CN1491947A - C10 ester carbonate substituted taxadane - Google Patents

C10 ester carbonate substituted taxadane Download PDF

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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
taxane
thienyl
furyl
coox
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R・A・赫尔顿
R·A·赫尔顿
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Florida State University Research Foundation Inc
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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

C10 carbonate substituted taxanes
Background
The present invention relates to novel taxanes having particular utility as antitumor agents.
The taxanes of terpenes, including baccatin III and paclitaxel, are the subject of interest in both biological and chemical fields. Paclitaxel itself is useful as a chemotherapeutic agent for cancer and has a wide range of tumor inhibiting activities. Paclitaxel has the 2 'R, 3' S configuration and the following structural formula:
Figure A0114240800141
wherein Ac is acetyl.
A specific taxol analog having significantly greater activity than taxol is reported by Colin et al in U.S. Pat. No. 4,814,470. One of these analogs, commonly referred to as docetaxel, has the following structural formula:
Figure A0114240800142
although both paclitaxel and docetaxel are useful chemotherapeutic agents, their efficacy is limited, including limited efficacy against a particular type of cancer and toxicity to the patient when administered at different doses, among others. Therefore, there is a need to develop other chemotherapeutic agents with better efficacy and lower toxicity.
Accordingly, it is an object of the present invention to provide a taxane which is more desirable than paclitaxel and docetaxel in terms of therapeutic effect and toxicity as an antitumor agent. Typically, these taxanes have a carbonate substituent at the C-10 position, a hydroxyl substituent at the C-7 position, and a range of C (2), C (9), C (14), and C (13) side chain substituents.
Thus, in brief summary, the present invention relates to taxane compositions, i.e., to pharmaceutical compositions comprising a taxane and a pharmaceutically acceptable carrier, and methods of administration.
Other objects and features of the present invention will be in part apparent and in part pointed out hereinafter.
Detailed description of the preferred embodiments
In one embodiment of the invention, the taxane of the invention corresponds to structural formula (1):
Figure A0114240800151
wherein:
R2is acyloxy;
R7is a hydroxyl group;
R9is a keto, hydroxyl, or acyloxy group;
R10is a carbonate;
R14is hydrogen or hydroxy;
X3is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclyl; wherein the alkyl group contains at least two carbon atoms
X5is-COX10，-COOX10or-CONHX10；
X10Is a hydrocarbyl, substituted hydrocarbyl, or heterocyclic ring;
ac is acetyl; and is
R7，R9And R10Independently have an alpha or beta stereochemical configuration.
In one embodiment, R2Is an ester group (R)2aC (O) O-), carbamate group (R)2aR2bNC (O) O-), carbonate group (R)2aOC (O) O-), or thiocarbamate (R)2aSC (O) O-), wherein R2aAnd R2bIndependently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclyl. In a preferred embodiment, R2Is an ester group (R)2aC(O)O-)，R2aIs aryl or heteroaryl. In another preferred embodiment, R2Is an ester group (R)2aC(O)O-)，R2aIs a substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl group. In a more preferred embodiment R2Is benzoyloxy.
When in one embodiment of the inventionR9When it is keto, in other embodiments R9May have an alpha or beta stereochemical configuration, preferably a beta stereochemical configuration, and may be, for example, an alpha-or beta-hydroxy or alpha-or beta-acyloxy group. For example, when R is9When it is an acyloxy group, it may be an ester group (R)9aC (O) O-), carbamate group (R)9aR9bNC (O) O-), carbonate group (R)9aOC (O) O-), or thiocarbamate (R)9aSC (O) O-), wherein R9aAnd R9bIndependently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclyl. If R is9Is an ester group (R)9aC(O)O-)，R9aIs a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. And more preferably R9Is an ester group (R)9aC(O)O-)，R9aIs a substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyridyl. In one embodiment R9Is an ester group (R)9aC (O) O-), wherein R9aIs methyl, ethyl, propyl (linear, branched or cyclic), butyl (linear, branched or cyclic), pentyl (linear, branched or cyclic), or hexyl (linear, branched or cyclic). In another embodiment, R9Is an ester group (R)9aC (O) O-), wherein R9aSubstituted methyl, substituted ethyl, substituted propyl (linear, branched or cyclic), substituted butyl (linear, branched or cyclic), substituted pentyl (linear, branched or cyclic), or substituted hexyl (linear, branched or cyclic), wherein the substituents are selected from the group consisting of heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, hydroxyl, protected hydroxyl, carbonyl, acyloxy, nitro, amino, amido, mercapto, ketal, acetal, ester and ether, but excluding phosphorus-containing groups.
In one embodiment, R10Is R10aOCOO-, wherein R10aIs (i) substituted or unsubstituted C1To C8Alkyl (linear, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substitutionOr unsubstituted C2To C8Alkenyl (linear, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl, or hexenyl; (iii) substituted or unsubstituted C2To C8Alkynyl (linear or branched), such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) a substituted or unsubstituted heteroaryl group such as furyl, thienyl or pyridyl. The substituent may be a hydrocarbyl group or any heteroatom-containing substituent elsewhere herein consistent with the definition of substituted hydrocarbyl groups. In a preferred embodiment, R10aIs methyl, ethyl, straight, branched or cyclopropyl, straight, branched or cyclobutyl, straight, branched or cyclopentyl, straight, branched or cyclohexyl, straight, branched or cyclopropenyl, isobutenyl, furyl, or thienyl. In another preferred embodiment, R10aSubstituted ethyl, substituted propyl (linear, branched or cyclic), substituted propenyl (linear or branched), substituted butenyl, substituted furyl or substituted thienyl, wherein the substituents are selected from the group consisting of heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, hydroxyl, protected hydroxyl, carbonyl, acyloxy, nitro, amino, amido, mercapto, ketal, acetal, ester and ether groups, but excluding phosphorus-containing groups.
X3Examples of the substituent include substituted or unsubstituted C2-C8Alkyl, substituted or unsubstituted C2-C8Alkenyl, substituted or unsubstituted C2-C8Alkynyl, substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Preferred X3Examples of the substituent include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutyl, furyl, thienyl and pyridyl.
