24 (
The United States Pharmacopeia 24), national drug formulary 19
(The National Formulary 19)(National publishes, Philadelphia, PA, 2000), people such as A.J.Spiegel, the purposes of non-aqueous solvent in non-enteron aisle product, (Use of NonaqueousSolvents in Parenteral Products), pharmaceutical science magazine (JOURNAL OF PHARMACEUTICALSCIENCES), the 52nd volume, the 10th phase, 917-927 page or leaf (1963).
Preferred solvent comprises that those are known to the stable material of antineoplastic compound, for example, be rich in the oils of tri-glyceride, Thistle oil for example, soybean oil or their mixture, and the fatty acid ester that alkene oxygen base is modified for example gathers the Viscotrol C (for example, Cremophor EL solution or Cremophor RH 40 solution) of-oxyl (polyoxyl) 40 hydrogenated castor oils and polyoxy ethylization (polyoxyethylated).The tri-glyceride that is purchased comprises Intralipid Salvilipid (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid emulsion (McGaw, Irvine,, California), Liposyn II 20% emulsion (20% lipomul solution, every ml soln contains the 109mg Thistle oil, the 100mg soybean oil, 12mg Yelkin TTS and 25mg glycerine; The Abbott laboratory, Chicago ', Illino is), Liposyn III2% emulsion (2% lipomul solution, every ml soln contains the 100mg Thistle oil, 100mg soybean oil, 12mg Yelkin TTS and 25mg glycerol; The Abbott laboratory; Chicago, Illino is), natural or synthetic glycerine derivative contains 25% to 100% 22 carbon six enoyl-s of lipid acid gross weight; (Dhasco (originates from Martek Biosciences company; Columbia, MD), DHA Maguro (originates from Daito enterprise; Los.Angeles; CA), Soyacal and Travemulsion .Ethanol is to be used to dissolve antineoplastic compound to form solution, the preferred solvent of emulsion etc.
The other accessory constituent that is used for the known various uses of pharmaceutical industry can be included in the composition of the present invention.These components will have the partial character of informing, can improve the stop of antineoplastic compound in the administration site, the stability of protection composition, and control pH value is convenient to the preparation of antineoplastic compound etc.Preferred these components occur separately for every kind being more preferably less than 5% of gross weight less than 15% of composition total weight, and are preferred especially less than 0.5% of composition total weight.Some components, for example filling agent or thinner, can as formulation art known, be constituted to 90% the component that accounts for composition total weight more.Such additive comprises cryoprotective agent preventing the redeposition of Taxan, surfactivity, wetting or emulsifying agent (Yelkin TTS for example; Tween-80, tween Tween 80, general stream Buddhist nun sieve (pluronic) 60; polyoxyethylene stearic acid ester), sanitas (for example, ethyl p-hydroxybenzoate); microbiological antiseptic medicine (for example, benzylalcohol, phenol; meta-cresol, butylene-chlorohydrin, Sorbic Acid; thiomersal(ate) and p-Hydroxybenzoate), be used to regulate the reagent or buffer reagent (for example, the acid of pH value; alkali, sodium acetate, lauric acid Isosorbide Dinitrate); be used to regulate the reagent (for example, glycerine) of osmolarity, thickening material (for example; monostearate aluminium, stearic acid, hexadecanol; stearyl alcohol, guar gum, methylcellulose gum; hydroxypropylcellulose, Tristearoylglycerol, hexadecyl wax ester; polyoxyethylene glycol), tinting material, dyestuff; flow promotor, nonvolatile organopolysiloxane (for example, cyclomethicone); clay (for example; the soap clay), tackiness agent, raising agent; food flavouring; sweetener, sorbent material, weighting agent are (for example; sugar is such as lactose; sucrose, mannitol, or Sorbitol Powder; Mierocrystalline cellulose; or calcium phosphate), diluent (for example, water; salt solution; electrolyte solution), (for example, starch is such as W-Gum for binding agent; wheat starch; rice starch, or yam starch, gelatin; natural gum; tragacanth gum, methylcellulose gum, Vltra tears; Xylo-Mucine; Polyvinylpyrolidone (PVP), carbohydrate, polymkeric substance; gum arabic); (for example, starch is such as W-Gum, wheat starch for decomposition agent; rice starch; yam starch, or carboxymethyl starch, cross-linking polyethylene pyrrolidone; agar; alginic acid, or its salt, for example sodiun alginate; croscarmellose sodium or polyvidone); lubricant (for example, silicon-dioxide, talcum; stearic acid; or its salt Magnesium Stearate for example, or polyoxyethylene glycol), Drug coating (for example; spissated sugar soln contains Sudan Gum-arabic; talcum powder, Polyvinylpyrolidone (PVP), card ripple Bo Er (carbopol) gel; polyoxyethylene glycol or titanium dioxide); and antioxidant (for example, Sodium Pyrosulfite, sodium bisulfite; S-WAT; glucose, phenol, and thiophenol).
In preferred embodiments, pharmaceutical composition of the present invention comprises at least a water-free, pharmacy acceptable solvent, and antineoplastic compound has in ethanol at least about 100,200,300,400,500,600,700 or the solubleness of 800mg/ml.When not being subjected to the restriction of special theory, can think that the dissolve with ethanol degree of antineoplastic compound may be directly relevant with its effect.Antineoplastic compound also can crystallize out in solution.That is to say, can be with crystalloid antineoplastic compound, for example compound 1393, are dissolved in a kind of solvent forming solution, and then, evaporation removes to desolvate carries out recrystallization, and can not form amorphous antineoplastic compound.Also preferred antineoplastic compound has at least less than taxol (paclitaxel) 4,5,6,7,8,9 when measuring according to the identical standard that is proposed in an embodiment, or 10 times IC50 value (that is, producing the drug level of the formation of inhibition 50% bacterium).
By the formulation of these administrations, according to for example patient's physiological condition, the purpose of administration is curative or preventative, and or the known and estimable factor of other professional and technical personnel, can be successive or interruption.
The those of ordinary skill of those treatment tumours can be easy to determine the dosage and the prescription of pharmaceutical composition of the present invention.Can think that the dosage of antineoplastic compound is according to the age, sex, health condition and recipient's weight needs the kinds of Diseases of treatment simultaneously, the number of times of treatment, and the character of target effect is determined.Administration to any pattern, the actual amount of antineoplastic compound, and the necessary dosage arrangement of arrival beneficial effect described herein, also will be partly according to following factor: the bioavailability of antineoplastic compound, the obstacle for the treatment of, required therapeutic dose, and other can conspicuous factor be determined those skilled in the art.In the context of the present invention, Mammals, particularly Ren Lei dosage must be enough to make the treatment curative effect that can reach target in one rational period in Mammals.The significant quantity of preferred antineoplastic compound is no matter be oral or through other route of administration administration, for can cause any dosage of goal treatment curative effect when according to this route of administration administration.The composition of preferred oral administration is preparation by the following method, promptly in the single dose of one or more oral minute preparation, comprise the long-pending 20mg antineoplastic compound at least of every square metre of body surface, or every square metre of body surface long-pending at least 50,100,150,200,300,400, or 500mg antineoplastic compound, wherein the body surface area average out to 1.8m of human body
2Comprise the long-pending about 20mg of every square metre of body surface in the single dose of the composition of preferred oral administration to about 600mg antineoplastic compound, more preferably about 25 to about 400mg/m
2, also more preferably from about 40 arrive about 300mg/m
2, and more preferably from about 50 arrive about 200mg/m
2The composition of preferred parenterai administration is preparation by the following method, promptly comprises the long-pending 20mg antineoplastic compound at least of every square metre of body surface in a single dose, or every square metre of body surface long-pending at least 40,50,100,150,200,300,400, or the 500mg antineoplastic compound.Preferably, in the single dose of one or more parenteral formulations, contain the long-pending about 20mg of every square metre of body surface to about 500mg antineoplastic compound, more preferably about 40 to about 400mg/m
2, also more preferably from about 60 arrive about 350mg/m
2
But dosage can be according to the dose form change for the adjustment that reaches the desired therapeutic effect needs.Should be noted that the effective dosage range that provides at this is not intended to limit the present invention and represents the preferred dosage scope.More preferred dose will be according to indivedual main body adjustment, can must excessive experiment just not known and determine by those of ordinary skills.
The concentration of the antineoplastic compound in composition of liquid medicine is preferably every milliliter of composition and arrives between about 10mg at about 0.01mg, more preferably arrive between about 7mg at every milliliter of 0.1mg, more preferably arrive between about 5mg, more preferably arrive between about 4mg at every milliliter of 1.5mg at every milliliter of 0.5mg.Usually low relatively concentration is preferred, is dissolved in the solution because antineoplastic compound is easier under lower concentration.Be used for oral administration solid composite medicament antineoplastic compound concentration preferably composition total weight about 5% to about 50%, more preferably about 8% to about 40%, and more preferably about 10% to about 30%.
In one embodiment, the solution of oral administration is following preparation, and antineoplastic compound is dissolved in the acceptable middle solution that forms of solvent (for example, ethanol or methylene dichloride) that can dissolve this compound of pharmacy arbitrarily.Add the carrier of the solution shape of proper volume to this solution, Cremophor EL solution for example stirs and forms in order to absorb the pharmacy of patient's oral administration is acceptable.If desired, such solution can be made into and contains minimum ethanol or do not contain the alcoholic acid preparation, because known ethanol can cause opposite pharmacotoxicological effect in a certain concentration of oral preparations in this area.
In another embodiment, the powder of oral administration or tablet are following preparations, and antineoplastic compound is dissolved in the acceptable middle solution that forms of solvent (for example, ethanol or methylene dichloride) that can dissolve this compound of pharmacy arbitrarily.This solution is volatilizable to its drying under reduced pressure the time preferably.Be to add in the dry forward direction solution other carrier, for example Cremophor EL solution.The dry in a vacuum glassy mass that forms of the solution that obtains.This glassy mass mixes the formation powder with tackiness agent.This powder can mix with filler or other conventional film-making agent, is processed into the tablet to patient's oral administration.Also powder can be joined the solution that forms oral administration in the above-mentioned liquid vehicle, emulsion, suspensoid etc.
The emulsion of parenterai administration is prepared as follows, and antineoplastic compound is dissolved in the acceptable middle solution that forms of solvent (for example, ethanol or methylene dichloride) that can dissolve this compound of pharmacy arbitrarily.Add the carrier of the emulsion shape of proper volume to this solution stirring, for example Liposyn II or Liposyn III emulsion form in order to the acceptable emulsion of the pharmacy of patient's parenterai administration.If desired, such emulsion can be made into and contains preparation minimum or that do not contain ethanol or Cremophor solution, because known its a certain concentration administration at parenteral formulation can cause bad pharmacotoxicological effect in this area.
The solution of parenterai administration is following preparation, and antineoplastic compound is dissolved in the acceptable middle solution that forms of solvent (for example, ethanol or methylene dichloride) that can dissolve this compound of pharmacy arbitrarily.Add the carrier of the solution shape of proper volume to this solution, Cremophor solution for example stirs and forms in order to the acceptable solution of the pharmacy of patient's parenterai administration.If desired, such solution can be made into and contains preparation minimum or that do not contain ethanol or Cremophor solution, because known its a certain concentration administration at parenteral formulation can cause bad pharmacotoxicological effect in this area.
If desired; The emulsion of above-mentioned oral or parenterai administration or solution can spissated packaged wrap at IV, in bottle or other conventional containers, and any pharmaceutically acceptable liquid of such usefulness that can be as be known in the art before use, as salt solution, dilution forms acceptable Taxan concentration.
Definition:
Term " hydrocarbon " and " alkyl " in this article refer to organic compound or the group that only is made of carbon and hydrogen.These parts comprise alkyl, thiazolinyl, alkynyl or aromatic base.Also be included as alkyl, thiazolinyl, alkynyl or aromatic base that other aliphatics or cyclic hydrocarbon are replaced.Alkaryl for example, alkene aryl, and alkynes aryl.Unless indication is arranged in addition, these parts preferably contain 1 to 20 carbon atom.
" alkyl of replacement " part is meant the hydrocarbyl portion that is replaced by at least one non-carbon atom, comprises a carbon atom by heteroatoms such as nitrogen, oxygen, silicon, phosphorus, boron, the part that sulphur or halogen atom replace.These substituting groups comprise halogen, heterocycle, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, hydroxyl, the hydroxyl of protection, ketone group, acyl group, acyloxy, nitro, amino, amide group, itrile group, sulfydryl, ketal, acetal, ester group and ether.
Unless indication is arranged in addition, alkyl as described herein is preferably has 1 to 8 carbon atom on the main chain, contain the low alkyl group of 20 carbon atoms at most.They can be straight chain, or side chain or ring-type, comprise methyl, ethyl, propyl group, sec.-propyl, butyl, hexyl etc.
Unless indication is arranged in addition, thiazolinyl as described herein is preferably has 2 to 8 carbon atoms on the main chain, contain the low-grade alkenyl of 20 carbon atoms at most, and they can be straight chain, or side chain or ring-type, comprise vinyl, propenyl, pseudoallyl, butenyl, hexenyl etc.
Unless indication is arranged in addition, alkynyl as described herein is preferably has 2 to 8 carbon atoms on the main chain, contain the low-grade alkynyl of 20 carbon atoms at most, and they can be straight chain, or side chain or ring-type, comprise ethynyl, proyl, butynyl, hexin base etc.
Term " aryl " or " virtue " are meant optional substituted carbocyclic ring aromatic group separately or as the part of other group at this, the monocycle or the bicyclic radicals that preferably in ring, contain 6 to 12 carbon atoms, phenyl for example, xenyl, naphthyl, the phenyl of replacement, the xenyl of replacement, or the naphthyl that replaces, the phenyl of phenyl and replacement is a preferred aryl groups.
Term " halogen " or " halogen " are meant chlorine, bromine, fluorine and iodine separately or as the part of other group at this.
Term " heterocycle " or " heterocyclic " are at this separately or be meant optional substituted as the part of other group, all saturated or undersaturated, monocycle or dicyclo, fragrant or non-fragrance in a ring, have at least one heteroatoms at least, and the group of 5 or 6 atoms is arranged in each ring preferably.Heterocyclic group preferably has 1 or 2 Sauerstoffatom in ring, 1 or 2 sulphur atom, and/or 1-4 nitrogen-atoms, and residue that can be by carbon atom or heteroatoms and molecule bonding mutually.The heterocyclic example comprises for example furyl of heteroaryl, thienyl, and pyridyl ， oxazolyl, pyrryl, indyl, quinolyl, or isoquinolyl etc.Substituent example comprises one or more following groups, alkyl, the alkyl of replacement, ketone group, hydroxyl, the hydroxyl of protection, acyl group; acyloxy, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, halogen, amide group; amino, nitro, itrile group, sulfydryl, ketal, acetal, ester group or ether.
Term " assorted virtue " has at least one heteroatoms at least, and the aromatic group of 5 or 6 atoms is preferably arranged in each ring at this separately or be meant optional substitutedly as the part of other group in a ring.Heterocyclic group preferably has 1 or 2 Sauerstoffatom in ring, 1 or 2 sulphur atom, and/or 1-4 nitrogen-atoms, and residue that can be by carbon atom or heteroatoms and molecule bonding mutually.The heterocyclic example comprises for example furyl of heteroaryl, thienyl, and pyridyl ， oxazolyl, pyrryl, indyl, quinolyl, or isoquinolyl etc.Substituent example comprises one or more following groups, alkyl, the alkyl of replacement, ketone group, hydroxyl, the hydroxyl of protection, acyl group; acyloxy, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, halogen, amide group; amino, nitro, itrile group, sulfydryl, ketal, acetal, ester group or ether.