X5Examples of the substituent include-COX10，-COOX10or-CONHX10Wherein X is10Is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroAryl, preferably X5Examples of the substituent include-COX10，-COOX10or-CONHX10Wherein X is10Is (i) substituted or unsubstituted C1-C8An alkyl group such as a substituted or unsubstituted methyl, ethyl, propyl (linear, branched or cyclic), butyl (linear, branched or cyclic), pentyl (linear, branched or cyclic), or hexyl (linear, branched or cyclic); (ii) substituted or unsubstituted C2-C8Alkenyl (linear, branched or cyclic), such as substituted or unsubstituted ethenyl, propenyl (linear, branched or cyclic), butenyl (linear, branched or cyclic), pentenyl (linear, branched or cyclic), or hexenyl (linear, branched or cyclic); (iii) substituted or unsubstituted C2-C8Alkynyl (linear or branched), such as substituted or unsubstituted ethynyl, propynyl (linear or branched), butynyl (linear or branched), pentynyl (linear or branched), or hexynyl (linear or branched); (iv) substituted or unsubstituted phenyl; or (v) a substituted or unsubstituted heteroaryl group such as furyl, thienyl or pyridyl. Wherein the substituents are selected from the group consisting of heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, hydroxy, protected hydroxy, carbonyl, acyloxy, nitro, amino, amido, mercapto, ketal, acetal, ester and ether groups, but excluding phosphorus-containing groups.
In a preferred embodiment, the taxanes of the invention correspond to the following structural formula (2):
Figure A0114240800171
wherein,
R7is a hydroxyl group;
R10is a carbonate;
X3is a substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclyl group, wherein the alkyl group contains at least two carbon atoms;
X5is-COX10，-COOX10or-CONHX10(ii) a And is
X10Is a hydrocarbyl, substituted hydrocarbyl, or heterocyclic ring.
For example, in a preferred embodiment of a taxane corresponding to structure (2), R10Is R10aOCOO-, wherein R10aIs a substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl or hexyl group, more preferably a substituted or unsubstituted methyl, ethyl or propyl group, even more preferably a substituted or unsubstituted methyl, ethyl group, particularly preferably an unsubstituted methyl or ethyl group, when R is10aWhen selected from the above groups, X in one embodiment3Selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclic group, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclic group, still more preferably substituted or unsubstituted phenyl or heterocyclic group, particularly preferably heterocyclic group such as furyl, thienyl or pyridyl; when R is10aAnd X3When selected from the above groups, X in one embodiment5Is selected from-COX10Wherein X is10Is phenyl, alkyl or heterocyclyl, more preferably phenyl, optionally when R is10aAnd X3When selected from the above groups, X in one embodiment5Is selected from-COX10Wherein X is10Is phenyl, alkyl or heterocyclyl, more preferably phenyl, or X5is-COOX10Wherein X is10Is an alkyl group, preferably a tert-butyl group, and in a more preferred embodiment, corresponds to a taxane of structure (2) wherein (i) X5is-COOX10Wherein X is10Is tert-butyl, or X5is-COX10Wherein X is10Is phenyl, (ii) X3Is a substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclyl group, more preferably a substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl or pyridyl group, and (iii) R10aIs unsubstituted methyl, ethyl or propyl, more preferably methyl or ethyl.
Preferred practice in the case of taxanes corresponding to the structures (1) or (2)In the scheme, wherein R10Is R10aOCOO-，R10aIs a substituted or unsubstituted ethyl or propyl group, more preferably an unsubstituted ethyl or propyl group, when R is10aWhen selected from the above groups, X in one embodiment3Selected from substituted or unsubstituted cycloalkyl, phenyl or heterocyclyl, more preferably substituted or unsubstituted cycloalkyl, phenyl, furyl, thienyl or pyridyl; when R is10aAnd X3When selected from the above groups, X in one embodiment5Is selected from-COOX10Wherein X is10Is tert-butyl, tert-pentyl, isobutyl, isopropyl or substituted or unsubstituted cycloalkyl, R2，R9And R14As defined in structures (1) and (2), benzoyloxy, keto, and hydrogen are preferred, respectively. In a more preferred embodiment, the taxane corresponding to structure (2) wherein (i) X5is-COOX10Wherein X is10Is tert-butyl, tert-pentyl, isobutyl, isopropyl or a substituted or unsubstituted cycloalkyl group, more preferably tert-butyl, (ii) X3Is a substituted or unsubstituted cycloalkyl, phenyl, furyl, thienyl or pyridyl group, more preferably an unsubstituted cycloalkyl, phenyl, furyl, thienyl or pyridyl group, and (iii) R10aIs unsubstituted ethyl or propyl, and in each alternative of this embodiment, when the taxane has structure (1), each R is7And R10May have a beta stereochemical configuration, each R7And R10May have an alpha stereochemical configuration when R10Having beta stereochemical configuration, R7Having an alpha stereochemical configuration, or when R is10Having alpha stereochemical configuration, R7Has beta stereochemical configuration.
In a preferred embodiment of the taxane corresponding to structure (1) or (2), wherein R10Is R10aOCOO-, wherein R10aIs methyl. In this embodiment, X3Preferably a cycloalkyl group, an isobutenyl group, or a heterocyclic group, more preferably a heterocyclic group, still more preferably a furyl group, a thienyl group or a pyridyl group; x5Preferably benzoyl, alkoxycarbonyl, or heterocyclylcarbonylMore preferably a benzoyl group, a tert-butoxycarbonyl group, or a tert-pentyloxycarbonyl group, and still more preferably a tert-butoxycarbonyl group. In an alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, R14Is hydrogen. In another alternative of this embodiment, X3Is a heterocyclic group; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, and R14Is hydrogen; in another alternative of this embodiment, X3Is a heterocyclic group; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, and R14Is a hydroxyl group; in another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is hydroxy, and R14Is a hydroxyl group. In another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is hydroxy, and R14Is hydrogen. In another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is acyloxy, and R14Is a hydroxyl group. In this embodimentIn another alternative of (1), X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is acyloxy, and R14Is hydrogen. In each alternative embodiment, when the taxane has structure 1, each R is7And R10May have an alpha stereochemical configuration, each R7And R10May have an alpha stereochemical configuration when R10Having beta stereochemical configuration, R7Having an alpha stereochemical configuration, or when R is10Having alpha stereochemical configuration, R7Has beta stereochemical configuration.
Also, in preferred embodiments where the taxane corresponds to structure 1 or 2, wherein R10Is R10aOCOO-, wherein R10aIs ethyl. In this embodiment, X3Preferably cycloalkyl, isobutylphenyl, substituted phenyl such as p-nitrophenyl, or heterocyclyl, more preferably heterocyclyl, still more preferably furyl, thienyl or pyridyl; x5Preferably a benzoyl group, an alkoxycarbonyl group, or a heterocyclylcarbonyl group, more preferably a benzoyl group, a tert-butoxycarbonyl group, or a tert-pentyloxycarbonyl group. In an alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, R14Is hydrogen. In another alternative of this embodiment, X3Is a heterocyclic group; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, and R14Is hydrogen; in another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, tert-butoxyCarbonyl, or tert-pentyloxycarbonyl, still more preferably tert-butyloxycarbonyl, R2Is benzoyl, R9Is a keto group, and R14Is a hydroxyl group; in another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is hydroxy, and R14Is a hydroxyl group; in another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is hydroxy, and R14Is hydrogen. In another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is acyloxy, and R14Is a hydroxyl group. In another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, tert-butoxycarbonyl, or tert-pentyloxycarbonyl, still more preferably tert-butoxycarbonyl, R2Is benzoyl, R9Is acyloxy, and R14Is hydrogen. In each alternative embodiment, when the taxane has structure 1, each R is7And R10May have an alpha stereochemical configuration, each R7And R10May have an alpha stereochemical configuration when R10Having beta stereochemical configuration, R7Having an alpha stereochemical configuration, or when R is10Having alpha stereochemical configuration, R7Has beta stereochemical configuration.
Also, in preferred embodiments where the taxane corresponds to structure 1 or 2, wherein R10Is R10aOCOO-, wherein R10aIs propyl. In this embodimentIn, X3Preferably cycloalkyl, isobutylphenyl, substituted phenyl such as p-nitrophenyl, or heterocyclyl, more preferably heterocyclyl, still more preferably furyl, thienyl or pyridyl; x5Preferably a benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl group, more preferably a benzoyl, tert-butoxycarbonyl, or tert-pentyloxycarbonyl group, in an alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, R14Is hydrogen. In another alternative of this embodiment, X3Is a heterocyclic group; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, and R14Is hydrogen; in another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is a keto group, and R14Is a hydroxyl group; in another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is hydroxy, and R14Is a hydroxyl group; in another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is hydroxy, and R14Is hydrogen. In another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, orA heterocyclylcarbonyl group, more preferably a benzoyl group, a tert-butoxycarbonyl group, or a tert-pentyloxycarbonyl group, still more preferably a tert-butoxycarbonyl group; r2Is benzoyl, R9Is acyloxy, and R14Is a hydroxyl group. In another alternative of this embodiment, X3Is a heterocycle; x5Is benzoyl, alkoxycarbonyl, or heterocyclylcarbonyl, more preferably benzoyl, t-butoxycarbonyl, or t-pentyloxycarbonyl, still more preferably t-butoxycarbonyl; r2Is benzoyl, R9Is acyloxy, and R14Is hydrogen. In each alternative embodiment, when the taxane has structure 1, each R is7And R10May have a beta stereochemical configuration, each R7And R10May have an alpha stereochemical configuration when R10Having beta stereochemical configuration, R7Having an alpha stereochemical configuration, or when R is10Having alpha stereochemical configuration, R7Has beta stereochemical configuration.
Taxanes having the general formula 1 can be obtained by treating the β -lactam with an alkoxide having a tetracyclic parent nucleus of the taxane and a C-13 metal oxide substituent to form a compound having a β -amido ester substituent at the C-13 position (see Holton U.S. patent No. s. Pat. 5,466,834 for details), followed by removal of the hydroxy protecting group. The beta-lactam has the following structural formula (3):
wherein P is2Is a hydroxy protecting group, X3And X5As previously defined, and the alkoxide is of formula (4):
Figure A0114240800221
wherein M is a metal or ammonium, P7Is a hydroxy protecting group, and R10As previously defined.
Alkoxides may be prepared from 10-deacetylbaccatin III by selective formation of a carbonate of the C (10) hydroxyl group followed by protection of the C (7) hydroxyl group (as described more fully by Holton et al in PCT patent application WO 99/09021) and subsequent treatment with a metal amide. Acylating agents useful for the selective acylation of the C (10) hydroxyl group of taxanes include dimethyl dicarbonate, diethyl dicarbonate, di-tert-butyl dicarbonate, dibenzyl dicarbonate, and the like. Although the acylation of the C (10) hydroxyl group of the taxane will proceed at a sufficient rate for many acylating agents, it has been found that the reaction rate will be increased when a Lewis acid is present in the reaction mixture. Preferred Lewis acids include zinc chloride, stannic chloride, cerium trichloride, cuprous chloride, lanthanum trichloride, dysprosium trichloride, and ytterbium trichloride. Zinc chloride or cerium trichloride are particularly preferred when the acylating agent is a dicarbonate.
Derivatives of 10-deacetylbaccatin III having substitutable substituents at the C (2), C (9) and C (14) positions and processes for their preparation are known in the prior art. Taxanes having an acyloxy substituent at the C (2) position other than benzoyloxy may be prepared, for example, as described in U.S. Pat. No. 5,728,725 to Holton et al, or U.S. Pat. No. 6,002,023 to Kingston et al. Taxanes having an acyloxy or hydroxy substituent at the C (9) position in place of the carbonyl group can be prepared, for example, as described by Holton et al in U.S. Pat. No. 6,011,056, or Gunawardana et al in U.S. Pat. No. 5,352,806. Taxanes having a β hydroxy substituent at the C (14) position may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.
Methods for preparing and resolving β -lactam starting materials are generally well known. For example, beta-lactams can be prepared according to the method of Holton in U.S. patent No. 5,430,160, and the resulting enantiomeric mixture of beta-lactams can be resolved by stereoselective hydrolysis using a lipase or an enzyme such as that described by Patel in U.S. patent No. 5,879,929 and Patel in U.S. patent No. 5,567,614, or by using liver homogenate such as that described in PCT application No. 00/41204. In a preferred embodiment, the β -lactam is a β -lactam substituted at the C (4) position with furan, and may be prepared by the method shown in the following reaction scheme:
Figure A0114240800231
where Ac is acetyl, NEt3Is triethylamine, CAN is ceric ammonium nitrate, and p-TsOH is p-toluenesulfonic acid. Bovine liver resolution can be performed, for example, by mixing the enantiomeric β -lactam mixture with a suspension of bovine liver (e.g., prepared by adding 20g of frozen bovine liver to a blender followed by addition of a buffer at pH8 to bring the total volume to 1 liter).
The compounds of formula 1 of the present invention are effective in inhibiting tumor growth in mammals, including humans, and are preferably administered in the form of a pharmaceutical composition comprising an anti-tumor effective amount of a compound of the present invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier. Carriers are also any substance known in the art, such as excipients, vehicles, adjuvants or diluents, which are pharmaceutically inert and which can be formed into compositions in a suitable consistency or form without diminishing the therapeutic effect of the anti-tumor compound. The carrier is "pharmaceutically or pharmacologically acceptable" as long as it does not cause an undesirable, allergic or other undesirable reaction when administered to a mammal or human.