Term " acyl group " is meant from organic acid-COOH group separately or as the part of other group at this removes hydroxyl and the part that forms, for example, RC (O)-, wherein R is R
1, R
1O-, R
1R
2N-, or R
1S-, R
1Be alkyl, the assorted alkyl that replaces, or heterocycle, R
2Be hydrogen, the alkyl of alkyl or replacement.
Term " acyloxy " is meant above-mentioned carboxyl groups by an oxygen connecting key Cheng Jian separately or as the part of other group at this, for example, and the definition that RC (O) O-wherein is correlated with in R such as the above-mentioned term " acyl group ".
Unless indication is arranged in addition, alkoxycarbonyloxy described herein comprises the hydrocarbon of lower hydrocarbon or replacement or the hydrocarbyl group of replacement.
Unless indication is arranged in addition, carbamoyloxy group described herein partly is carbamic derivative, and wherein one or two hydrogen on the amino is selectable by alkyl, and the alkyl or the heterocyclic group of replacement substitute.
Term " hydroxy protecting group " and " hydroxyl protecting group " are meant the group that can protect the free hydroxyl, and this group (" hydroxyl of protection ") will be used in reaction, not the nubbin of disturbing molecule and being removed.The various protecting groups and the synthetic book below thereof that are used for hydroxyl find, " protecting group in the organic synthesis " (" Protective Groups in Organic Synthesis ") T.W.Greene work, John ' Wiley and Sons publishes, and 1981, or Fieser ﹠amp; Fieser.The example of hydroxyl protecting group comprises methoxymethyl, 1-ethoxyethyl group, benzyloxymethyl; (β-trimethylsilylethoxy)) methyl, THP trtrahydropyranyl, 2; 2; 2-trichlorine ethoxy carbonyl, the tertiary butyl (phenylbenzene) silyl, trialkylsilkl; the trichlorine methoxycarbonyl; with 2,2,2-trichlorine ethoxyl methyl.
As used in this, " Ac " refers to ethanoyl; " Bz " refers to benzoyl; " Et " refers to ethyl; " Me " nail base; " Ph " refers to phenyl; " Pr " refers to propyl group; " Bu " refers to butyl; " Am " refers to amyl group; " cpro " finger ring propyl group; " iPr " refers to sec.-propyl; " tBu " and " t-Bu " refers to the tertiary butyl; " R " refers to low alkyl group, unless otherwise defined; " Py " refers to pyridine or pyridyl; " TES " refers to triethylsilyl; " TMS " refers to trimethyl silyl; " LAH " refers to lithium aluminum hydride; " 10-DAB " refers to that 10-removes the acetyl Baccatine III; " amino protecting group " includes, but are not limited to carbamate, and for example carboxylamine 2,2,2-trichloro ethyl ester, or t-butyl carbamate; " hydroxyl protecting group " refer to-OP wherein P be hydroxy-protective group; " PhCO " refers to phenylcarbonyl group; " tBuOCO " and " Boc " refers to tert-butoxycarbonyl; " tAmOCO " refers to tert-pentyloxy carbonyl; " 2-FuCO " refers to the 2-furyl carbonyl; " 2-ThCO " refers to the 2-thienyl carbonyl; " 2-PyCO " refers to 2-pyridyl carbonyl; " 3-PyCO " refers to 3-pyridyl carbonyl; " 4-PyCO " refers to 4-pyridyl carbonyl; " C
4H
7CO " refer to the butenyl carbonyl; " tC
3H
5CO " refer to trans-propenyl carbonyl; " EtOCO " refers to ethoxy carbonyl; " ibueCO " refers to the isobutenyl carbonyl; " iBuCO " refers to the isobutyl-carbonyl; " iBuOCO " refers to isobutoxy carbonyl; " iPrOCO " refers to isopropoxy carbonyl; " nPrOCO " propoxycarbonyl of making a comment or criticism; " nPrCO " the propyl group carbonyl of making a comment or criticism; " ibue " refers to isobutenyl; " THF " refers to tetrahydrofuran (THF); " DMAP " refers to 4-dimethylaminopyridine; " LHMDS " refers to hexamethyl dimethyl silanyl lithium nitride (LithiumHexamethylDiSilazanide).
Illustrate the present invention with the following examples.
Embodiment 1
10-ethoxycarbonyl-10-deacetylate Baccatine III
Under 25 ℃, at 0.941 gram (1.73 mmole) 10-deacetylate Baccatine III and 0.043 gram (0.17 mmole) CeCl
3Add 0.64 milliliter of (4.32 mmole) diethylpyrocarbonate in the mixture that in 40 milliliters of THF, forms.After 3 hours reaction mixture is diluted with 200 milliliters of ethyl acetate, uses 50 milliliters of saturated aqueous solution of sodium bicarbonate and salt water washing 3 times then, with organic extraction with dried over sodium sulfate and vacuum concentration.The crude product solid is dodged the formula column chromatography purification by silica gel,, obtain 0.960 gram (90%) 10-ethoxycarbonyl-10-deacetylate Baccatine III with 40% ethyl acetate/hexane wash-out.
7-3,5-dimethylphenyl silyl-10-ethoxycarbonyl-10-deacetylate Baccatine III.
Under-10 ℃ and nitrogen atmosphere, in 1.02 gram (1.65 mmole) 10-solution that ethoxycarbonyl-10-deacetylate Baccatine III forms, drip 0.668 milliliter of (4.00 mmole) Chlorodimethyl phenyl silicomethane and 2.48 milliliters of (30.64 mmole) pyridines in 30 milliliters of THF.After 90 minutes, with the mixture diluted of this mixture with 200 milliliters of 1: 1 ethyl acetate and hexane.This mixture is washed with 30 milliliters of saturated aqueous solution of sodium bicarbonate, separate organic layer.With the mixture extraction of water layer,, use dried over sodium sulfate, vacuum concentration with the organic layer salt water washing that merges with 50 milliliters of 1: 1 ethyl acetate and hexane.The crude product solid by silica gel rapid column chromatography purifying, with 30% ethyl acetate/hexane wash-out, is obtained 1.16 gram (94%) 7-3,5-dimethylphenyl silyl-10-ethoxycarbonyl-10-deacetylate Baccatine IIIs.
1HNMR (400MHz, CDCl
3): δ 8.09 (dm, J=7.64Hz, 2H, benzoic ether, o), 7.59 (tt, J=7.54,1.43Hz, 1H, benzoic ether, p), 7.57 (m, 2H, phenyl, o), 7.46 (t, J=7.54Hz, 2H, benzoic ether, m), 7.37-7.33 (m, 3H, phenyl, m, p), 6.21 (s, 1H, H10), 5.63 (d, J=7.05Hz, 1H, H2), 4.87-4.80 (m, 2H, H5 and H13), 4.44 (dd, J=6.84,10.37Hz, 1H, H7), (4.27 d, J=8.27Hz, 1H, H20 α), 4.16 (qm, J=7.00Hz, 2H, CH
3-CH
2-), 4.13 (d, J=8.27Hz, 1H, H20 β), 3.83 (d, J=7.05Hz, 1H, H3), 2.34 (ddd, J=6.84,9.63,14.66Hz, 1H, H6 α), 2.26 (d, J=7.65Hz, 2H, H14 α, β), 2.25 (s, 3H, Ac4), 2.03 (s, 3H, Me18), 1.98 (d, J=5.29,1H, C13OH), 1.77 (ddd, J=2.12,10.37,14.66Hz, 1H, H6 β), 1.73 (s, 1H, Me19), 1.59 (s, 1H, C1OH), 1.32 (t, J=7.00Hz, 3H, CH
3-CH
2-), 1.19 (s, 3H, Me17), 1.07 (s, 3H, Me16), 0.45 (s, 3H, PhMe
2Si-), 0.35 (s, 3H, PhMe
2Si-).
7-3,5-dimethylphenyl silyl-2 '-O-triethylsilyl-3 '-go phenyl-3 '-(2-thienyl)-10-ethoxycarbonyl-10-deacetylate taxotere (taxotere).
Under-45 ℃ of nitrogen atmosphere, 0.409 gram (0.544 mmole) 7-3,5-dimethylphenyl first silica-based-add 0.681 milliliter of 1M solution that (0.681 mmole) LHMDS forms in the solution that the 10-ethoxycarbonyl-10-deacetylate Baccatine III forms in THF in 5.5 milliliters of THF.After 1 hour, slowly add 0.317 gram (0.818 mmole) cis-N-benzoyl-3-silicoheptane alcoxyl base-4-(2-thienyl) solution that azetine-2-ketone forms in 3 milliliters of THF.This mixture is warmed to 0 ℃, after 3 hours, adds 10 milliliters of saturated aqueous solution of sodium bicarbonate, with this mixture with 50 milliliters of ethyl acetate extractions 3 times.With organic extract salt water washing, use dried over sodium sulfate, vacuum concentration.Thick product is dodged the formula column chromatography purification by silica gel; with 40% ethyl acetate/hexane wash-out, obtain 0.574 gram (93%) solid state 7-3,5-dimethylphenyl silyl-2 '-O-triethylsilyl-3 '-go phenyl-3 '-(2-thienyl)-10-ethoxycarbonyl-10-deacetylate taxotere (taxotere).
3 '-remove phenyl-3 '-(2-thienyl)-10-oxyethyl group-10-deacetylate taxotere (taxotere).
Under 0 ℃, in 0.527 gram (0.464 mmole) 7-3,5-dimethylphenyl silyl-2 '-O-triethylsilyl-3 '-go phenyl-3 '-(2-thienyl)-10-ethoxycarbonyl-10-deacetylate taxol (taxotere) in 2 milliliters of CH
3Add 0.5 milliliter of 30%HF aqueous solution in the solution that forms in CN and the 2 milliliters of pyridines, after 3 hours, add 20 milliliters of saturated aqueous solution of sodium bicarbonate, with this mixture with 50 milliliters of ethyl acetate extractions 3 times.With organic extract salt water washing, use dried over sodium sulfate, vacuum concentration.Thick product is dodged the formula column chromatography purification by silica gel, with 70% ethyl acetate/hexane wash-out, obtain 0.411 restraining (100% solid state 3 '-go phenyl-3 '-(2-thienyl)-10-ethoxycarbonyl-10-deacetylate taxotere (taxotere).
M.p.160-161 ℃; [α]
D 25=-59.1 (c1.0in CH
2Cl
2); Calculated value C
44H
55NO
16S:C, 59.65; H, 6.26; Measured value: C, 59.39; H, 6.34.3 '-go phenyl-3 '-(2-thienyl)-10-ethoxycarbonyl-10-deacetylate
Taxotere (taxotere)
1H NMR data
(500MHz，CDCl
3)
| Proton | ??δ(ppm) | Peak shape | ????J(Hz) |
| ???1OH | ????1.68 | ????s | |
| ???2 | ????5.68 | ????d | ????H3(7.0) |
| ???3 | ????3.80 | ????d | ????H3(7.0) |
| ???4Ac | ????2.38 | ????s | |
| ???5 | ????4.95 | ????dd | ????H6β(2.0)，H6β(9.8) |
| ???6α | ????2.56 | ????ddd | ????H7(6.6)，H5(9.8)，H6β(14.65) |
| ???6β | ????1.89 | ????ddd | ????H5(2.0)，H7(10.9)，H6α(14.65) |
| ???7 | ????4.40 | ????ddd | ????C7OH(4.2)，H6α(6.6)，H6β(10.9) |
| ???7OH | ????2.50 | ????d | ????H7(4.2) |
| ???10 | ????6.12 | ????s | |
| ???13 | ????6.25 | ????t | ????H14α(9.1)，H14β(9.1) |
| ???14α | ????2.35 | ????dd | ????H13(9.1)，H14β(14.2) |
| ???14β | ????2.34 | ????dd | ????H13(9.1)，H14α(14.2) |
| ???16Me | ????1.17 | ????s | |
| ???17Me | ????1.26 | ????s | |
| ???18Me | ????1.90 | ????s | |
| ???19Me | ????1.70 | ????s | |
| ???20α | ????4.31 | ????d | ????H20β(8.6) |
| ???20β | ????4.19 | ????d | ????H20α(8.6) |
| ???2′ | ????4.64 | ????dd | ????C2′OH(5.5)，H3′(2.0) |
| ???2′OH | ????3.38 | ????d | ????H3′(5.5) |
| ???3′ | ????5.51 | ????brd | ????NH(9.5) |
| ???NH | ????5.28 | ????d | ????H3′(9.5) |
| 3 ' (2-thienyl), H3 " | ????7.29 | ????dd | 3 ' (2-thienyl), H5 " (1.1), 3 ' (2-thienyl), H3 " (5.1) |
| 3 ' (2-thienyl), H4 " | ????7.02 | ????dd | 3 ' (2-thienyl), H5 " (3.6), 3 ' (2-thienyl), H3 " (5.1) |
| 3 ' (2-thienyl), H5 " | ????7.09 | ????d | 3 ' (2-thienyl), H4 " (3.6) |
| ???Boc | ????1.34 | ????s | |
| Benzoic ether, m | ????7.51 | ????t | Benzoic ether, o (7.8), benzoic ether p (7.8) |
| Benzoic ether, o | ????8.12 | ????D | Benzoic ether, m (7.8) |
| Benzoic ether, p | ????7.61 | ????T | Benzoic ether, m (7.8) |
| ??CH3-CH2-OCO | ????1.37 | ????T | ????CH3-CH2-OCO(7.1) |
| ??CH3-CH2-OCO | ????4.28 | ????M |
Embodiment 2
Except that using other beta-lactams of suitably being protected to replace repeating embodiment 1 described step the beta-lactam, preparation has the series compound of structural formula (13), and wherein substituting group is as shown in the table.