The pharmaceutical compositions containing the anti-tumor compounds of the present invention can be formulated by any conventional method. Suitable formulations depend on the chosen route of administration. The compositions of the present invention may be formulated for any route of administration, depending on the route of administration chosen. The compositions of the invention may be formulated for any route of administration, as long as the target tissue is compatible with the route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavitary, vaginal, transurethral, intradermal, otic, intramammary, buccal, orthotopic, intratracheal, intralesional, transdermal, endoscopic, intramucosal, sublingual, and enteral administration.
Pharmaceutically acceptable carriers for use in the compositions of the invention are well known to those skilled in the art and are selected based on several factors: the specific anti-tumor compound used, its concentration, stability, and bioavailability of the target; the disease, disorder or condition to be treated with the composition; the individual, his age, physical size and general condition; and the route of administration. Suitable vectors can be readily determined by one of ordinary skill in the art. (see, e.g., J.G.Nairn, inReminciton’s Pharmaceutical Science(Gennaro eds.), Mack publishing company, Easton, Pa., (1985), pp.1492-1517, the contents of which are incorporated herein by reference).
The composition is preferably in the form of a tablet, powder, pill, capsule, gelcap, caplet, gel, liposome, granule, solution, suspension, emulsion, syrup, elixir, lozenge, dragee, troche, or any other form that can be administered orally. The techniques and compositions of the present invention for preparing oral dosage forms are described in the following references:
modern pharmacology 7: (7Modern Pharmaceutics) Chapters 9 and 10 (Banker)&Rhodes, eds, 1979); lieberman et al, pharmaceutical dosage form: tablet (A)Pharmaceutical Dosage Forms： Tablets) (1981); and Ansel, pharmaceutical dosage formsIntroduction to Pharmaceutical Dosage Forms) 2 nd edition (1976).
The orally administered compositions of the invention comprise an anti-tumor effective amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches and other conventional materials including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar-mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid. In addition, the solid dosage forms may be uncoated or they may be coated according to known techniques, i.e. disintegration and absorption may be delayed.
The antitumor compounds of the present invention may also preferably be formulated for parenteral administration, i.e., as injections by intravenous, intraperitoneal or intrasternal routes. Compositions of the invention for parenteral administration comprise an anti-tumor effective amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable dosage forms for parenteral administration include solutions, suspensions, dispersions, emulsions or any other suitable dosage form for parenteral administration. Techniques and compositions for preparing parenteral dosage forms are known in the art.
Suitable carriers for preparing liquid dosage forms for oral or parenteral administration include non-aqueous, pharmaceutically acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solution, dextrose solution (i.e., DW5), electrolyte solution, or other aqueous, pharmaceutically acceptable liquids.
Suitable non-aqueous, pharmaceutically acceptable polar solvents include, but are not limited to, alcohols (e.g., α -glycerol formal, β -glycerol formal, 1, 3-butylene glycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, pentene hydrate, benzyl alcohol, glycerol (glycerol), ethylene glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols, such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol) sorbitan, sucrose, and cholesterol); amides (e.g. Dimethylacetamide (DMA), benzylbenzoyl ester DMA, dimethylformamide, N- (. beta. -hydroxyethyl) -lactamide, N, N-Dimethylacetamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidone, acetates such as monoacetin, diacetin, and triacetin, fatty or aromatic esters such as ethyl caprylate or heptanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO), glycerides such as citric acid or tartaric acid mono-, di-or triglycerides, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, sorbitan fatty acid esters, fatty acid derived PEG esters, glycerol monostearate, glycerides such as mono-, di, or triglycerides, fatty acid esters such as isopropyl myristate, fatty acid derivatized PEG esters such as PEG-hydroxyoleate, and PEG-hydroxystearate, N-methylpyrrolidone, pluronic 60, polyoxyethylene sorbitan oleate polyesters such as poly (ethoxylated).30-60Sorbitol poly (oleate)2-4Poly (oxyethylene)15-20Monooleate, poly (oxyethylene)15-20Mono 12-hydroxystearate, and poly (oxyethylene)15-20Monoricinoleate, polyoxyethylene sorbitan esters, e.g. polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate
Polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, and polysorbate 20, 40, 60 or 80 (from ICI America, Wilmington, DE), polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters, such as polyhydroxyl 40 hydrogenated castor oil and polyoxyethylated castor oil (e.g., Cremophor  EL solution or Cremophor  RH 40 solution), fatty acid esters of sugars (i.e., condensates of monosaccharides (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose, and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, triose, tetrose, heptose, and octose), disaccharides (e.g., sucrose, maltose, lactose, and trehalose), or oligosaccharides or their mixtures with C4-C22Fatty acids (e.g., saturated fatty acids such as caprylic acid, lauric acid, myristic acid, palmitic acid, and stearic acid, and unsaturated fatty acids such asMixtures of palmitoleic, oleic, elaidic, erucic, and linoleic acids), or steroidal esters); alkyl, aryl, or cyclic ethers having 2 to 30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, isosorbide dimethyl ether, divinyl glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyglycol ether); ketones having 3 to 30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4 to 30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolane, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylene sulfoxide, toluene, dimethyl sulfoxide (DM50), or tetramethylene sulfoxide); oils of mineral, vegetable, animal, natural or synthetic origin (for example, mineral oils such as aliphatic or waxy hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic hydrocarbon-based hydrocarbons, and refined paraffin oils, vegetable oils such as linseed oil, tung oil, safflower oil, soybean oil, castor oil, cottonseed oil, groundnut oil, rapeseed oil, coconut oil, palm oil, olive oil, corn oil, maize germ oil, sesame oil and peanut oil, and glycerides such as mono, di, triglycerides, animal oils such as fish oils, marine oils, sperm oil, cod-cod liver oil, halibut liver oil, squalene, squalane, and shark liver oil, oils of oleic acid, and polyoxyethylated castor oil); an alkyl or aryl halide having 1 to 30 carbon atoms and optionally more than one halogen atom; dichloromethane; monoethanolamine; petroleum spirits, triethanolamine (trolamine); omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyethylene glycol esters of 12-hydroxystearic acid and polyethylene glycol (Solutol  HS-15 from BASF, Ludwigshafen, germany); polyoxyethylene glycerol; sodium laurate; sodium oleate, or sorbitan monooleate.