| Compound | ?X 5 | ?X 3 | ?R 10 |
| 1755 | ?tBuOCO- | The 2-thienyl | EtOCOO- |
| 1767 | ?tBuOCO- | Sec.-propyl | EtOCOO- |
| 1781 | ?tBuOCO- | Isobutenyl | EtOCOO- |
| 1799 | ?tBuOCO- | The 2-pyridyl | EtOCOO- |
| 1808 | ?tBuOCO- | The 3-pyridyl | EtOCOO- |
| 1811 | ?tBuOCO- | The 4-pyridyl | EtOCOO- |
| 1822 | ?tBuOCO- | The 2-furyl | EtOCOO- |
| 1838 | ?tBuOCO- | The 3-furyl | EtOCOO- |
| 1841 | ?tBuOCO- | The 3-thienyl | EtOCOO- |
| 1855 | ?tBuOCO- | Cyclobutyl | EtOCOO- |
| 1999 | ?tBuOCO- | Isobutenyl | MeOCOO- |
| 2002 | ?tBuOCO- | The 2-pyridyl | MeOCOO- |
| 2011 | ?tBuOCO- | The 3-pyridyl | MeOCOO- |
| 2020 | ?tBuOCO- | The 4-pyridyl | MeOCOO- |
| 2032 | ?tBuOCO- | The 3-furyl | MeOCOO- |
| 2044 | ?tBuOCO- | The 2-thienyl | MeOCOO- |
| 2050 | ?tBuOCO- | The 3-thienyl | MeOCOO- |
| 2062 | ?tBuOCO- | Sec.-propyl | MeOCOO- |
| 2077 | ?tBuOCO- | Cyclobutyl | MeOCOO- |
| 2666 | ?tBuOCO- | The 2-furyl | MeOCOO- |
| 2972 | ?PhCO- | The 2-thienyl | EtOCOO- |
| 2988 | ?EtOCO- | The 2-thienyl | EtOCOO- |
| 2999 | ?iPrOCO- | The 2-thienyl | EtOCOO- |
| 3003 | ?iBuOCO- | The 2-thienyl | EtOCOO- |
| 3011 | ?2-FuCO- | The 2-thienyl | EtOCOO- |
| 3020 | ?2-ThCO- | The 2-thienyl | EtOCOO- |
| 3033 | ?C 4H 7CO- | The 2-thienyl | EtOCOO- |
| 3155 | ?nPrCO- | The 2-thienyl | EtOCOO- |
| 3181 | ?iBuOCO- | The 2-furyl | EtOCOO- |
| 3243 | ?tC 3H 5CO- | The 2-thienyl | EtOCOO- |
| ??3300 | ??3-PyCO- | The 2-thienyl | ??EtOCOO- |
| ??3393 | ??4-PyCO- | The 2-thienyl | ??EtOCOO- |
| ??3433 | ??2-PyCO- | The 2-thienyl | ??EtOCOO- |
| ??3911 | ??2-FuCO- | The 2-furyl | ??EtOCOO- |
| ??3929 | ??nPrCO- | The 2-furyl | ??EtOCOO- |
| ??3963 | ??iPrOCO- | The 2-furyl | ??EtOCOO- |
| ??4000 | ??tC 3H 5CO- | The 2-furyl | ??EtOCOO- |
| ??4020 | ??EtOCO- | The 2-furyl | ??EtOCOO- |
| ??4074 | ??C 4H 7CO- | The 2-furyl | ??EtOCOO- |
| ??4088 | ??2-ThCO- | The 2-furyl | ??EtOCOO- |
| ??4090 | ??PhCO- | The 2-furyl | ??EtOCOO- |
| ??4374 | ??ibueCO- | The 2-thienyl | ??EtOCOO- |
| ??4636 | ??iBuOCO- | The 3-furyl | ??EtOCOO- |
| ??6466 | ??iPrCO- | The 2-furyl | ??EtOCOO- |
| ??4959 | ??tC 3H 5CO- | The 3-furyl | ??EtOCOO- |
| ??4924 | ??iBuOCO- | The 3-thienyl | ??EtOCOO- |
| ??4844 | ??iBuOCO- | ??Cpro | ??EtOCOO- |
| ??5171 | ??tBuOCO- | ??Cpro | ??EtOCOO- |
| ??5155 | ??iBuOCO- | Isobutenyl | ??EtOCOO- |
| ??1788 | ??tBuOCO- | Isobutenyl | ??EtOCOO- |
| ??1767 | ??tBuOCO- | Sec.-propyl | ??EtOCOO- |
| ??1771 | ??tBuOCO- | Phenyl | ??EtOCOO- |
| ??1866 | ??tBuOCO- | P-nitrophenyl | ??EtOCOO- |
| ??2060 | ??tBuOCO- | Sec.-propyl | ??MeOCOO- |
| ??2092 | ??tBuOCO- | Phenyl | ??MeOCOO- |
| ??2088 | ??tBuOCO- | P-nitrophenyl | ??MeOCOO- |
Embodiment 3
According to embodiment 1 described method and other methods, can prepare following specific Taxan, wherein R with structural formula 14
10As preceding qualification, comprise R
10Be R
10aOCOO-, R
10aReplace or the unsubstituted C for (i)
1To C
8Alkyl such as methyl, ethyl, or straight chain, side chain or ring-type propyl group, butyl, amyl group, or hexyl; (ii) replace or unsubstituted C
3To C
8Alkenyl such as propenyl or straight chain, side chain or ring-type butenyl, pentenyl or hexenyl; (iii) replace or unsubstituted C
3To C
8Alkynyl such as proyl or straight or branched butynyl, pentynyl or hexin base; (iv) replace or unsubstituted phenyl, or (v) replace or unsubstituted heteroaryl such as pyridyl, substituting group can be the group of above-mentioned definition, also can be the alkyl that replaces.For example, R
10Can be R
10aOCOO-is R wherein
10aBe methyl, ethyl, or straight chain, side chain or ring-type propyl group.
| X 5 | ?X 3 | R 10 |
| tBuOCO | The 2-furyl | R aOCOO- |
| tBuOCO | The 3-furyl | R aOCOO- |
| tBuOCO | The 2-thienyl | R aOCOO- |
| tBuOCO | The 3-thienyl | R aOCOO- |
| tBuOCO | The 2-pyridyl | R aOCOO- |
| tBuOCO | The 3-pyridyl | R aOCOO- |
| tBuOCO | The 4-pyridyl | R aOCOO- |
| tBuOCO | Isobutenyl | R aOCOO- |
| tBuOCO | Sec.-propyl | R aOCOO- |
| tBuOCO | Cyclopropyl | R aOCOO- |
| tBuOCO | Cyclobutyl | R aOCOO- |
| tBuOCO | Cyclopentyl | R aOCOO- |
| tBuOCO | Phenyl | R aOCOO- |
| Benzoyl | The 2-furyl | R aOCOO- |
| Benzoyl | The 3-furyl | R aOCOO- |
| Benzoyl | The 2-thienyl | R aOCOO- |
| Benzoyl | The 3-thienyl | R aOCOO- |
| Benzoyl | The 2-pyridyl | R aOCOO- |
| Benzoyl | The 3-pyridyl | R aOCOO- |
| Benzoyl | The 4-pyridyl | R aOCOO- |
| Benzoyl | Isobutenyl | R aOCOO- |
| Benzoyl | Sec.-propyl | R aOCOO- |
| Benzoyl | Cyclopropyl | R aOCOO- |
| Benzoyl | Cyclobutyl | R aOCOO- |
| Benzoyl | Cyclopentyl | R aOCOO- |
| Benzoyl | Phenyl | R aOCOO- |
| 2-FuCO- | The 2-furyl | R aOCOO- |
| 2-FuCO- | The 3-furyl | R aOCOO- |
| 2-FuCO- | The 2-thienyl | R aOCOO- |
| 2-FuCO- | The 3-thienyl | R aOCOO- |
| 2-FuCO- | The 2-pyridyl | R aOCOO- |
| 2-FuCO- | The 3-pyridyl | R aOCOO- |
| 2-FuCO- | The 4-pyridyl | R aOCOO- |
| 2-FuCO- | Isobutenyl | R aOCOO- |
| 2-FuCO- | Sec.-propyl | R aOCOO- |
| 2-FuCO- | Cyclopropyl | R aOCOO- |
| 2-FuCO- | Cyclobutyl | R aOCOO- |
| 2-FuCO- | Cyclopentyl | R aOCOO- |
| 2-FuCO- | Phenyl | R aOCOO- |
| 2-ThCO- | The 2-furyl | R aOCOO- |
| 2-ThCO- | The 3-furyl | R aOCOO- |
| 2-ThCO- | The 2-thienyl | R aOCOO- |
| 2-ThCO- | The 3-thienyl | R aOCOO- |
| 2-ThCO- | The 2-pyridyl | R aOCOO- |
| 2-ThCO- | The 3-pyridyl | R aOCOO- |
| 2-ThCO- | The 4-pyridyl | R aOCOO- |
| 2-ThCO- | Isobutenyl | R aOCOO- |
| 2-ThCO- | Sec.-propyl | R aOCOO- |
| 2-ThCO- | Cyclopropyl | R aOCOO- |
| 2-ThCO- | Cyclobutyl | R aOCOO- |
| 2-ThCO- | Cyclopentyl | R aOCOO- |
| 2-ThCO- | Phenyl | R aOCOO- |
| 2-PyCO- | The 2-furyl | R aOCOO- |
| 2-PyCO- | The 3-furyl | R aOCOO- |
| 2-PyCO- | The 2-thienyl | R aOCOO- |
| 2-PyCO- | The 3-thienyl | R aOCOO- |
| 2-PyCO- | The 2-pyridyl | R aOCOO- |
| 2-PyCO- | The 3-pyridyl | R aOCOO- |
| 2-PyCO- | The 4-pyridyl | R aOCOO- |
| 2-PyCO- | Isobutenyl | R aOCOO- |
| 2-PyCO- | Sec.-propyl | R aOCOO- |
| 2-PyCO- | Cyclopropyl | R aOCOO- |
| 2-PyCO- | Cyclobutyl | R aOCOO- |
| 2-PyCO- | Cyclopentyl | R aOCOO- |
| 2-PyCO- | Phenyl | R aOCOO- |
| 3PyCO- | The 2-furyl | R aOCOO- |
| 3-PyCO- | The 3-furyl | R aOCOO- |
| 3-PyCO- | The 2-thienyl | R aOCOO- |
| 3-PyCO- | The 3-thienyl | R aOCOO- |
| 3-PyCO- | The 2-pyridyl | R aOCOO- |
| 3-PyCO- | The 3-pyridyl | R aOCOO- |
| 3-PyCO- | The 4-pyridyl | R aOCOO- |
| 3-PyCO- | Isobutenyl | R aOCOO- |
| 3-PyCO- | Sec.-propyl | R aOCOO- |
| 3-PyCO- | Cyclopropyl | R aOCOO- |
| 3-PyCO- | Cyclobutyl | R aOCOO- |
| 3-PyCO- | Cyclopentyl | R aOCOO- |
| 3-PyCO- | Phenyl | R aOCOO- |
| 4-PyCO- | The 2-furyl | R aOCOO- |
| 4-PyCO- | The 3-furyl | R aOCOO- |
| 4-PyCO- | The 2-thienyl | R aOCOO- |
| 4-PyCO- | The 3-thienyl | R aOCOO- |
| 4-PyCO- | The 2-pyridyl | R aOCOO- |
| 4-PyCO- | The 3-pyridyl | R aOCOO- |
| 4-PyCO- | The 4-pyridyl | R aOCOO- |
| 4-PyCO- | Isobutenyl | R aOCOO- |
| 4-PyCO- | Sec.-propyl | R aOCOO- |
| 4-PyCO- | Cyclopropyl | R aOCOO- |
| 4-PyCO- | Cyclobutyl | R aOCOO- |
| 4-PyCO- | Cyclopentyl | R aOCOO- |
| 4-PyCO- | Phenyl | R aOCOO- |
| C 4H 7CO- | The 2-furyl | R aOCOO- |
| C 4H 7CO- | The 3-furyl | R aOCOO- |
| C 4H 7CO- | The 2-thienyl | R aOCOO- |
| C 4H 7CO- | The 3-thienyl | R aOCOO- |
| C 4H 7CO- | The 2-pyridyl | R aOCOO- |
| C 4H 7CO- | The 3-pyridyl | R aOCOO- |
| C 4H 7CO- | The 4-pyridyl | R aOCOO- |
| C 4H 7CO- | Isobutenyl | R aOCOO- |
| C 4H 7CO- | Sec.-propyl | R aOCOO- |
| C 4H 7CO- | Cyclopropyl | R aOCOO- |
| C 4H 7CO- | Cyclobutyl | R aOCOO- |
| C 4H 7CO- | Cyclopentyl | R aOCOO- |
| C 4H 7CO- | Phenyl | R aOCOO- |
| EtOCO- | The 2-furyl | R aOCOO- |
| EtOCO- | The 3-furyl | R aOCOO- |
| EtOCO- | The 2-thienyl | R aOCOO- |
| EtOCO- | The 3-thienyl | R aOCOO- |
| EtOCO- | The 2-pyridyl | R aOCOO- |
| EtOCO- | The 3-pyridyl | R aOCOO- |
| EtOCO- | The 4-pyridyl | R aOCOO- |
| EtOCO- | Isobutenyl | R aOCOO- |
| EtOCO- | Sec.-propyl | R aOCOO- |
| EtOCO- | Cyclopropyl | R aOCOO- |
| EtOCO- | Cyclobutyl | R aOCOO- |
| EtOCO- | Cyclopentyl | R aOCOO- |
| EtOCO- | Phenyl | R aOCOO- |
| ibueCO- | The 2-furyl | R aOCOO- |
| ibueCO- | The 3-furyl | R aOCOO- |
| ibueCO- | The 2-thienyl | R aOCOO- |
| ibueCO- | The 3-thienyl | R aOCOO- |
| ibueCO- | The 2-pyridyl | R aOCOO- |
| ibueCO- | The 3-pyridyl | R aOCOO- |
| ibueCO- | The 4-pyridyl | R aOCOO- |
| ibueCO- | Isobutenyl | R aOCOO- |
| ibueCO- | Sec.-propyl | R aOCOO- |
| ibueCO- | Cyclopropyl | R aOCOO- |
| ibueCO- | Cyclobutyl | R aOCOO- |
| ibueCO- | Cyclopentyl | R aOCOO- |
| ibueCO- | Phenyl | R aOCOO- |
| iBuCO- | The 2-furyl | R aOCOO- |
| iBuCO- | The 3-furyl | R aOCOO- |
| iBuCO- | The 2-thienyl | R aOCOO- |
| iBuCO- | The 3-thienyl | R aOCOO- |
| iBuCO- | The 2-pyridyl | R aOCOO- |
| iBuCO- | The 3-pyridyl | R aOCOO- |
| iBuCO- | The 4-pyridyl | R aOCOO- |
| iBuCO- | Isobutenyl | R aOCOO- |
| iBuCO- | Sec.-propyl | R aOCOO- |
| iBuCO- | Cyclopropyl | R aOCOO- |
| iBuCO- | Cyclobutyl | R aOCOO- |
| iBuCO- | Cyclopentyl | R aOCOO- |
| iBuCO- | Phenyl | R aOCOO- |
| iBuOCO- | The 2-furyl | R aOCOO- |
| iBuOCO- | The 3-furyl | R aOCOO- |
| iBuOCO- | The 2-thienyl | R aOCOO- |
| iBuOCO- | The 3-thienyl | R aOCOO- |
| iBuOCO- | The 2-pyridyl | R aOCOO- |
| iBuOCO- | The 3-pyridyl | R aOCOO- |
| iBuOCO- | The 4-pyridyl | R aOCOO- |
| iBuOCO- | Isobutenyl | R aOCOO- |
| iBuOCO- | Sec.-propyl | R aOCOO- |
| iBuOCO- | Cyclopropyl | R aOCOO- |
| iBuOCO- | Cyclobutyl | R aOCOO- |
| iBuOCO- | Cyclopentyl | R aOCOO- |
| iBuOCO- | Phenyl | R aOCOO- |
| iPrOCO- | The 2-furyl | R aOCOO- |
| iPrOCO- | The 3-furyl | R aOCOO- |
| iPrOCO- | The 2-thienyl | R aOCOO- |
| iPrOCO- | The 3-thienyl | R aOCOO- |
| iPrOCO- | The 2-pyridyl | R aOCOO- |
| iPrOCO- | The 3-pyridyl | R aOCOO- |
| iPrOCO- | The 4-pyridyl | R aOCOO- |
| iPrOCO- | Isobutenyl | R aOCOO- |
| iPrOCO- | Sec.-propyl | R aOCOO- |
| iPrOCO- | Cyclopropyl | R aOCOO- |
| iPrOCO- | Cyclobutyl | R aOCOO- |
| iPrOCO- | Cyclopentyl | R aOCOO- |
| iPrOCO- | Phenyl | R aOCOO- |
| nPrOCO- | The 2-furyl | R aOCOO- |
| nPrOCO- | The 3-furyl | R aOCOO- |
| nPrOCO- | The 2-thienyl | R aOCOO- |
| nPrOCO- | The 3-thienyl | R aOCOO- |
| nPrOCO- | The 2-pyridyl | R aOCOO- |
| nPrOCO- | The 3-pyridyl | R aOCOO- |
| nPrOCO- | The 4-pyridyl | R aOCOO- |
| nPrOCO- | Isobutenyl | R aOCOO- |
| nPrOCO- | Sec.-propyl | R aOCOO- |
| nPrOCO- | Cyclopropyl | R aOCOO- |
| nPrOCO- | Cyclobutyl | R aOCOO- |
| nPrOCO- | Cyclopentyl | R aOCOO- |
| nPrOCO- | Phenyl | R aOCOO- |
| nPrCO- | The 2-furyl | R aOCOO- |
| nPrCO- | The 3-furyl | R aOCOO- |
| nPrCO- | The 2-thienyl | R aOCOO- |
| nPrCO- | The 3-thienyl | R aOCOO- |
| nPrCO- | The 2-pyridyl | R aOCOO- |
| nPrCO- | The 3-pyridyl | R aOCOO- |
| nPrCO- | The 4-pyridyl | R aOCOO- |
| nPrCO- | Isobutenyl | R aOCOO- |
| nPrCO- | Sec.-propyl | R aOCOO- |
| nPrCO- | Cyclopropyl | R aOCOO- |
| nPrCO- | Cyclobutyl | R aOCOO- |
| nPrCO- | Cyclopentyl | R aOCOO- |
| nPrCO- | Phenyl | R aOCOO- |
| Benzoyl | Cyclopentyl | EtOCOO- |
| Benzoyl | The 3-furyl | EtOCOO- |
| Benzoyl | The 3-thienyl | EtOCOO- |
| Benzoyl | The 2-pyridyl | EtOCOO- |
| Benzoyl | The 3-pyridyl | EtOCOO- |
| Benzoyl | The 4-pyridyl | EtOCOO- |
| Benzoyl | Isobutenyl | EtOCOO- |
| Benzoyl | Sec.-propyl | EtOCOO- |
| Benzoyl | Cyclopropyl | EtOCOO- |
| Benzoyl | Cyclobutyl | EtOCOO- |
| Benzoyl | Cyclopentyl | EtOCOO- |
| Benzoyl | Phenyl | EtOCOO- |
| 2-FuCO- | 3 furyls | EtOCOO- |
| 2-FuCO- | The 3-thienyl | EtOCOO- |
| 2-FuCO- | The 2-pyridyl | EtOCOO- |
| 2-FuCO- | The 3-pyridyl | EtOCOO- |
| 2-FuCO- | The 4-pyridyl | EtOCOO- |
| 2-FuCO- | Isobutenyl | EtOCOO- |
| 2-FuCO- | Sec.-propyl | EtOCOO- |
| 2-FuCO- | Cyclopropyl | EtOCOO- |
| 2-FuCO- | Cyclobutyl | EtOCOO- |