Other pharmaceutically acceptable solvents for use in the present invention are well known to those skilled in the art and are defined in the following book: chemotherapy source roster (The Chemotherapy Source Book)(Williams&Wilkens publication), pharmaceuticalsHandbook of excipients (The Handbook of Pharmaceutical Excipients)(American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of great britain, London, England, 1968), modern medicine (American Pharmaceutical Association)Modern Pharmaceutics)(G.Bank et al, 3 rd edition) (Marcel Dekker, Inc., New York, 1995),pharmacology of therapeutics Science foundation (The Pharmacological base of Therapeutics)；(Goodman &' Gilman, McGraw Hill publication), pharmaceutical dosage forms (Pharmaceutical Dosaae Forms) (H.Lieberman et al, eds.) (Marcel Dekker, Inc., New York, 1980),Remington’s Pharmaceutical Sciences(edited by Gennaro, 19 th edition) (Mack published, Easton, PA, 1995), United states Pharmacopeia 24(The United States Pharmacopeia 24)National drug formulary 19(The National Formulary 19)(National publication, Philadelphia, PA, 2000), A.J. Spiegel et al, Use OF non-aqueous solvents in Parenteral Products, (Use OF NonaqueousSolvents in Parenteral Products), JOURNAL OF pharmaceutical sciences (JOURNAL OF PHARMACEUTICAL SCIEENCES), Vol.52, No. 10, p.917-.
Preferred solvents include those known to be stable against neoplastic compounds, for example, triglyceride-rich oils such as safflower oil, soybean oil or mixtures thereof, and alkyleneoxy-modified fatty acid esters such as polyoxyl (polyoxyl)40 hydrogenated castor oil and polyoxyethylated (polyoxyethylated) castor oil (e.g., Cremophor  EL solution or Cremophor  RH 40 solution). Commercially available triglycerides include Intralipid  emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid  emulsion (McGaw, Irvine, California), Liposon  II 20% emulsion (20% fat emulsion solution containing 109mg safflower oil, 100mg soybean oil, 12mg lecithin, and 25mg of glycerol; abbott laboratory, Chicago', Illino), Liposon  III 2% emulsion (2% fat emulsion solution containing 100mg safflower oil, 100mg soybean oil, 12mg lecithin per ml solution, and 25mg of glycerol; abbott laboratories, Chicago, Illino), natural or synthetic glycerol derivatives contain from 25% to 100% docosahexaenoic acid based on the total weight of fatty acids, (Dhasco  (available from Martek Biosciences, Columbia, Md.), DHA Maguro  (available from Daito corporation, los. Angeles, Calif.), Soyacal , and Travemulsion . ethanol is the preferred solvent for dissolving the anti-tumor compound to form solutions, emulsions, and the like.
Additional minor components for various uses known in the pharmaceutical industry may be included in the compositions of the present invention. These components will have local notification properties that will improve the retention of the anti-tumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate formulation of the anti-tumor compound, and the like. Preferably, these components are each present individually in an amount of less than 15% by weight of the total composition, more preferably less than 5% by weight, and especially preferably less than 0.5% by weight of the total composition. Some components, such as fillers or diluents, may constitute up to 90% of the total weight of the composition, as is well known in the formulation art. Such additives include cryoprotectants to prevent re-precipitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween  80, pluronic 60, polyoxyethylene stearate), preservatives (e.g., ethyl paraben), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents or buffers for adjusting pH (e.g., acids, bases, sodium acetate, sorbitan laurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methylcellulose, hydroxypropylcellulose, glycerol tristearate, cetyl ceryl ester, polyethylene glycol), a coloring agent, a dye, a flow aid, a non-volatile organopolysiloxane (e.g., cyclomethicone), a clay (e.g., a soap clay), a binder, a leavening agent, a flavoring agent, a sweetener, an adsorbent, a filler (e.g., a sugar such as lactose, sucrose, mannitol, or sorbitol, cellulose, or calcium phosphate), a diluent (e.g., water, saline, an electrolyte solution), a binder (e.g., a starch such as corn starch, wheat starch, rice starch, or potato starch, gelatin, a gum, tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, a saccharide, a polymer, acacia), a disintegrant (e.g., a starch such as corn starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, croscarmellose sodium, or povidone, a lubricant (e.g., silicon dioxide, talc, stearic acid, or a salt thereof such as magnesium stearate, or polyethylene glycol), a coating agent (e.g., a concentrated sugar solution containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide), and an antioxidant (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, glucose, phenol, and thiophenol).
In a preferred embodiment, the pharmaceutical composition of the invention comprises at least one non-aqueous, pharmaceutically acceptable solvent, and the anti-neoplastic compound has a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700, or 800 mg/ml. While not being bound by a particular theory, it is believed that the ethanol solubility of an anti-tumor compound may be directly related to its effect. The anti-tumor compound can also be crystallized out in solution. That is, a crystalline antitumor compound, such as compound 1393, may be dissolved in a solvent to form a solution, and then the solvent is removed by evaporation to recrystallize without forming an amorphous antitumor compound. It is also preferred that the anti-neoplastic compound has an IC50 value (i.e., a concentration of drug that produces inhibition of 50% of bacterial formation) that is at least less than 4, 5, 6, 7, 8, 9, or 10-fold less than paclitaxel (paclitaxel) when assayed according to the same criteria set forth in the examples.
Dosage forms for administration by these routes may be continuous or intermittent, depending, for example, on the physiological condition of the patient, whether the purpose of administration is therapeutic or prophylactic, and other factors known and appreciated by those skilled in the art.
The dosage and prescription of the pharmaceutical composition of the present invention can be readily determined by those of ordinary skill in the treatment of tumors. It is considered that the dosage of the antitumor compound is determined depending on the age, sex, health condition, and weight of the recipient, the kind of disease to be treated simultaneously, the number of treatments, and the nature of the target effect. The actual amount of the anti-tumor compound to be administered, and the dosage schedule necessary to achieve the beneficial effects described herein, for any mode of administration, will also depend in part on the following factors: the bioavailability of the anti-neoplastic compound, the disorder to be treated, the desired therapeutic dose, and other factors that will be apparent to those skilled in the art. In the context of the present invention, a mammal, particularly a human, must be administered in a dose sufficient to achieve the desired therapeutic effect in the mammal within a reasonable period of time. Preferably, the effective amount of the anti-neoplastic compound, whether administered orally or via other routes of administration, is any dose that results in the desired therapeutic effect when administered according to the route of administration. Preferably, the orally administered composition is formulated by including at least 20mg of the anti-neoplastic compound per square meter of body surface area of the subject, or at least 50, 100, 150, 200, 300, 400, or 500mg of the anti-neoplastic compound per square meter of body surface area of the subject in a single dose of one or more oral sub-formulations, wherein the body surface area of the human is 1.8m on average2. Preferably, the orally administered composition comprises in a single dose from about 20mg to about 600mg of the anti-neoplastic compound per square meter of patient body surface area, more preferably from about 25 to about 400mg/m2And still more preferably from about 40 to about 300mg/m2And more preferably from about 50 to about 200mg/m2. Preferably, the compositions for parenteral administration are formulated by including at least 20mg of the anti-neoplastic compound per square meter of patient's body surface area, or at least 40, 50, 100, 150, 200, 300, 400, or 500mg of the anti-neoplastic compound per square meter of patient's body surface area in a single doseA compound (I) is provided. Preferably, the one or more parenteral formulations comprise from about 20mg to about 500mg of the anti-neoplastic compound per square meter of patient body surface area in a single dose, more preferably from about 40 to about 400mg/m2And still more preferably from about 60 to about 350mg/m2。
However, the dosage can be varied according to the adjusted dosage regimen needed to achieve the desired therapeutic effect. It should be noted that the effective dosage ranges provided herein are not intended to limit the invention and represent preferred dosage ranges. More preferred dosages will be adjusted for individual subjects and can be known and determined by one of ordinary skill in the art without undue experimentation.