| 2-FuCO- | Cyclopentyl | EtOCOO- |
| 2-FuCO- | Phenyl | EtOCOO- |
| 2-ThCO- | The 3-furyl | EtOCOO- |
| 2-ThCO- | The 3-thienyl | EtOCOO- |
| 2-ThCO- | The 2-pyridyl | EtOCOO- |
| 2-ThCO- | The 3-pyridyl | EtOCOO- |
| 2-ThCO- | The 4-pyridyl | EtOCOO- |
| 2-ThCO- | Isobutenyl | EtOCOO- |
| 2-ThCO- | Sec.-propyl | EtOCOO- |
| 2-ThCO- | Cyclopropyl | EtOCOO- |
| 2-ThCO- | Cyclobutyl | EtOCOO- |
| 2-ThCO- | Cyclopentyl | EtOCOO- |
| 2-ThCO- | Phenyl | EtOCOO- |
| 2-PyCO- | The 2-furyl | EtOCOO- |
| 2-PyCO- | The 3-furyl | EtOCOO- |
| 2-PyCO- | The 3-thienyl | EtOCOO- |
| 2-PyCO- | The 2-pyridyl | EtOCOO- |
| 2-PyCO- | The 3-pyridyl | EtOCOO- |
| 2-PyCO- | The 4-pyridyl | EtOCOO- |
| 2-PyCO- | Isobutenyl | EtOCOO- |
| 2-PyCO- | Sec.-propyl | EtOCOO- |
| 2-PyCO- | Cyclopropyl | EtOCOO- |
| 2-PyCO- | Cyclobutyl | EtOCOO- |
| 2-PyCO- | Cyclopentyl | EtOCOO- |
| 2-PyCO- | Phenyl | EtOCOO- |
| 3PyCO- | The 2-furyl | EtOCOO- |
| 3-PyCO- | The 3-furyl | EtOCOO- |
| 3-PyCO- | The 3-thienyl | EtOCOO- |
| 3-PyCO- | The 2-pyridyl | EtOCOO- |
| 3-PyCO- | The 3-pyridyl | EtOCOO- |
| 3-PyCO- | The 4-pyridyl | EtOCOO- |
| 3-PyCO- | Isobutenyl | EtOCOO- |
| 3-PyCO- | Sec.-propyl | EtOCOO- |
| 3-PyCO- | Cyclopropyl | EtOCOO- |
| 3-PyCO- | Cyclobutyl | EtOCOO- |
| 3-PyCO- | Cyclopentyl | EtOCOO- |
| 3-PyCO- | Phenyl | EtOCOO- |
| 4-PyCO- | The 2-furyl | EtOCOO- |
| 4-PyCO- | The 3-furyl | EtOCOO- |
| 4-PyCO- | The 3-thienyl | EtOCOO- |
| 4-PyCO- | The 2-pyridyl | EtOCOO- |
| 4-PyCO- | The 3-pyridyl | EtOCOO- |
| 4-PyCO- | The 4-pyridyl | EtOCOO- |
| 4-PyCO- | Isobutenyl | EtOCOO- |
| 4-PyCO- | Sec.-propyl | EtOCOO- |
| 4-PyCO- | Cyclopropyl | EtOCOO- |
| 4-PyCO- | Cyclobutyl | EtOCOO- |
| 4-PyCO- | Cyclopentyl | EtOCOO- |
| 4-PyCO- | Phenyl | EtOCOO- |
| C 4H 7CO- | The 3-furyl | EtOCOO- |
| C 4H 7CO- | The 3-thienyl | EtOCOO- |
| C 4H 7CO- | The 2-pyridyl | EtOCOO- |
| C 4H 7CO- | The 3-pyridyl | EtOCOO- |
| C 4H 7CO- | The 4-pyridyl | EtOCOO- |
| C 4H 7CO- | Isobutenyl | EtOCOO- |
| C 4H 7CO- | Sec.-propyl | EtOCOO- |
| C 4H 7CO- | Cyclopropyl | EtOCOO- |
| C 4H 7CO- | Cyclobutyl | EtOCOO- |
| C 4H 7CO- | Cyclopentyl | EtOCOO- |
| C 4H 7CO- | Phenyl | EtOCOO- |
| EtOCO- | The 3-furyl | EtOCOO- |
| EtOCO- | The 3-thienyl | EtOCOO- |
| EtOCO- | The 2-pyridyl | EtOCOO- |
| EtOCO- | The 3-pyridyl | EtOCOO- |
| EtOCO- | The 4-pyridyl | EtOCOO- |
| EtOCO- | Isobutenyl | EtOCOO- |
| EtOCO- | Sec.-propyl | EtOCOO- |
| EtOCO- | Cyclopropyl | EtOCOO- |
| EtOCO- | Cyclobutyl | EtOCOO- |
| EtOCO- | Cyclopentyl | EtOCOO- |
| EtOCO- | Phenyl | EtOCOO- |
| ibueCO- | The 2-furyl | EtOCOO- |
| ibueCO- | The 3-furyl | EtOCOO- |
| ibueCO- | The 2-thienyl | EtOCOO- |
| ibueCO- | The 3-thienyl | EtOCOO- |
| ibueCO- | The 2-pyridyl | EtOCOO- |
| ibueCO- | The 3-pyridyl | EtOCOO- |
| ibueCO- | The 4-pyridyl | EtOCOO- |
| ibueCO- | Isobutenyl | EtOCOO- |
| ibueCO- | Sec.-propyl | EtOCOO- |
| ibueCO- | Cyclopropyl | EtOCOO- |
| ibueCO- | Cyclobutyl | EtOCOO- |
| ibueCO- | Cyclopentyl | EtOCOO- |
| ibueCO- | Phenyl | EtOCOO- |
| iBuCO- | The 2-furyl | EtOCOO- |
| iBuCO- | The 3-furyl | EtOCOO- |
| iBuCO- | The 2-thienyl | EtOCOO- |
| iBuCO- | The 3-thienyl | EtOCOO- |
| iBuCO- | The 2-pyridyl | EtOCOO- |
| iBuCO- | The 3-pyridyl | EtOCOO- |
| iBuCO- | The 4-pyridyl | EtOCOO- |
| iBuCO- | Isobutenyl | EtOCOO- |
| iBuCO- | Sec.-propyl | EtOCOO- |
| iBuCO- | Cyclopropyl | EtOCOO- |
| iBuCO- | Cyclobutyl | EtOCOO- |
| iBuCO- | Cyclopentyl | EtOCOO- |
| iBuCO- | Phenyl | EtOCOO- |
| iBuOCO- | The 2-pyridyl | EtOCOO- |
| iBuOCO- | The 3-pyridyl | EtOCOO- |
| iBuOCO- | The 4-pyridyl | EtOCOO- |
| iBuOCO- | Sec.-propyl | EtOCOO- |
| iBuOCO- | Cyclobutyl | EtOCOO- |
| iBuOCO- | Cyclopentyl | EtOCOO- |
| iBuOCO- | Phenyl | EtOCOO- |
| iPrOCO- | The 3-furyl | EtOCOO- |
| iPrOCO- | The 3-thienyl | EtOCOO- |
| iPrOCO- | The 2-pyridyl | EtOCOO- |
| iPrOCO- | The 3-pyridyl | EtOCOO- |
| iPrOCO- | The 4-pyridyl | EtOCOO- |
| iPrOCO- | Isobutenyl | EtOCOO- |
| iPrOCO- | Sec.-propyl | EtOCOO- |
| iPrOCO- | Cyclopropyl | EtOCOO- |
| iPrOCO- | Cyclobutyl | EtOCOO- |
| iPrOCO- | Cyclopentyl | EtOCOO- |
| iPrOCO- | Phenyl | EtOCOO- |
| nPrOCO- | The 2-furyl | EtOCOO- |
| nPrOCO- | The 3-furyl | EtOCOO- |
| nPrOCO- | The 2-thienyl | EtOCOO- |
| nPrOCO- | The 3-thienyl | EtOCOO- |
| nPrOCO- | The 2-pyridyl | EtOCOO- |
| nPrOCO- | The 3-pyridyl | EtOCOO- |
| nPrOCO- | The 4-pyridyl | EtOCOO- |
| nPrOCO- | Isobutenyl | EtOCOO- |
| nPrOCO- | Sec.-propyl | EtOCOO- |
| nPrOCO- | Cyclopropyl | EtOCOO- |
| nPrOCO- | Cyclobutyl | EtOCOO- |
| nPrOCO- | Cyclopentyl | EtOCOO- |
| nPrOCO- | Phenyl | EtOCOO- |
| nPrCO- | The 3-furyl | EtOCOO- |
| nPrCO- | The 3-thienyl | EtOCOO- |
| nPrCO- | The 2-pyridyl | EtOCOO- |
| nPrCO- | The 3-pyridyl | EtOCOO- |
| nPrCO- | The 4-pyridyl | EtOCOO- |
| nPrCO- | Isobutenyl | EtOCOO- |
| nPrCO- | Sec.-propyl | EtOCOO- |
| nPrCO- | Cyclopropyl | EtOCOO- |
| nPrCO- | Cyclobutyl | EtOCOO- |
| nPrCO- | Cyclopentyl | EtOCOO- |
| nPrCO- | Phenyl | EtOCOO- |
| tBuOCO | Cyclopropyl | MeOCOO- |
| tBuOCO | Cyclopentyl | MeOCOO- |
| Benzoyl | The 2-furyl | MeOCOO- |
| Benzoyl | The 3-furyl | MeOCOO- |
| Benzoyl | The 2-thienyl | MeOCOO- |
| Benzoyl | The 3-thienyl | MeOCOO- |
| Benzoyl | The 2-pyridyl | MeOCOO- |
| Benzoyl | The 3-pyridyl | MeOCOO- |
| Benzoyl | The 4-pyridyl | MeOCOO- |
| Benzoyl | Isobutenyl | MeOCOO- |
| Benzoyl | Sec.-propyl | MeOCOO- |
| Benzoyl | Cyclopropyl | MeOCOO- |
| Benzoyl | Cyclobutyl | MeOCOO- |
| Benzoyl | Cyclopentyl | MeOCOO- |
| Benzoyl | Phenyl | MeOCOO- |
| 2-FuCO- | The 2-furyl | MeOCOO- |
| 2-FuCO- | The 3-furyl | MeOCOO- |
| 2-FuCO- | The 2-thienyl | MeOCOO- |
| 2-FuCO- | The 3-thienyl | MeOCOO- |
| 2-FuCO- | The 2-pyridyl | MeOCOO- |
| 2-FuCO- | The 3-pyridyl | MeOCOO- |
| 2-FuCO- | The 4-pyridyl | MeOCOO- |
| 2-FuCO- | Isobutenyl | MeOCOO- |
| 2-FuCO- | Sec.-propyl | MeOCOO- |
| 2-FuCO- | Cyclopropyl | MeOCOO- |
| 2-FuCO- | Cyclobutyl | MeOCOO- |
| 2-FuCO- | Cyclopentyl | MeOCOO- |
| 2-FuCO- | Phenyl | MeOCOO- |
| 2-ThCO- | The 2-furyl | MeOCOO- |
| 2-ThCO- | The 3-furyl | MeOCOO- |
| 2-ThCO- | The 2-thienyl | MeOCOO- |
| 2-ThCO- | The 3-thienyl | MeOCOO- |
| 2-ThCO- | The 2-pyridyl | MeOCOO- |
| 2-ThCO- | The 3-pyridyl | MeOCOO- |
| 2-ThCO- | The 4-pyridyl | MeOCOO- |
| 2-ThCO- | Isobutenyl | MeOCOO- |
| 2-ThCO- | Sec.-propyl | MeOCOO- |
| 2-ThCO- | Cyclopropyl | MeOCOO- |
| 2-ThCO- | Cyclobutyl | MeOCOO- |
| 2-ThCO- | Cyclopentyl | MeOCOO- |
| 2-ThCO- | Phenyl | MeOCOO- |
| 2-PyCO- | The 2-furyl | MeOCOO- |
| 2-PyCO- | The 3-furyl | MeOCOO- |
| 2-PyCO- | The 2-thienyl | MeOCOO- |
| 2-PyCO- | The 3-thienyl | MeOCOO- |
| 2-PyCO- | The 2-pyridyl | MeOCOO- |
| 2-PyCO- | The 3-pyridyl | MeOCOO- |
| 2-PyCO- | The 4-pyridyl | MeOCOO- |
| 2-PyCO- | Isobutenyl | MeOCOO- |
| 2-PyCO- | Sec.-propyl | MeOCOO- |
| 2-PyCO- | Cyclopropyl | MeOCOO- |
| 2-PyCO- | Cyclobutyl | MeOCOO- |
| 2-PyCO- | Cyclopentyl | MeOCOO- |
| 2-PyCO- | Phenyl | MeOCOO- |
| 3PyCO- | The 2-furyl | MeOCOO- |
| 3-PyCO- | The 3-furyl | MeOCOO- |
| 3-PyCO- | The 2-thienyl | MeOCOO- |
| 3-PyCO- | The 3-thienyl | MeOCOO- |
| 3-PyCO- | The 2-pyridyl | MeOCOO- |
| 3-PyCO- | The 3-pyridyl | MeOCOO- |
| 3-PyCO- | The 4-pyridyl | MeOCOO- |
| 3-PyCO- | Isobutenyl | MeOCOO- |
| 3-PyCO- | Sec.-propyl | MeOCOO- |
| 3-PyCO- | Cyclopropyl | MeOCOO- |
| 3-PyCO- | Cyclobutyl | MeOCOO- |
| 3-PyCO- | Cyclopentyl | MeOCOO- |
| 3-PyCO- | Phenyl | MeOCOO- |
| 4-PyCO- | The 2-furyl | MeOCOO- |
| 4-PyCO- | The 3-furyl | MeOCOO- |
| 4-PyCO- | The 2-thienyl | MeOCOO- |
| 4-PyCO- | The 3-thienyl | MeOCOO- |
| 4-PyCO- | The 2-pyridyl | MeOCOO- |
| 4-PyCO- | The 3-pyridyl | MeOCOO- |
| 4-PyCO- | The 4-pyridyl | MeOCOO- |
| 4-PyCO- | Isobutenyl | MeOCOO- |
| 4-PyCO- | Sec.-propyl | MeOCOO- |
| 4-PyCO- | Cyclopropyl | MeOCOO- |
| 4-PyCO- | Cyclobutyl | MeOCOO- |
| 4-PyCO- | Cyclopentyl | MeOCOO- |
| 4-PyCO- | Phenyl | MeOCOO- |
| C 4H 7CO- | The 2-furyl | MeOCOO- |
| C 4H 7CO- | The 3-furyl | MeOCOO- |
| C 4H 7CO- | The 2-thienyl | MeOCOO- |
| C 4H 7CO- | The 3-thienyl | MeOCOO- |
| C 4H 7CO- | The 2-pyridyl | MeOCOO- |
| C 4H 7CO- | The 3-pyridyl | MeOCOO- |
| C 4H 7CO- | The 4-pyridyl | MeOCOO- |
| C 4H 7CO- | Isobutenyl | MeOCOO- |
| C 4H 7CO- | Sec.-propyl | MeOCOO- |
| C 4H 7CO- | Cyclopropyl | MeOCOO- |
| C 4H 7CO- | Cyclobutyl | MeOCOO- |
| C 4H 7CO- | Cyclopentyl | MeOCOO- |
| C 4H 7CO- | Phenyl | MeOCOO- |
| EtOCO- | The 2-furyl | MeOCOO- |
| EtOCO- | The 3-furyl | MeOCOO- |
| EtOCO- | The 2-thienyl | MeOCOO- |
| EtOCO- | The 3-thienyl | MeOCOO- |
| EtOCO- | The 2-pyridyl | MeOCOO- |
| EtOCO- | The 3-pyridyl | MeOCOO- |
| EtOCO- | The 4-pyridyl | MeOCOO- |
| EtOCO- | Isobutenyl | MeOCOO- |
| EtOCO- | Sec.-propyl | MeOCOO- |
| EtOCO- | Cyclopropyl | MeOCOO- |
| EtOCO- | Cyclobutyl | MeOCOO- |
| EtOCO- | Cyclopentyl | MeOCOO- |
| EtOCO- | Phenyl | MeOCOO- |
| ibueCO- | The 2-furyl | MeOCOO- |
| ibueCO- | The 3-furyl | MeOCOO- |
| ibueCO- | The 2-thienyl | MeOCOO- |
| ibueCO- | The 3-thienyl | MeOCOO- |
| ibueCO- | The 2-pyridyl | MeOCOO- |
| ibueCO- | The 3-pyridyl | MeOCOO- |
| ibueCO- | The 4-pyridyl | MeOCOO- |
| ibueCO- | Isobutenyl | MeOCOO- |
| ibueCO- | Sec.-propyl | MeOCOO- |
| ibueCO- | Cyclopropyl | MeOCOO- |
| ibueCO- | Cyclobutyl | MeOCOO- |
| ibueCO- | Cyclopentyl | MeOCOO- |
| ibueCO- | Phenyl | MeOCOO- |
| iBuCO- | The 2-furyl | MeOCOO- |
| iBuCO- | The 3-furyl | MeOCOO- |
| iBuCO- | The 2-thienyl | MeOCOO- |
| iBuCO- | The 3-thienyl | MeOCOO- |
| iBuCO- | The 2-pyridyl | MeOCOO- |
| iBuCO- | The 3-pyridyl | MeOCOO- |
| iBuCO- | The 4-pyridyl | MeOCOO- |
| iBuCO- | Isobutenyl | MeOCOO- |
| iBuCO- | Sec.-propyl | MeOCOO- |
| iBuCO- | Cyclopropyl | MeOCOO- |
| iBuCO- | Cyclobutyl | MeOCOO- |
| iBuCO- | Cyclopentyl | MeOCOO- |
| iBuCO- | Phenyl | MeOCOO- |
| iBuOCO- | The 2-furyl | MeOCOO- |
| iBuOCO- | The 3-furyl | MeOCOO- |
| iBuOCO- | The 2-thienyl | MeOCOO- |
| iBuOCO- | The 3-thienyl | MeOCOO- |
| iBuOCO- | The 2-pyridyl | MeOCOO- |
| iBuOCO- | The 3-pyridyl | MeOCOO- |
| iBuOCO- | The 4-pyridyl | MeOCOO- |
| iBuOCO- | Isobutenyl | MeOCOO- |
| iBuOCO- | Sec.-propyl | MeOCOO- |
| iBuOCO- | Cyclopropyl | MeOCOO- |
| iBuOCO- | Cyclobutyl | MeOCOO- |
| iBuOCO- | Cyclopentyl | MeOCOO- |
| iBuOCO- | Phenyl | MeOCOO- |
| iPrOCO- | The 2-furyl | MeOCOO- |
| iPrOCO- | The 3-furyl | MeOCOO- |
| iPrOCO- | The 2-thienyl | MeOCOO- |
| iPrOCO- | The 3-thienyl | MeOCOO- |
| iPrOCO- | The 2-pyridyl | MeOCOO- |
| iPrOCO- | The 3-pyridyl | MeOCOO- |
| iPrOCO- | The 4-pyridyl | MeOCOO- |
| iPrOCO- | Isobutenyl | MeOCOO- |
| iPrOCO- | Sec.-propyl | MeOCOO- |
| iPrOCO- | Cyclopropyl | MeOCOO- |
| iPrOCO- | Cyclobutyl | MeOCOO- |
| iPrOCO- | Cyclopentyl | MeOCOO- |
| iPrOCO- | Phenyl | MeOCOO- |
| nPrOCO- | The 2-furyl | MeOCOO- |
| nPrOCO- | The 3-furyl | MeOCOO- |
| nPrOCO- | The 2-thienyl | MeOCOO- |
| nPrOCO- | The 3-thienyl | MeOCOO- |
| nPrOCO- | The 2-pyridyl | MeOCOO- |
| nPrOCO- | The 3-pyridyl | MeOCOO- |
| nPrOCO- | The 4-pyridyl | MeOCOO- |
| nPrOCO- | Isobutenyl | MeOCOO- |
| nPrOCO- | Sec.-propyl | MeOCOO- |
| nPrOCO- | Cyclopropyl | MeOCOO- |
| nPrOCO- | Cyclobutyl | MeOCOO- |
| nPrOCO- | Cyclopentyl | MeOCOO- |
| nPrOCO- | Phenyl | MeOCOO- |
| nPrCO- | The 2-furyl | MeOCOO- |
| nPrCO- | The 3-furyl | MeOCOO- |
| nPrCO- | The 2-thienyl | MeOCOO- |
| nPrCO- | The 3-thienyl | MeOCOO- |
| nPrCO- | The 2-pyridyl | MeOCOO- |
| nPrCO- | The 3-pyridyl | MeOCOO- |
| nPrCO- | The 4-pyridyl | MeOCOO- |
| nPrCO- | Isobutenyl | MeOCOO- |
| nPrCO- | Sec.-propyl | MeOCOO- |
| nPrCO- | Cyclopropyl | MeOCOO- |
| nPrCO- | Cyclobutyl | MeOCOO- |
| nPrCO- | Cyclopentyl | MeOCOO- |
| nPrCO- | Phenyl | MeOCOO- |
Embodiment 4
According to embodiment 1 described method and other methods, can prepare following specific Taxan, R in each compound of series (that is, series " A " arrives " K " each compound) with structural formula 15
7Be hydroxyl, R
10As preceding definition, comprise R
10Be R
10Be R
10aOCOO-, R
10aBe (i) replacement or unsubstituted, preferred unsubstituted C
2To C
8Alkyl (straight chain, side chain or ring-type), as ethyl, propyl group, butyl, amyl group, or hexyl; People's C is not preferably arrived in (ii) replacement or unsubstituted
2To C
8Alkenyl (straight chain, side chain or ring-type), as vinyl, propenyl, butenyl, pentenyl or hexenyl; (iii) replacement or unsubstituted, preferred unsubstituted C
2To C
8Alkynyl (straight chain, side chain or ring-type), as ethynyl, proyl, butynyl, pentynyl or hexin base; (iv) replacement or unsubstituted, preferred unsubstituted phenyl; Or (v) replacement or unsubstituted, preferred unsubstituted heteroaryl such as furyl, thienyl, or pyridyl.
In " A " series compound, X
10Be definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10For replacing or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
7And R
10Respectively has the β three-dimensional chemical configuration.
In " B " series compound, X
10And R
2aBe definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
2aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7And R
10Respectively has the β three-dimensional chemical configuration.
In " C " series compound, X
10And R
9aBe definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
9aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7, R
9And R
10Respectively has the β three-dimensional chemical configuration.
In " D " and " E " series compound, X
10Be definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
7, R
9(only serial D) and R
10Respectively has the β three-dimensional chemical configuration.
In " F " series compound, X
10, R
2aAnd R
9aBe definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
2aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7, R
9And R
10Respectively has the β three-dimensional chemical configuration.
In " G " series compound, X
10And R
2aBe definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
2aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7, R
9And R
10Respectively has the β three-dimensional chemical configuration.
In " H " series compound, X
10Be definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
2aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7And R
10Respectively has the β three-dimensional chemical configuration.
In " I " series compound, X
10And R
2aBe definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
2aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7And R
10Respectively has the β three-dimensional chemical configuration.
In " J " series compound, X
10And R
2aBe definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
2aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7, R
9And R
10Respectively has the β three-dimensional chemical configuration.
In " K " series compound, X
10, R
2aAnd R
9aBe definition group or other groups as above.Preferably, heterocyclic radical is for replacing or unsubstituted furyl thienyl or pyridyl, X
10Be preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group (for example tertiary butyl), R
2aBe preferably and replace or unsubstituted furyl thienyl, pyridyl, phenyl, or low alkyl group, R
7, R
9And R
10Respectively has the β three-dimensional chemical configuration.
X
3, X
5, R
2, R
9And R
10Substituting group can be hydroxyl or anyly contain heteroatomic substituting group, be selected from heterocyclic radical, alkoxyl group, alkenyloxy, alkynyloxy group, aryloxy; hydroxyl, protected hydroxyl, ketone group, acyloxy, nitro, amino; amide group, sulfydryl, ketal group, acetal radical, ester group and ether, but be not the phosphorated substituting group.
| Group | X 5 | ?X 3 | R 10 | ?R 2 | R 9 | R 14 |
| ?A1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?A12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | O | ?H |
| ?B1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?B12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | O | ?H |
| ?C1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?C12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | R 9aCOO- | ?H |
| ?D1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?D12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | OH | ?H |
| ?E1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?E12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | O | ?OH |
| ?F1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?F12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | R 9aCOO- | ?H |
| ?G1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | OH | ?H |
| ?G2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | OH | ?H |
| ?G3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | R 2aCOO- | OH | ?H |
| ?G4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | OH | ?H |
| ????G5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????G6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????G7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????G8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????G9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????G10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????G11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????G12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | R 2aCOO- | ????OH | ????H |
| ????H1 | -COOX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H2 | -COX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H3 | -CONHX 10 | Heterocyclic radical | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H4 | -COOX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H5 | -COX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H6 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H7 | -COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H8 | -COX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H9 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H10 | -COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H11 | -COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ????H12 | -CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | R 10aOCOO- | C 6H 5COO- | ????OH | ????OH |
| ?I1 | ??-COOX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I2 | ??-COX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I3 | ??-CONHX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I4 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I5 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I6 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I7 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I8 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I9 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I10 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I11 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?I12 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | O | ?OH |
| ?J1 | ??-COOX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J2 | ??-COX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J3 | ??-CONHX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J4 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J5 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J6 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J7 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J8 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J9 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ?J10 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ??J11 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ??J12 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | ??OH | ??OH |
| ??K1 | ??-COOX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K2 | ??-COX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K3 | ??-CONHX 10 | Heterocyclic radical | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K4 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K5 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K6 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkyl | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K7 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K8 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K9 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkenyl | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K10 | ??-COOX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K11 | ??-COX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
| ??K12 | ??-CONHX 10 | The C that selectivity replaces 2-C 8Alkynyl group | ??R 10aOCOO- | ??R 2aCOO- | ??R 9aCOO- | ??OH |
Embodiment 5
Form the analysis to measure vitro cytotoxicity by cell colony
With 400 cells (HCT116) at 60 millimeters Petri dish middle berth flat boards that contain 2.7 milliliters of substratum (improved McCoy ' the s 5a substratum that contains 10% fetal bovine serum and 100 units per ml penicillin and 100 mg/ml Streptomycin sulphates).CO at 37 ℃
2With these cell cultures 5 hours, make it be adsorbed on the bottom of Petri dish in the incubator.With the ten times of preparations with ultimate density in substratum of embodiment 2 described compounds, then 0.3 milliliter of above-mentioned solution is added in 2.7 milliliters of substratum in the culture dish.Then cell and medicine were cultivated 72 hours at 37 ℃.After cultivating end, decant pastille substratum with 4 milliliters of Hank ' s Balance Salt solution (HBSS) flushing, adds 5 milliliters of fresh medium with culture dish, places incubator to carry out colony again in culture dish and forms.Cultivate after 7 days, use colony count device statistics cell colony.Calculate the survival rate of cell, measure the ID50 value (colony is formed produce 50% drug level that suppresses) of each test compound.
| Compound | External ID50 (nm) HCT116 |
| Taxol | ??2.1 |
| ????Docetaxel | ??0.6 |
| ????1755 | ??＜1 |
| ????1767 | ??＜10 |
| ????1781 | ??＜1 |
| ????1799 | ??＜1 |
| ????1808 | ??＜10 |
| ????1811 | ??＜1 |
| ????1822 | ??＜1 |
| ????1838 | ??＜1 |
| ????1841 | ??＜1 |
| ????1855 | ??＜10 |
| ????1867 | ??＜1 |
| ????1999 | ??＜1 |
| ????2002 | ??＜1 |
| ????2011 | ??＜10 |
| ????2020 | ??＜1 |
| ????2032 | ??＜1 |
| ????2044 | ??＜1 |
| ????2050 | ??＜1 |
| ????2062 | ??＜10 |
| ????2077 | ??＜10 |
| ????2086 | ??＜1 |
| ????2097 | ??＜1 |
| ????2666 | ??＜1 |
| ????2972 | ??＜10 |
| ????2988 | ??＜1 |
| ????2999 | ??＜1 |
| ????3003 | ??＜10 |
| ????3011 | ??＜1 |
| ????3020 | ??＜1 |
| ????3033 | ??＜1 |
| ????3155 | ??＜1 |
| ????3181 | ??＜1 |
| ????3243 | ??＜1 |
| ????3300 | ??＜1 |
| ????3393 | ??＞50 |
| ????3433 | ??22.3 |
| ????3911 | ??＜1 |
| ????3929 | ??＜1 |
| ????3963 | ??＜1 |
| ????4000 | ??＜1 |
| ????4020 | ??＜1 |
| ?4074 | ＜1 |
| ?4088 | ＜10 |
| ?4090 | ＜1 |
| ?4374 | ＜1 |
| ?4636 | ＜10 |
| ?6466 | ＜10 |
| ?4959 | ＜1 |
| ?4924 | ＜10 |
| ?4844 | ＜1 |
| ?5171 | ＜1 |
| ?5155 | ＜10 |
| ?1788 | ＜1 |
| ?1767 | ＜10 |
| ?1771 | ＜10 |
| ?1866 | ＜1 |
| ?2060 | ＜10 |
| ?2092 | ＜1 |
| ?2088 | ＜1 |
Embodiment 6
The preparation of oral liquid
Solution 1: antineoplastic compound 1771 is dissolved in ethanol forms the solution that every ml soln contains 145 milligrams of compounds.Stir the Cremophor EL solution that adds the monovalent volume down, obtain every milliliter of solution that contains 72.5 milligrams of compounds 1771.Use the salt solution of 9 parts of weight to dilute this solution, obtain the pharmaceutically acceptable solution that the patient takes.