The concentration of the anti-neoplastic compound in the liquid pharmaceutical composition is preferably between about 0.01mg to about 10mg per ml of the composition, more preferably between 0.1mg to about 7mg per ml, more preferably between 0.5mg to about 5mg per ml, more preferably between 1.5mg to about 4mg per ml. Generally, relatively low concentrations are preferred because antitumor compounds are more soluble in solution at lower concentrations. The concentration of the anti-neoplastic compound in the solid pharmaceutical composition for oral administration is preferably from about 5% to about 50%, more preferably from about 8% to about 40%, and more preferably from about 10% to about 30% by weight of the total composition.
In one embodiment, the solution for oral administration is formulated by dissolving the anti-neoplastic compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. To this solution is added an appropriate volume of a vehicle in solution form, such as Cremophor  EL solution, and stirred to form a pharmaceutically acceptable infusion for oral administration to a patient. Such solutions can be formulated with minimal or no ethanol, if desired, as it is known in the art that ethanol at a certain concentration in an oral formulation can result in the opposite pharmacological effect.
In another embodiment, the powder or tablet for oral administration is formulated by dissolving the anti-neoplastic compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. The solution is preferably volatile when dried under reduced pressure. An additional vehicle, such as Cremophor  EL solution, is added to the solution prior to drying. The resulting solution was dried in vacuo to form a glassy material. The glassy material is mixed with a binder to form a powder. The powder can be mixed with a filler or other conventional tableting agents and processed into tablets for oral administration to a patient. The powders may also be incorporated into the liquid carriers described above to form solutions, emulsions, suspensions, and the like for oral administration.
Emulsions for parenteral administration are prepared by dissolving the antineoplastic compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. To this solution is added, with stirring, an appropriate volume of an emulsion-like carrier, such as Liposyn  II or Liposyn  III emulsion, to form a pharmaceutically acceptable emulsion for parenteral administration to a patient. Such emulsions can be formulated with minimal or no ethanol or Cremophor  solution if desired, as it is known in the art that administration of a certain concentration of a parenteral formulation can result in adverse pharmacological effects.
Solutions for parenteral administration are prepared by dissolving the antineoplastic compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. To this solution is added an appropriate volume of a solution-like carrier, such as Cremophor  solution, and stirred to form a pharmaceutically acceptable solution for parenteral administration to a patient. Such solutions can be formulated with minimal or no ethanol or Cremophor  solution if desired, as it is known in the art that administration of a certain concentration of a parenteral formulation can result in adverse pharmacological effects.
If necessary; the emulsions or solutions for oral or parenteral administration described above may be packaged in concentrated form in IV bags, vials or other conventional containers and diluted to an acceptable taxane concentration with any pharmaceutically acceptable liquid, such as saline, as is known in the art, prior to use.
Defining:
the terms "hydrocarbon" and "hydrocarbyl" refer herein to an organic compound or group consisting only of carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl or aryl groups. Also included are alkyl, alkenyl, alkynyl or aryl groups substituted with other aliphatic or cyclic hydrocarbons. Such as alkaryl, alkenaryl, and alkynylaryl. Unless otherwise indicated, these moieties preferably contain 1 to 20 carbon atoms.
A "substituted hydrocarbyl" moiety refers to a hydrocarbyl moiety substituted with at least one atom other than carbon, including moieties in which one carbon atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or a halogen atom. These substituents include halogen, heterocycle, alkoxy, alkenyloxy, alkynyloxy, aryloxy, hydroxyl, protected hydroxyl, keto, acyl, acyloxy, nitro, amino, amide, nitrile, mercapto, ketal, acetal, ester, and ether groups.
Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl groups having 1 to 8 carbon atoms in the main chain and up to 20 carbon atoms. They may be straight chain, or branched or cyclic, and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, and the like.
Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl groups having from 2 to 8 carbon atoms in the main chain and up to 20 carbon atoms, which may be straight chain, or branched or cyclic, and include ethenyl, propenyl, isopropenyl, butenyl, hexenyl and the like.
Unless otherwise indicated, alkynyl groups described herein are preferably lower alkynyl groups having from 2 to 8 carbon atoms in the backbone and up to 20 carbon atoms, which may be straight chain, or branched or cyclic, including ethynyl, propynyl, butynyl, hexynyl, and the like.
The term "aryl" or "aryl" as used herein alone or as part of another group refers to an optionally substituted carbocyclic aromatic group, preferably a monocyclic or bicyclic group containing from 6 to 12 carbon atoms in the ring, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl, with phenyl and substituted phenyl being preferred aryl groups.
The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine and iodine.
The term "heterocycle" or "heterocyclic" as used herein alone or as part of another group refers to an optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic group having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1-4 nitrogen atoms in the ring, and may be bonded to the residue of the molecule through a carbon atom or a heteroatom. Examples of heterocycles include heteroaryl groups such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl, and the like. Examples of substituents include one or more of the following groups, hydrocarbyl groups, substituted hydrocarbyl groups, keto groups, hydroxyl groups, protected hydroxyl groups, acyl groups, acyloxy groups, alkoxy groups, alkenyloxy groups, alkynyloxy groups, aryloxy groups, halogens, amide groups, amino groups, nitro groups, nitrile groups, mercapto groups, ketals, acetals, ester groups or ether groups.
The term "heteroaromatic" as used herein alone or as part of another group refers to an optionally substituted aromatic group having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1-4 nitrogen atoms in the ring, and may be bonded to the residue of the molecule through a carbon atom or a heteroatom. Examples of heterocycles include heteroaryl groups such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl, and the like. Examples of substituents include one or more of the following groups, hydrocarbyl groups, substituted hydrocarbyl groups, keto groups, hydroxyl groups, protected hydroxyl groups, acyl groups, acyloxy groups, alkoxy groups, alkenyloxy groups, alkynyloxy groups, aryloxy groups, halogens, amide groups, amino groups, nitro groups, nitrile groups, mercapto groups, ketals, acetals, ester groups or ether groups.
The term "acyl" as used herein alone or as part of another group refers to a moiety formed by removal of a hydroxyl group from a-COOH group of an organic acid, e.g., RC (O) -, wherein R is R1，R1O-，R1R2N-, or R1S-，R1Is a hydrocarbyl, hetero-substituted hydrocarbyl, or a heterocycle, R2Is hydrogen, hydrocarbyl or substituted hydrocarbyl.
The term "acyloxy", alone or as part of another group, refers to an acyl group as described above bonded through an oxygen linkage, e.g., RC (O) O-where R is as defined above in connection with the term "acyl".
Unless otherwise indicated, the alkoxycarbonyloxy groups described herein comprise lower hydrocarbons or substituted hydrocarbon groups.
Unless otherwise indicated, carbamoyloxy moieties described herein are derivatives of carbamic acid wherein one or two hydrogens on the amino group may optionally be replaced by a hydrocarbyl, substituted hydrocarbyl or heterocyclic group.
The terms "hydroxyl-protecting group" and "hydroxyl-protecting group" refer to a group that protects a free hydroxyl group, which group (the "protected hydroxyl group") is used in the reaction and can be removed without interfering with the remainder of the molecule. Various protecting Groups for hydroxyl Groups and their Synthesis can be found in the following book, "Protective Groups in Organic Synthesis" ("Protective Groups in Organic Synthesis") T.W.Greene, published by John' Wiley and Sons, 1981, or Fieser & Fieser. Examples of hydroxy protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β -trimethylsilylethoxy) methyl, tetrahydropyranyl, 2, 2, 2-trichloroethoxycarbonyl, t-butyl (diphenyl) silyl, trialkylsilyl, trichloromethoxycarbonyl, and 2, 2, 2-trichloroethoxymethyl.
As used herein, "Ac" refers to BAn acyl group; "Bz" refers to benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" refers to phenyl; "Pr" refers to propyl; "Bu" means butyl; "Am" means pentyl; "cpro" refers to cyclopropyl; "iPr" refers to isopropyl; "tBu" and "t-Bu" refer to tert-butyl; "R" refers to lower alkyl unless otherwise defined; "Py" refers to pyridine or pyridyl; "TES" refers to triethylsilyl; "TMS" means trimethylsilyl; "LAH" refers to lithium aluminum hydride; "10-DAB" means 10-deacetyl baccatin III; "amino protecting group" includes, but is not limited to, carbamates, such as 2, 2, 2-trichloroethyl carbamate, or t-butyl carbamate; "hydroxy protecting group" means-OP wherein P is a hydroxy protecting group; "PhCO" refers to phenylcarbonyl; "tBuOCO" and "Boc" refer to tert-butoxycarbonyl; "tAMOCO" refers to a tert-pentyloxycarbonyl group; "2-FuCO" means 2-furyl carbonyl; "2-ThCO" refers to 2-thienylcarbonyl; "2-PyCO" means 2-pyridylcarbonyl; "3-PyCO" means 3-pyridylcarbonyl; "4-PyCO" means 4-pyridylcarbonyl; "C4H7CO "refers to butenyl carbonyl; "tC3H5CO "refers to trans-propenyl carbonyl; "EtOCO" refers to ethoxycarbonyl; "ibueCO" refers to isobutenylcarbonyl; "iBuCO" refers to isobutylcarbonyl; "iBuOCO" refers to isobutoxycarbonyl; "iPrOCO" refers to isopropoxycarbonyl; "nPROCO" means n-propoxycarbonyl; "nPrCO" means n-propylcarbonyl; "ibue" refers to an isobutenyl group; "THF" refers to tetrahydrofuran; "DMAP" refers to 4-dimethylaminopyridine; "LHMDS" refers to lithium hexamethyldisilylazide (LithiumHexamethylDiSilazanide).
The following examples illustrate the invention.
Example 1
10-ethoxycarbonyl-10-deacetylbaccatin III
At 25 ℃ at 0.941 g (1.73 mmol) of 10Deacetylbaccatin III and 0.043 g (0.17 mmol) CeCl3To the mixture formed in 40 ml of THF was added 0.64 ml (4.32 mmol) of diethyl pyrocarbonate. After 3 hours the reaction mixture was diluted with 200 ml of ethyl acetate and then washed 3 times with 50 ml of saturated aqueous sodium bicarbonate solution and brine, the organic extract was dried over sodium sulfate and concentrated in vacuo. The crude solid was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate/hexane to give 0.960 g (90%) of 10-ethoxycarbonyl-10-deacetylbaccatin III.
7-Dimethylphenylsilyl-10-ethoxycarbonyl-10-deacetylbaccatin III.
To a solution of 1.02 g (1.65 mmol) of 10-ethoxycarbonyl-10-deacetylbaccatin III in 30 ml of THF, 0.668 ml (4.00 mmol) of chlorodimethylphenylsilane and 2.48 ml (30.64 mmol) of pyridine are added dropwise at-10 ℃ under a nitrogen atmosphere. After 90 minutes, the mixture was diluted with 200 ml of a 1: 1 mixture of ethyl acetate and hexane. The mixture was washed with 30 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted with 50 ml of a 1: 1 mixture of ethyl acetate and hexane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude solid was purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexanes to give 1.16 g (94%) of 7-dimethylphenylsilyl-10-ethoxycarbonyl-10-deacetylbaccatin III.
1HNMR(400MHz，CDCl3): δ 8.09(dm, J ═ 7.64Hz, 2H, benzoate, o), 7.59(tt, J ═ 7.54, 1.43Hz, 1H, benzoate, p), 7.57(m, 2H, phenyl, o), 7.46(t, J ═ 7.54Hz, 2H, benzoate, 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 H1)3)，4.44(dd，J＝6.84，10.37Hz，1H，H7)，4.27(d，J＝8.27Hz，1H，H20α)，4.16(qm，J＝7.00Hz，2H，CH3-CH2-)，4.13(d，J＝8.27Hz，1H，H20β)，3.83(d，J＝7.05Hz，1H，H3)，2.34(ddd，J＝6.84，9.63，14.66Hz，1H，H6α)，2.26(d，J＝7.65Hz，2H，H14α，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，H6β)，1.73(s，1H，Me19)，1.59(s，1H，C1OH)，1.32(t，J＝7.00Hz，3H，CH3-CH2-)，1.19(s，3H，Me17)，1.07(s，3H，Me16)，0.45(s，3H，PhMe2Si-)，0.35(s，3H，PhMe2Si-).