Solution 2: antineoplastic compound 1781 is dissolved in ethanol forms the solution that every ml soln contains 98 milligrams of compounds.Stir the Cremophor EL solution that adds the monovalent volume down, obtain every milliliter of solution that contains 49 milligrams of compounds 1781.Use the salt solution of 9 parts of weight to dilute this solution, obtain the pharmaceutically acceptable solution that the patient takes.
Embodiment 7
The preparation of oral suspension
25 milligrams of micro mist shape compounds are suspended in the deionized water carrier that contains 1% carboxymethyl cellulose (CMC), can prepare the oral compositions of antineoplastic compound.
Embodiment 8
The preparation of oral tablet
Antineoplastic compound (100 milligrams) is dissolved in the ethylene dichloride (2 milliliters), adds CRemophor EL (100 milligrams).Methylene dichloride is removed in vacuum-evaporation, forms glassy mass.Add Microcrystalline Cellulose (600 milligrams) in glassy mass, mix, formation can be pressed into the powder of tablet.
Embodiment 9
The preparation of parenteral route medication emulsion
Emulsion 1: antineoplastic compound is dissolved in 100% ethanol forms the solution that every ml soln contains 40 milligrams of compounds.Stir the Liposyn II (2%) that adds 19 parts of weight down, obtain every milliliter of emulsion that contains the parenteral route medication of 2 milligrams of compounds.
Emulsion 2: antineoplastic compound is dissolved in 100% ethanol forms the solution that every ml soln contains 40 milligrams of compounds.Stir the Liposyn III (2%) that adds 19 parts of weight down, obtain every milliliter of emulsion that contains the parenteral route medication of 2 milligrams of compounds.
Emulsion 3: antineoplastic compound is dissolved in 100% ethanol forms the solution that every ml soln contains 40 milligrams of compounds.Stir the Liposyn III (2%) that adds 9 parts of weight down, obtain every milliliter of emulsion that contains the parenteral route medication of 4 milligrams of compounds.
Embodiment 10
Contain of the preparation of the parenteral route of compound with drug solns
Solution 1: antineoplastic compound is dissolved in 100% ethanol forms the solution that every ml soln contains 140 milligrams of compounds.Stir the Cremophor EL solution that adds the monovalent volume down, the common salt solution dilution with 9 parts of weight obtains every milliliter of solution that contains the parenteral route medication of 7 milligrams of compounds.
Solution 2: antineoplastic compound is dissolved in 100% ethanol forms the solution that every ml soln contains 140 milligrams of compounds.Stir the Cremophor EL solution that adds the monovalent volume down, the common salt solution dilution with 4 parts of weight obtains every milliliter of solution that contains the parenteral route medication of 11.7 milligrams of compounds.
Solution 3: antineoplastic compound is dissolved in 100% ethanol forms the solution that every ml soln contains 140 milligrams of compounds.Stir the Cremophor EL solution that adds the monovalent volume down, the common salt solution dilution with 2.33 parts of weight obtains every milliliter of solution that contains the parenteral route medication of 16.2 milligrams of compounds.
Embodiment 11
Antineoplastic compound moves the activity in vivo of growing to the Human Lung Cancer xenogenesis
Use following carrier: 10% ethanol, 10%Cremophor and 80% isotonic saline solution are mixed with quiet notes preparation with antineoplastic compound 1755.The preparation of antineoplastic compound 1755 that is used for this mensuration is as described in embodiment 10 solution 2.Taxol (paclitaxel, Bristol Meyers Squibb) as contrast is a marketed drugs.
Two kinds of lung tumor xenogenesis that are used to study move to be grown for to the highstrung SK-MES cancer of taxol with taxol more there is NCI-H1299 (H1299) cancer of tolerance than SK-MES tumour.
First day, will suffer from the female NCr-nude mouse of SK-MES cancer or H1299 cancer (with 1mm
3The Human Lung Cancer fragment is in the subcutaneous implantation of veutro) by sex pairing grouping, every group of six mouse, the magnitude range of average tumor is the 241-244 milligram.Treatment group comprises: with (1 group) of vehicle processing; (2 groups) with taxol treatment; With (3 groups) handled with antineoplastic compound 1755.
With maximum tolerated dose (MTD) the intravenous injection taxol treatment group and the antineoplastic compound 1755 treatment group animals of each compound, on qd * 1 timetable, one hour interval gives a half-value dose.The MTD of antineoplastic compound 1755 is by the single dose data computation of early stage these compounds of mouse mainline.Taxol itself is 36 mg/kg administrations with isolating i.v. dosage, gives 18 mg/kg before and after one hour respectively.With half of total amount the vehicle control animals is administered twice before and after one hour.Finished to measure research at the 60th day.
Overview comprises the average fate (MDS) of survival, the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part in table 1 as a result.The average fate of surviving refers to the fate after SKMES tumour size reaches 1.5 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 1.5 grams, promptly produce " stable disease ".
The tumour points-scoring system that designs below moves the effect (potential result of treatment) of growing to the different human entity tumour xenogenesis of evaluation antineoplastic agent treatment more quantitative scope is provided.When research finished, every mouse that is studied had all provided 1 to 10 scoring.Scoring is summarized as follows:
Scoring is described
＜1 serious toxicity
The 2-3 tumour arrives the limit greatly, but tangible tumor growth delay occurs
The 4-6 tumor growth obviously suppresses (stable disease)
7-9 part tumour is dwindled (partial reaction)
10 complete reactions (full marks)
The scoring of each mouse is on average obtained the average score of each treatment group.This tumour points-scoring system provides a kind of method of more different antineoplastic compound preferably by quantizing result (complete reaction vs partial reaction).
Table 1
| Group | ???????MDS(n) | Poison number with poison | The survival number | Complete reaction | Partial reaction | Stable disease | Average mark |
| ????1 | ????12.2±1.3(6) | ????0 | ????0 | ????0 | ????0 | ????0 | ????1±0 |
| ????2 | ????16±2.0(6) | ????0 | ????0 | ????0 | ????0 | ????0 | ????1.3±0.3 |
| ????3 | ????-- | ????0 | ????6 | ????5 | ????0 | ????1 | ????9.2±0.8 |
Handling control group calculating MDS value by vehicle is 12.2 days.Compare taxol (36 mg/kg with the vehicle control group; 2 groups) only produce and be no more than 30% survival and increase (MDS=16.0 days), and the record that does not have tumour to reduce.On the contrary, antineoplastic compound 1755 has high reactivity.Antineoplastic compound 1755 (49 mg/kg; 4 groups) produce five routine complete reactions, and the survival time obviously prolongs than the control animals with vehicle or taxol treatment.Antineoplastic compound 1755 has good tolerance.
In the H1299 test, first day, mouse is divided into six groups by the sex pairing, every group of six mouse, the magnitude range of average tumor is the 229-233 milligram.H1299 test processing way is identical with the SK-MES test.Handling contrast 1 batch total calculation MDS value by vehicle is 24.5.Compare taxol (36 mg/kg with the vehicle control group; 2 groups) non-activity in the H1299 model, to compare with the vehicle control animals, five animals only produce and are no more than 10% survival increase (MDS=27.0 days) (not statistically significant).In taxol treatment, observe a routine partial reaction.
Table 2
| Group | ????MDS(n) | Poison number with poison | The survival number | Complete reaction | Partial reaction | Stable disease | Average mark |
| ????1 | ???24.5±3.3(6) | ????0 | ????0 | ????0 | ????0 | ????0 | ????1.2±0.2 |
| ????2 | ???27.0±4.6(5) | ????0 | ????1 | ????0 | ????1 | ????0 | ????2.7±1.3 |
| ????3 | ???-- | ????2 | ????4 | ????3 | ????0 | ????1 | ????5.8±2 |
Antineoplastic compound 1755 (49 mg/kg; 4 groups) have tangible treatment for the invalid H1299 tumour of taxol and put, in the H1299 test, produce three routine complete reactions.Compare with the animal of vehicle processing or taxol treatment, other mouse survival time of this compound treatment obviously increase.
In the H1299 toxicity test, two dead mouses in antineoplastic compound 1755 treatment group.Because identical in the dosage of three kinds of compounds and treatment sequence and the SK-MES test, the side effect that bare mouse is subjected to is not the drug toxicity owing to system probably.A kind of explanation is the extreme reaction of H1299 tumour to antineoplastic compound 1755, and this reaction comprises that this compound makes the tumour lump and a matter is downright bad and the hemorrhage toxicant that causes discharges from the tumour of host mouse.
When with single dose bolus form administration, (250mg) the Human Lung Cancer xenogenesis moved and grew effectively 1755 pairs of late periods of antineoplastic compound (upstaged).
Embodiment 12
Antineoplastic compound moves the interior evaluating of growing to DU145 human prostate cancer xenogenesis
Use following carrier: 5% ethanol, 5%Cremophor and 90% isotonic saline solution are pressed the 1 described preparation of embodiment 10 solution with antineoplastic compound.Taxol (paclitaxel, Bristol MeyersSquibb) as contrast is a marketed drugs.Dose volume is 0.3 milliliter of per 20 gram mouse.
With male NCr-nude mouse (with 1mm
3DU145 human prostate cancer fragment is in the subcutaneous implantation of veutro) grouping, every group of five mouse.The magnitude range of 145 groups of average tumors of DU is the 223-228 milligram.Beginning administration in first day.With the maximum tolerated dose (MTD) that is suitable for each reagent, press qd * 1 timetable intravenous injection antineoplastic compound.Press qd * twice taxol of 1 timetable intravenous injection (total dose 24 mg/kg) with the dosage of each 12 mg/kg before and after one hour.Also with the dosage of taxol, press qd * 5 timetable i.p. administrations simultaneously with mg/kg every days 18.1 group of mouse of control group is pressed qd * 1 timetable intravenous injection vehicle.Measured research at the 91st day.Treatment group sees Table 3.
Table 3
| Group | Compound | ?Mg/kg | Route of administration | The administration system |
| ????1 | Vehicle | ???--- | ????i.v. | ??qd×1 |
| ????2 | ??Taxol | ???24 | ????i.v. | ??qd×1 |
| ????3 | ??Taxol | ???18 | ????i.p | ??qd×5 |
| ????4 | ??1781 | ???72.6 | ????i.v. | ??qd×1 |
The result is summarized in table 4, comprises average survival fate (MDS), the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part.Average survival fate refers to the fate after the tumour size reaches 1.5 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 1.5 grams, promptly produce " stable disease ".
Table 4
| Group | ???????MDS(n) | Poison number with poison | The survival number | Complete reaction | Partial reaction | Stable disease | Average mark |
| ????1 | ????34.3±9.4(3) | ????1 | ????1 | ????1 | ????0 | ????0 | ????2.8±1.8 |
| ????2 | ????37.4±8.9(3) | ????1 | ????1 | ????0 | ????0 | ????1 | ????2±1 |
| ????3 | ????--- | ????5 | ????0 | ????0 | ????0 | ????0 | ????0±0 |
| ????4 | ????--- | ????5 | ????0 | ????0 | ????0 | ????0 | ????0±0 |
Increase gradually with three DU145 tumour in (1 group) five mouse of vehicle processing.The MDS value of these mouse is 34.3 days (calculated value).A mouse is without any known reason in death in the 40th day in 1 group, and 220 milligram the size of the tumour of another mouse when beginning to match slowly dwindled up to the 71st day tumour and become not obvious in 1 group.The example of back has been chosen unsuitable tumour probably.
With 24 mg/kg (i.v.; Three tumor of prostate in five animals of qd * 1) taxol administration (2 groups) stably increases, and MDS=37.4 days, reaches 1.5 end values that restrain.It improves 9% than the survival rate of 1 group of control group, does not have obviously different (p=0.82 statistically; The t-that do not match test).An animal dies from drug side effect probably death in the 32nd day in 2 groups; The tumour of the 5th mouse does not increase in 91 days research in 2 groups; The 91st day tumour size identical with the 6th day (196 milligrams).With the dosage of mg/kg every days 18, has high toxicity by the taxol of qd * 5 timetable i.p. administrations.All five mouse all die from the side effect relevant with medicine, and comprise significantly and losing weight (surpassing 20%).
Antineoplastic compound 1781 is when the dosage of five animals of each compound treatment, and mortality ratio is higher than 40%.Antineoplastic compound is 100% fatal when this dosage.This compound makes it lose weight 20% before causing animal dead.
Embodiment 13
Antineoplastic compound moves the interior evaluating of growing to A2780 human ovarian carcinoma xenogenesis
Use following carrier: 5% ethanol, 5%Cremophor and 90% isotonic saline solution are pressed the 1 described preparation of embodiment 10 solution with antineoplastic compound.Taxol (paclitaxel, Bristol MeyersSquibb) and Taxotere (many Xi Taqi as contrast; Rhonen-Poulenc Rorer) is marketed drugs.Dose volume is 0.3 milliliter of per 20 gram mouse.
First day, with female NCr-nude mouse (with 1mm
3The human melanoma fragment of A2780 is in the subcutaneous implantation of veutro) grouping, every group of five mouse, but the Taxotere treatment group comprises six mouse.The magnitude range of A2780 group is the 237-243 milligram.Beginning administration in first day.With the maximum tolerated dose (MTD) that is suitable for each reagent, press qd * 1 timetable intravenous injection antineoplastic compound (compound is individually dosed).(before and after one hour) presses qd * twice taxol of 1 timetable intravenous injection (total dose 24 mg/kg) with the dosage of 12 mg/kg.Also with the dosage of taxol, press qd * 5 timetable i.p. administrations simultaneously with mg/kg every days 15.Press the dosage intravenous injection Taxotere of qd * 1 timetable with 70 mg/kg.1 group of mouse of control group is pressed qd * 1 timetable intravenous injection vehicle.Finished to measure research at the 60th day.Treatment group sees table 5 for details.
Table 5
| Group | Compound | ???Mg/kg | Route of administration | The administration system |
| ????1 | Vehicle | ????--- | ????i.v. | ??qd×1 |
| ????2 | ????Taxol | ????24 | ????i.v. | ??qd×1 |
| ????3 | ????Taxol | ????15 | ????i.p. | ??qd×5 |
| ????4 | ????1781 | ????60.6 | ????i.v. | ??qd×1 |
| ????5 | ????Taxotere | ????70 | ????i.v. | ??qd×1 |
The result is summarized in table 6, comprises average survival fate (MDS), the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part.Average survival fate refers to the fate after the tumour size reaches 2.0 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 2.0 grams, promptly produce " stable disease ".
Table 6
| Group | ????????MDS(n) | Poison number with poison | The survival number | Complete reaction | Partial reaction | Stable disease | Average mark |
| ????1 | ????11.7±2.5(5) | ????0 | ????0 | ????0 | ????0 | ????0 | ????1.2±0.2 |
| ????2 | ????21.9±5.5(5) | ????0 | ????1 | ????0 | ????0 | ????0 | ????1.8±0.4 |
| ????3 | ????26.5(1) | ????4 | ????0 | ????0 | ????0 | ????0 | ????0.6±0.6 |
| ????4 | ????38.5±8.3(2) | ????0 | ????3 | ????0 | ????2 | ????1 | ????6±1.3 |
| ????5 | ????27.4±3.5(5) | ????0 | ????0 | ????0 | ????0 | ????0 | ????2.5±0.3 |
The MDS value that increases the end values that reach 2.0 grams with the ovarian tumors of five mouse of 1 group of vehicle-treated group gradually is 11.7 days.Therefore, the ovarian cancer xenogenesis moves that to grow be quick growing tumors, and it is shorter that it kills the required time ratio of host.
The activity that in this test, shows appropriateness with the taxol (2 groups) of qd * 1 timetable administration.2 groups MDS calculated value is 21.9 days, and than the prolonged survival period 87% of 1 group of control animal, it is not obvious (p=0.13 also; The t-that do not match test).The stable disease of an animal is recorded as 61 days in 2 groups.Taxol group (3 groups) with qd * 5 timetables and 15 mg/kg dosage i.p. administrations shows high toxicity.Four mouse die from drug side effect.
In this test, taxotere (70 mg/kg; I.v.; Qd * 1) shows the activity higher than taxol.The MDS calculated value of 5 groups of five mouse is 27.4 days, than the prolonged survival period 134% of 1 group of control animal, has tangible statistical significance (p=0.007; The t-that do not match test).
A kind of antineoplastic compound (1781) produces at least one routine complete reaction or partial reaction (total reaction rate at least 20%) to the mouse that suffers from the A2780 ovarian cancer.Compound 1781 is handled at five and is produced 2 routine partial reactions in the mouse.
At the 11st day, antineoplastic compound 1781 treatment group caused maximum mean body weight to alleviate 3% to 19%, afterwards, and the weight of animals bounce-back.The side effect of antineoplastic compound 1781 is fully in the acceptable scope of NCI, and it is suitable that this is presented in the A2780 test MTD dosage to animal.
Embodiment 14
Antineoplastic compound moves the activity in vivo of growing to the human melanoma xenogenesis of A375
Use following carrier: 5% ethanol, 5%Cremophor and 90% isotonic saline solution are pressed the 1 described preparation of embodiment 10 solution with antineoplastic compound.Taxol (paclitaxel, Bristol MeyersSquibb) and Taxotere (many Xi Taqi as contrast; Rhonen-Poulenc Rorer) is marketed drugs.Dose volume is 0.3 milliliter of per 20 gram mouse.
With female NCr-nude mouse (with 1mm
3The human melanoma fragment of A375 is in the subcutaneous implantation of veutro) be divided into treatment group, every group of six mouse, but the Taxotere treatment group comprises seven mouse.The mean size scope of tumor group is the 206-212 milligram.Beginning administration in first day.With the maximum tolerated dose (MTD) that is suitable for each reagent, press qd * 1 timetable intravenous injection antineoplastic compound (compound is individually dosed).(before and after one hour) presses qd * twice taxol of 1 timetable intravenous injection (total dose 24 mg/kg) with the dosage of 12 mg/kg.Also with the dosage of taxol, press qd * 5 timetable i.p. administrations simultaneously with mg/kg every days 18.Press the dosage intravenous injection Taxotere of qd * 1 timetable with 70 mg/kg.1 group of mouse of control group is pressed qd * 1 timetable intravenous injection vehicle.Finished to measure research at the 60th day.Treatment group sees Table 7.
Table 7
| Group | Compound | ???Mg/kg | Route of administration | The administration system |
| ????1 | Vehicle | ????--- | ????i.v. | ??qd×1 |
| ????2 | Taxol | ????24 | ????i.v. | ??qd×1 |
| ????3 | Taxol | ????18 | ????i.p. | ??qd×5 |
| ????4 | ??1781 | ????72.6 | ????i.p. | ??qd×1 |
| ????5 | ??Taxotere | ????70 | ????i.v. | ??qd×1 |
The result is summarized in table 8, comprises average survival fate (MDS), the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part.Average survival fate refers to the fate after the tumour size reaches 2.0 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 2.0 grams, promptly produce " stable disease ".
Table 8
| Group | ??????MDS(n) | Poison number with poison | The survival number | Complete reaction | Partial reaction | Stable disease | Average mark |
| ??1 | ????14.4±0.9(6) | ????0 | ????0 | ????0 | ????0 | ????0 | ????1±0 |
| ??2 | ????18.1±0.6(4) | ????2 | ????0 | ????0 | ????0 | ????0 | ????0.8±0.3 |
| ??3 | ?????--- | ????6 | ????0 | ????0 | ????0 | ????0 | ????0±0 |
| ??4 | ????45.6(1) | ????5 | ????0 | ????0 | ????0 | ????0 | ????0.5±0.5 |
| ??5 | ????21.5±0.5(7) | ????0 | ????0 | ????0 | ????0 | ????0 | ????2±0 |
The A375 melanoma xenogenesis of handling all six mouse of (1 group) with vehicle moves to grow and continues fast to increase.The MDS value that reaches the end value of 2.0 grams is 14.4 days.
This test in qd * 1 timetable i.v. administration (24 mg/kg; 2 groups) the taxol treated animal show and the activity of appropriateness to be suitable for use as chemotherapeutic agent.The MDS value is 18.1 days, than the prolonged survival period 26% of 1 group of control animal.This prolongation has statistical significance (p=0.016; The t-that do not match test).With qd * 5 timetables (18 mg/kg; I.p.) the taxol group of administration shows high toxicity to mouse.
With 70 mg/kg i.v. administration (qd * 1; 5 groups) the MDS value that produces of taxotere be 21.5 days, than the prolonged survival period 49% of 1 group of control animal, p=0.0001 (t-that do not match test).
Antineoplastic compound 1781 causes five to be poisoned to death in six mouse.These compounds cause the mean body weight of 20-30% to alleviate.
Embodiment 15
Antineoplastic compound is to the activity in vivo of human Panc-1 carcinoma of the pancreas
Use following carrier: 5% ethanol, 5%Cremophor and 90% isotonic saline solution are pressed the 1 described preparation of embodiment 10 solution with antineoplastic compound.Taxol (paclitaxel, Bristol MeyersSquibb) as contrast is a marketed drugs.Dose volume is 0.3 milliliter of per 20 gram mouse.
With female NCr-nude mouse (with 1mm
3Panc-1 carcinoma of the pancreas fragment is in the subcutaneous implantation of veutro) be divided into treatment group, every group of six mouse.The mean size scope of Panc-1 pancreatic tumour group is the 192-213 milligram.Beginning administration in first day.With the maximum tolerated dose (MTD) that is suitable for each reagent, press qd * 1 timetable intravenous injection antineoplastic compound (compound is individually dosed).(before and after one hour) presses qd * twice taxol of 1 timetable intravenous injection (total dose 24 mg/kg) with the dosage of 12 mg/kg.Also with the dosage of taxol, press qd * 5 timetable i.p. administrations simultaneously with mg/kg every days 15.1 group of mouse of control group is pressed qd * 1 timetable intravenous injection vehicle.Finished research at the 63rd day.Treatment group sees Table 9.
Table 9
| Group | Compound | ???Mg/kg | Route of administration | The administration system |
| ????1 | Vehicle | ????--- | ????i.v. | ????qd×1 |
| ????2 | Taxol | ????24 | ????i.v. | ????qd×1 |
| ????3 | Taxol | ????15 | ????i.p. | ????qd×5 |
| ????4 | ???1781 | ????60 | ????i.v. | ????qd×1 |
The result is summarized in table 10, comprises average survival fate (MDS), the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part.Average survival fate refers to the fate after the tumour size reaches 1.5 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 1.5 grams, promptly produce " stable disease ".
Table 10
| Group | ??????MDS(n) | Poison number with poison | The survival number | Complete reaction | Partial reaction | Stable disease | Average mark |
| ????1 | ???23.0±3.1(5) | ????0 | ????1 | ????0 | ????0 | ????1 | ????2±0.8 |
| ????2 | ???34.7±3.4(4) | ????1 | ????1 | ????0 | ????0 | ????1 | ????2.2±0.8 |
| ????3 | ???--- | ????4 | ????1 | ????0 | ????1 | ????0 | ????1.2±1.2 |
| ????4 | ???59.3±2.9(2) | ????0 | ????4 | ????0 | ????4 | ????0 | ????6.7±1.2 |
The MDS calculated value that the Panc-1 tumour of handling the mouse of (1 group) with vehicle reaches the end values of 1.5 grams is 23.0 days.A routine tumour does not increase in the control group, has chosen unsuitable tumor specimen probably.
The intravenous taxol of dosage (2 groups) with 24 mg/kg (qd * 1) produces a routine stable disease, and the MDS that produces 34.7 days in other four mouse is (obviously different with 1 group of control group; P=0.038; The t-that do not match test).Die from the toxicity of taxol next mouse of this dosage.Taxol with 15 mg/kg dosage (qd * 5) i.p. administration causes four to be poisoned to death in six mouse.
Antineoplastic compound 1781 produces 66.7% total reaction rate.Antineoplastic compound 1781 has good tolerability, does not cause animal dead, only causes small group mean body weight to alleviate.Therefore, this compound can administration in suitable MTD dosage range.
Embodiment 16
Antineoplastic compound is to the activity in vivo of human VM46 colorectal carcinoma
Use following carrier: 5% ethanol, 5%Cremophor and 90% isotonic saline solution are pressed the 1 described preparation of embodiment 10 solution with antineoplastic compound.Taxol (paclitaxel, Bristol MeyersSquibb) and Taxotere (many Xi Taqi as contrast; Rhonen-Poulenc Rorer) is marketed drugs.Dose volume is 0.3 milliliter of per 20 gram mouse.
With female NCr-nude mouse (with 1mm
3Human VM46 colorectal carcinoma fragment is in the subcutaneous implantation of veutro) be divided into treatment group, every group of six mouse.The mean size scope of VM46 colon tumor group is the 181-188 milligram.Beginning administration in first day.With the maximum tolerated dose (MTD) of the estimation that is suitable for each reagent, press qd * 1 timetable intravenous injection antineoplastic compound (compound is individually dosed).(before and after one hour) presses qd * twice taxol of 1 timetable intravenous injection (total dose 24 mg/kg) with the dosage of 12 mg/kg.Also with the dosage of taxol, press qd * 5 timetable i.p. administrations simultaneously with mg/kg every days 15.Press the dosage intravenous injection Taxotere of qd * 1 timetable with 70 mg/kg.1 group of mouse of control group is pressed qd * 1 timetable intravenous injection vehicle.Finished research at the 64th day.Treatment group sees Table 11.
Table 11
| Group | Compound | ?Mg/kg | Route of administration | The administration system |
| ????1 | Vehicle | ????--- | ????i.v. | ????qd×1 |
| ????2 | Taxol | ????24 | ????i.v. | ????qd×1 |
| ????3 | Taxol | ????15 | ????i.p. | ????qd×5 |
| ????4 | ??1781 | ????60 | ????i.v. | ????qd×1 |
| ????5 | ??Taxotere | ????70 | ????i.v. | ????qd×1 |
The result is summarized in table 12, comprises average survival fate (MDS), the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part.Average survival fate refers to the fate after the tumour size reaches 1.5 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 1.5 grams, promptly produce " stable disease ".
Table 12
| Group | ????MDS(n) | Poison number with poison | Complete reaction | Partial reaction | Stable disease | Average mark |
| ????1 | ????31.0±4.4(6) | ????0 | ????0 | ????0 | ????0 | ????1.2±0.2 |
| ????2 | ????43.3±3.7(4) | ????0 | ????0 | ????1 | ????1 | ????3.8±1.4 |
| ????3 | ????36.1±12.2(2) | ????3 | ????0 | ????1 | ????0 | ????1.8±1.3 |
| ????4 | ????42.2±7.1(5) | ????0 | ????0 | ????1 | ????0 | ????3±1.2 |
| ????5 | ????45.3±3.6(6) | ????0 | ????0 | ????0 | ????0 | ????2±0 |
Handle the colon tumor sustainable growth of all six mouse of (1 group) with vehicle, the MDS calculated value that reaches the end value of 1.5 grams is 31.0 days.
With 24 mg/kg (i.v.; The taxol of dosed administration qd * 1) (2 groups) produces a routine partial reaction, a routine stable disease, and the MDS that produced 43.3 days in other four mouse (does not have obviously different with control group; P=0.086; The t-that do not match test).Taxol with 15 mg/kg dosage (qd * 5) i.p. administration shows high toxicity, causes three to be poisoned to death in six mouse of handling.In this test, Taxotere shows greater activity, and the MDS value that produced 45.3 days (has statistical significance, p=0.05; The t-that do not match test).
Antineoplastic compound 1781 reactivities are 16.7%.The MDS length of the survival time that antineoplastic compound 1781 obtains than 31.0 days that calculate by control group 11 to 20 days.Antineoplastic compound 1781 has good tolerability, does not cause toxicity death, and maximum group mean body weight alleviated 3-14% at the 8th day.
Embodiment 17
Antineoplastic compound 1755 oral administrations move the activity in vivo of growing to human SKMES lung cancer xenogenesis
Antineoplastic compound 1755 is prepared in following carrier by 1 of embodiment 6 solution are described: 5% ethanol, 5%Cremophor and 90% isotonic saline solution.In order to study antineoplastic compound human SKMES lung cancer xenogenesis is moved the activity of growing, with this compound with single dose bolus form oral administration.
(age in 6-8 week is with 1mm with female Nu/Nu-nude mouse
3Human SKMES lung cancer fragment is in the subcutaneous implantation of veutro) be divided into 4 treatment group, every group of six mouse.SKMES size and group SKMES mean size scope are respectively 126-448 milligram and 238-241 milligram.Treatment group comprises: non-processor group (1 group), vehicle-treated group (2 groups), taxol group (40 mg/kg; 3 groups), 1755 groups of (49 mg/kg of antineoplastic compound; 4 groups).Beginning in first day finished research with single dose bolus administration at the 60th day.
The result is summarized in table 13, comprises average survival fate (MDS), the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part.Average survival fate refers to the fate after SKMES tumour size reaches 2.0 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 2.0 grams, promptly produce " stable disease ".
Table 13
| Group | ??????MDS(n) | Poison number with poison | The survival number | Complete reaction | Partial reaction | Stable disease | The total reaction rate |
| ????1 | ????14.5±1.7(5) | ??0 | ??1 | ??0 | ??0 | ??1 | ??0 |
| ????2 | ????13.7±1.4(6) | ??0 | ??0 | ??0 | ??0 | ??0 | ??0 |
| ????3 | ????13.2±1.4(6) | ??0 | ??0 | ??0 | ??0 | ??0 | ??0 |
| ????4 | ????--- | ??0 | ??6 | ??4 | ??2 | ??0 | ??100 |
During the single oral dose administration, antineoplastic compound 1755 has high reactivity.The total reaction rate is 100%, four routine complete reaction, two routine partial reactions.The total reaction rate accounts for the evaluated animal percentage ratio of (comprising because operation or the lethal animal of toxicity) for what produce complete reaction or partial reaction when research finishes.
Embodiment 18
The antineoplastic compound oral administration moves the activity in vivo of growing to human MX-1 mammary cancer xenogenesis
In this test, in order to study this formulation human MX-1 mammary cancer xenogenesis is moved the activity of growing, with this compound oral administration.Antineoplastic compound is prepared in following carrier: 90% salt solution, 5%Cremophor, 5% ethanol.Antineoplastic compound 1771 is pressed the 1 described preparation of embodiment 6 solution.Antineoplastic compound 1781 is pressed the 2 described preparations of embodiment 6 solution.
(age in 11-12 week is with 1mm with female Nu/Nu mouse
3Human MX-1 mammary cancer fragment is in the subcutaneous implantation of veutro) be divided into a control group (n=10) and two treatment group (n=6) (organizing tumour mean size scope is the 47-49 milligram).Treatment group sees table 14 for details.The beginning in first day of all treatment group finished research with the administration of single dose bolus at the 60th day.
The result is summarized in table 14, comprises average survival fate (MDS), the quantity of poisoning with poison, the quantity of survival, the quantity of Fan Ying quantity, and stable disease wholly or in part.Average survival fate refers to the fate after MX-1 tumour size reaches 1.5 grams and animal dead.If the existence of tumour was not obvious when research finished, promptly obtain complete reaction.If tumour be retracted to than research first day little, promptly obtain partial reaction.When research finishes, when drug treating is restricted to growth of tumor less than 1.5 grams, promptly produce " stable disease ".
Table 14
| Group | Antineoplastic compound | Dosage (mg/kg) | Average survival fate (n) | Maximum weight alleviates | Poison number with poison | Complete reaction | Partial reaction | Stable disease |
| ????1 | Vehicle | ????n/a | ???21.5±0.7(8) | ????n/a | ????0 | ????0 | ????0 | ????2 |
| ????2 | ??1771 | ????107 | ???60.8±1.0(2)) | ????-8.1％(5) | ????0 | ????4 | ????0 | ????0 |
| ????3 | ??1781 | ????73 | ???33.3±2.9(5) | ????-9.4％(5) | ????0 | ????0 | ????0 | ????1 |
Move at MX-1 human breast cancer xenogenesis and to grow in the model, evaluated tumour compound has all shown activity in very wide tolerance dose scope.Antineoplastic compound 1771 causes four tumour in six processed animals to stop growing fully, and during off-test, other two survival time is than the obvious increase of control group mice.The feature of antineoplastic compound 1781 shown reactions is the survival time than control group mice tangible increase to be arranged.
Dwindle the reaction except that assessing survival time and tumour, also measured influence the hemocyte group.These antineoplastic compound are the quantity that obviously reduces neutrophil leucocyte to hemocyte group's main influence.And for each antineoplastic compound, the minimizing of neutrophil leucocyte and monocytic loss are relative.These antineoplastic compound do not influence general white blood cell count, lymphocyte, and thrombocyte.Between anti-tumor activity and the neutrophil leucocyte number certain relation is arranged.In general, toxicity (measuring) and lose weight relevant with activity by neutrophil leucocyte loss.Importantly, the active very strong viewed toxicity of antineoplastic compound is control easily and transforms; Only in several days, neutrophil leucocyte quantity and body weight all rebound from low spot.Table 15 has been summarized the 4th day losing weight, neutrophil leucocyte and monocytic observed value, and the dwindling of the tumor weight that calculated at the 18th day:
Table 15
| Group | Antineoplastic compound | Dosage (mg/kg) | Weight (mg) | The % decrement | Neutrophil leucocyte (K/ μ L) | The % decrement | Monocyte (K/ μ L) | The % decrement |
| ????1 | Vehicle | ????n/a | ??868.5 | ????- | ????0.9115 | ????0.096 | ??- | |
| ????2 | ??1771 | ????107 | ??0.1 | ????100.0％ | ????0.044 | ??95.2％ | ????0.045 | ??53.1％ |
| ????3 | ??1781 | ????73 | ??275.3 | ????68.3％ | ????0.117 | ??87.2％ | ????0.101 | ??- |
Claims (141)
1. the Taxan that has following formula:
Wherein:
R
2Be acyloxy;
R
7Be hydroxyl;
R
9Be ketone group, hydroxyl, or acyloxy;
R
10Be carbonic ether;
R
14Be hydrogen or hydroxyl;
X
3Be alkyl that replace or non-replacement, thiazolinyl, alkynyl or heterocyclic radical, wherein alkyl comprises at least two carbon atoms;
X
5For-COX
10,-COOX
10, or-CONHX
10
X
10Be alkyl, substituted hydrocarbon radical, or heterocycle; And
Ac is an ethanoyl.
2. the Taxan of claim 1, wherein R
10Be R
10aOCOO-, and R
10aFor replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
3. the Taxan in the claim 2, wherein X
3Be furyl, thienyl, pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
4. the Taxan of claim 2, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
5. the Taxan of claim 2, wherein R
14Be hydrogen.
6. the Taxan of claim 5, wherein X
3Be furyl, thienyl, pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
7. the Taxan of claim 5, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
8. the Taxan of claim 2, wherein R
2Be benzoyloxy.
9. the Taxan of claim 8, wherein X
3Be furyl, thienyl, pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
10. the Taxan of claim 8, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
11. the Taxan of claim 2, wherein R
14Be hydrogen, and R
9Be ketone group.
12. the Taxan of claim 11, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
3-C
8Alkynyl.
13. the Taxan of claim 11, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
14. the Taxan of claim 2, wherein R
2Be benzoyloxy and R
9Be ketone group.
15. the Taxan of claim 14, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
16. the Taxan of claim 14, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
17. the Taxan of claim 2, wherein R
14Be hydrogen and R
2Be benzoyloxy.
18. the Taxan of claim 17, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
19. the Taxan of claim 17, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
20. the Taxan of claim 2, wherein R
14Be hydrogen, R
9Be ketone group, and R
2Be benzoyloxy.
21. the Taxan of claim 20, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
22. the Taxan of claim 20, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
23. the Taxan of claim 1, wherein R
10Be R
10aOCOO-, and R
10aBe C
1-C
8Alkyl.
24. the Taxan of claim 23, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
25. the Taxan of claim 23, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
26. the Taxan of claim 23, wherein R
14Be hydrogen.
27. the Taxan of claim 26, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
28. the Taxan of claim 26, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
29. the Taxan of claim 23, wherein R
2Be benzoyloxy.
30. the Taxan of claim 29, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
31. the Taxan of claim 29, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
32. the Taxan of claim 23, wherein R
14Be hydrogen, R
9Be ketone group, and R
2Be benzoyloxy.
33. the Taxan of claim 32, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
34. the Taxan of claim 32, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
35. the Taxan of claim 1, wherein R
10Be R
10aOCOO-, and R
10aBe methyl or ethyl.
36. the Taxan of claim 35, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
37. the Taxan of claim 35, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
38. the Taxan of claim 35, wherein R
14Be hydrogen.
39. the Taxan of claim 38, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
40. the Taxan of claim 38, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
41. the Taxan of claim 35, wherein R
2Be benzoyloxy.
42. the Taxan of claim 41, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
43. the Taxan of claim 41, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
44. the Taxan of claim 35, wherein R
14Be hydrogen and R
9Be ketone group.
45. the Taxan of claim 44, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
46. the Taxan of claim 44, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
47. the Taxan of claim 35, wherein R
2Be benzoyloxy and R
9Be ketone group.
48. the Taxan of claim 47, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
49. the Taxan of claim 47, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
50. the Taxan of claim 35, wherein R
14Be hydrogen.And R
2Be benzoyloxy.
51. the Taxan of claim 50, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
52. the Taxan of claim 50, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
53. the Taxan of claim 35, wherein R
14Be hydrogen, R
9Be ketone group, and R
2Be benzoyloxy.
54. the Taxan of claim 53, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
55. the Taxan of claim 53, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
56. the Taxan of claim 53, wherein X
5For-COOX
10And X
10Be the tertiary butyl.
57. the Taxan of claim 56, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
58. Taxan with following formula:
Wherein:
R
2Be benzoyloxy;
R
7Be hydroxyl;
R
10Be R
10aOCOO-;
X
3Be alkyl that replace or non-replacement, thiazolinyl, alkynyl, or heterocyclic radical; Wherein alkyl contains at least two carbon atoms;
X
5For-COX
10,-COOX
10, or-CONHX
10
X
10Be alkyl, the alkyl of replacement, or heterocycle; And
R
10aBe alkyl, the alkyl of replacement, or heterocyclic radical; And
Ac is an ethanoyl.
59. the Taxan of claim 58, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
60. the Taxan of claim 59, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
61. the Taxan of claim 58, wherein X
3Be furyl or thienyl.
62. the Taxan of claim 61, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
63. the Taxan of claim 61, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
64. the Taxan of claim 58, wherein R
10aBe methyl or ethyl.
65. the Taxan of claim 64, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
66. the Taxan of claim 65, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
67. the Taxan of claim 65, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
68. the Taxan of claim 64, wherein X
3Be furyl or thienyl.
69. the Taxan of claim 68, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
70. the Taxan of claim 68, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
71. the Taxan of claim 64, wherein X
3Be cycloalkyl.
72. the Taxan of claim 71, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyrrole pyrrole base, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
73. the Taxan of claim 71, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
74. the Taxan of claim 64, wherein X
3Be isobutenyl.
75. the Taxan of claim 74, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
76. the Taxan of claim 74, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
77. the Taxan of claim 58, wherein X
3Be furyl or thienyl, R
10aBe ethyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
78. the Taxan of claim 58, wherein X
3Be 2-furyl or 2-thienyl, R
10aBe ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
79. the Taxan of claim 58, wherein X
3Be isobutenyl, and X
5For-COOX
10And X
10Be the tertiary butyl.
80. the Taxan of claim 58, wherein X
3Be cycloalkyl, R
10aBe methyl or ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
81. Taxan with following formula:
Wherein:
R
2Be benzoyl;
R
7Be hydroxyl;
R
10Be R
10aOCOO-;
X
3Be cycloalkyl, thiazolinyl, alkynyl, phenyl or heterocyclic radical;
X
5For-COX
10,-COOX
10, or-CONHX
10
X
10Be alkyl, the alkyl of replacement, or heterocycle; And
R
10aBe alkyl, thiazolinyl, alkynyl, phenyl or heterocyclic radical; Wherein alkyl contains at least two carbon atoms;
And
Ac is an ethanoyl.
82. the Taxan of claim 81, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
83. the Taxan of claim 82, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
84. the Taxan of claim 82, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
85. the Taxan of claim 81, wherein X
3Be furyl or thienyl.
86. the Taxan of claim 85, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
87. the Taxan of claim 85, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
88. the Taxan of claim 81, wherein X
3Be phenyl.
89. the Taxan of claim 88, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
90. the Taxan of claim 88, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
91. the Taxan of claim 81, wherein X
3Be isobutenyl.
92. the Taxan of claim 91, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
93. the Taxan of claim 91, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
94. the Taxan of claim 81, wherein R
10aBe ethyl.
95. the Taxan of claim 94, wherein X
3Be the 2-furyl, the 3-furyl.The 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
96. the Taxan of claim 94, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
97. the Taxan of claim 94, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
98. the Taxan of claim 94, wherein X
3Be furyl or thienyl.
99. the Taxan of claim 98, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
100. the Taxan of claim 98, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
101. the Taxan of claim 98, wherein X
5For-COOX
10And X
10Be the tertiary butyl.
102. a pharmaceutical composition, the Taxan and at least a pharmacy that comprise claim 1 are acceptable, inertia or have the thinner or the auxiliary of physiologically active.
103. the pharmaceutical composition of claim 102, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
104. the pharmaceutical composition of claim 103, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
105. the pharmaceutical composition of claim 103, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
106. the pharmaceutical composition of claim 102, wherein R
10aBe methyl, ethyl or propyl group.
107. the pharmaceutical composition of claim 106, wherein X
3Be the 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
2-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
108. the pharmaceutical composition of claim 107, wherein X
5For-COX
10And X
10For replacing or unsubstituted phenyl 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl, or X
5For-COOX
10And X
10For replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
109. the pharmaceutical composition of claim 107, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
110. the pharmaceutical composition of claim 103, wherein X
3Be furyl or thienyl, R
10aBe methyl or ethyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
111. the pharmaceutical composition of claim 103, wherein X
3For replacing or unsubstituted furyl R
10aBe methyl or ethyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
112. the pharmaceutical composition of claim 103, wherein X
3For replacing or unsubstituted thienyl R
10aBe methyl or ethyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
113. the pharmaceutical composition of claim 103, wherein X
3Be isobutenyl, R
10aBe methyl or ethyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
114. the pharmaceutical composition of claim 103, wherein X
3Be alkyl, R
10aBe methyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
115. the pharmaceutical composition of claim 103, wherein X
3Be 2-furyl or 2-thienyl, R
10aBe methyl, X
5For-COOX
10And X
10Be the tertiary butyl.
116. the pharmaceutical composition of claim 103, wherein X
3Be 2-furyl, R
10aBe ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
117. the pharmaceutical composition of claim 103, wherein X
3Be 2-thienyl, R
10aBe ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
118. the pharmaceutical composition of claim 103, wherein X
3Be isobutenyl, X
5For-COOX
10And X
10Be the tertiary butyl.
119. the pharmaceutical composition of claim 103, wherein X
3Be cycloalkyl, R
10aBe methyl, X
5For-COOX
10And X
10Be the tertiary butyl.
120. a pharmaceutical composition, the Taxan and at least a pharmacy that comprise claim 58 are acceptable, inertia or have the thinner or the auxiliary of physiologically active.
121. a pharmaceutical composition, the Taxan and at least a pharmacy that comprise claim 61 are acceptable, inertia or have the thinner or the auxiliary of physiologically active.
122. a liquid preparations for oral administration comprises the Taxan and at least a pharmaceutically acceptable carrier of claim 1.
123. the composition of claim 122, wherein R
10Be R
10aOCOO-, and R
10aFor replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
124. the composition of claim 123, wherein X
3Be phenyl, isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
125. the composition of claim 124, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
126. the composition of claim 125, wherein R
10aBe methyl, ethyl or propyl group.
127. the composition of claim 126, wherein X
3Be isobutenyl, R
10aBe methyl or ethyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
128. the composition of claim 127, wherein X
3Be 2-furyl or 2-thienyl, R
10aBe ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
129. the composition of claim 127, wherein X
3Be isobutenyl, X
5For-COOX
10, R
10aBe ethyl, and X
10Be the tertiary butyl.
130. the composition of claim 122, wherein X
3Be phenyl, R
10aBe ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
131. a pharmaceutical composition comprises the Taxan and at least a pharmaceutically acceptable carrier of claim 92.
132. a method that suppresses mammal tumor development, this method comprises oral administration, comprises the composition of the treatment significant quantity of the Taxan of claim 122 and at least a pharmaceutical acceptable carrier.
133. the method for claim 132, wherein R
10Be R
10aOCOO-, and R
10aFor replacing or unsubstituted C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
134. the method for claim 133, wherein X
3Be phenyl, isobutenyl, the 2-furyl, the 3-furyl, the 2-thienyl, 3-thienyl, 2-are given a tongue-lashing the pyridine base, 3-pyridyl, 4-pyridyl, C
1-C
8Alkyl, C
2-C
8Thiazolinyl or C
2-C
8Alkynyl.
135. the method for claim 134, wherein X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
136. the method for claim 135, wherein R
10aBe methyl, ethyl or propyl group.
137. the method for claim 136, wherein X
3Be isobutenyl, R
10aBe methyl or ethyl, and X
5For-COX
10And X
10Be phenyl, or X
5For-COOX
10And X
10Be the tertiary butyl.
138. the method for claim 137, wherein X
3Be isobutenyl, X
5For-COOX
10, R
10aBe ethyl and X
10Be the tertiary butyl.
139. the method for claim 132, wherein X
3Be 2-furyl or 2-thienyl, R
10aBe ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
140. the method for claim 132, wherein X
3Be phenyl, R
10aBe ethyl, X
5For-COOX
10And X
10Be the tertiary butyl.
141. a method that suppresses mammal tumor growth, this method comprises oral administration, comprises the composition of the treatment significant quantity of the Taxan of claim 92 and at least a pharmaceutical acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA011424087A CN1491947A (en) | 2001-08-06 | 2001-08-06 | C10 ester carbonate substituted taxadane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA011424087A CN1491947A (en) | 2001-08-06 | 2001-08-06 | C10 ester carbonate substituted taxadane |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1491947A true CN1491947A (en) | 2004-04-28 |
Family
ID=34230919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA011424087A Pending CN1491947A (en) | 2001-08-06 | 2001-08-06 | C10 ester carbonate substituted taxadane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1491947A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632296A (en) * | 2016-12-28 | 2017-05-10 | 吉林医药学院 | Novel taxane anti-tumor compound as well as synthesis method and application thereof |
-
2001
- 2001-08-06 CN CNA011424087A patent/CN1491947A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632296A (en) * | 2016-12-28 | 2017-05-10 | 吉林医药学院 | Novel taxane anti-tumor compound as well as synthesis method and application thereof |
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