Figure A0114240800342
7-Dimethylphenylsilyl-2 ' -O-triethylsilyl-3 ' -desmethyl-3 ' - (2-thienyl) -10-ethoxycarbonyl-10-deacetyltaxotere (taxotere).
0.681 ml (0.681 mmol) of a 1M solution of LHMDS in THF is added to a solution of 0.409 g (0.544 mmol) of 7-dimethylphenylsilyl-10-ethoxycarbonyl-10-deacetylbaccatin III in 5.5 ml of THF at-45 ℃ under a nitrogen atmosphere. After 1 hour, a solution of 0.317 g (0.818 mmol) of cis-N-benzoyl-3-triethylsiloxy-4- (2-thienyl) azetidin-2-one in 3 ml THF was slowly added. The mixture was warmed to 0 ℃ and after 3 hours, 10 ml of a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted 3 times with 50 ml of ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with 40% ethyl acetate/hexanes to give 0.574 g (93%) of 7-dimethylphenylsilyl-2 ' -O-triethylsilyl-3 ' -dimethylphenyl-3 ' - (2-thienyl) -10-ethoxycarbonyl-10-deacetyl taxotere (taxotere) as a solid.
3 '-Desphenyl-3' - (2-thienyl) -10-ethoxy-10-deacetyltaxotere (taxotere).
At 0 ℃ in 2 ml of CH, 0.527 g (0.464 mmol) of 7-dimethylphenylsilyl-2 ' -O-triethylsilyl-3 ' -dimethylphenyl-3 ' - (2-thienyl) -10-ethoxycarbonyl-10-deacetyl taxol (taxotere)3To the solution of CN and 2 ml of pyridine was added 0.5 ml of 30% aqueous HF, and after 3 hours, 20 ml of saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted 3 times with 50 ml of ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with 70% ethyl acetate/hexanes to give 0.411 g (100% solid 3 '-methylphenyl-3' - (2-thienyl) -10-ethoxycarbonyl-10-deacetyl taxotere).
m.p.160-161℃；[α]D 25＝-59.1(c1.0in CH2Cl2) (ii) a Calculated value C44H55NO16S: c, 59.65; h, 6.26; measured value: c, 59.39; h, 6.34.3 '-Desphenyl-3' - (2-thienyl) -10-ethoxycarbonyl-10-deacetyl
Teddy emperor (taxotere)1H NMR data
(500MHz，CDCl3)
Proton(s) 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-thia)Thienyl), H4' (3.6)
Boc 1.34 s
Benzoic acid esters, m 7.51 t Benzoic acid esters, o (7.8), benzoic acid esters p (7.8)
Benzoic acid esters o 8.12 D Benzoic acid ester, m (7.8)
Benzoic acid esters, p 7.61 T Benzoic acid ester, m (7.8)
CH3-CH2-OCO 1.37 T CH3-CH2-OCO(7.1)
CH3-CH2-OCO 4.28 M
Example 2
The procedure described in example 1 was repeated except that other suitably protected β -lactams were used in place of the β -lactam to prepare a series of compounds having the structural formula (13) wherein the substituents are as shown in the following table.
Compound (I) X5 X3 R10
1755 tBuOCO- 2-thienyl radical EtOCOO-
1767 tBuOCO- Isopropyl group EtOCOO-
1781 tBuOCO- Isobutylene radical EtOCOO-
1799 tBuOCO- 2-pyridyl group EtOCOO-
1808 tBuOCO- 3-pyridyl group EtOCOO-
1811 tBuOCO- 4-pyridyl group EtOCOO-
1822 tBuOCO- 2-furyl radical EtOCOO-
1838 tBuOCO- 3-furyl radical EtOCOO-
1841 tBuOCO- 3-thienyl radical EtOCOO-
1855 tBuOCO- Cyclobutyl radical EtOCOO-
1999 tBuOCO- Isobutylene radical MeOCOO-
2002 tBuOCO- 2-pyridyl group MeOCOO-
2011 tBuOCO- 3-pyridyl group MeOCOO-
2020 tBuOCO- 4-pyridyl group MeOCOO-
2032 tBuOCO- 3-furyl radical MeOCOO-
2044 tBuOCO- 2-thienyl radical MeOCOO-
2050 tBuOCO- 3-thienyl radical MeOCOO-
2062 tBuOCO- Isopropyl group MeOCOO-
2077 tBuOCO- Cyclobutyl radical MeOCOO-
2666 tBuOCO- 2-furyl radical MeOCOO-
2972 PhCO- 2-thienyl radical EtOCOO-
2988 EtOCO- 2-thienyl radical EtOCOO-
2999 iPrOCO- 2-thienyl radical EtOCOO-
3003 iBuOCO- 2-thienyl radical EtOCOO-
3011 2-FuCO- 2-thienyl radical EtOCOO-
3020 2-ThCO- 2-thienyl radical EtOCOO-
3033 C4H7CO- 2-thienyl radical EtOCOO-
3155 nPrCO- 2-thienyl radical EtOCOO-
3181 iBuOCO- 2-furyl radical EtOCOO-
3243 tC3H5CO- 2-thienyl radical EtOCOO-
3300 3-PyCO- 2-thienyl radical EtOCOO-
3393 4-PyCO- 2-thienyl radical EtOCOO-
3433 2-PyCO- 2-thienyl radical EtOCOO-
3911 2-FuCO- 2-furyl radical EtOCOO-
3929 nPrCO- 2-furyl radical EtOCOO-
3963 iPrOCO- 2-furyl radical EtOCOO-
4000 tC3H5CO- 2-furyl radical EtOCOO-
4020 EtOCO- 2-furyl radical EtOCOO-
4074 C4H7CO- 2-furyl radical EtOCOO-
4088 2-ThCO- 2-furyl radical EtOCOO-
4090 PhCO- 2-furyl radical EtOCOO-
4374 ibueCO- 2-thienyl radical EtOCOO-
4636 iBuOCO- 3-furyl radical EtOCOO-
6466 iPrCO- 2-furyl radical EtOCOO-
4959 tC3H5CO- 3-furyl radical EtOCOO-
4924 iBuOCO- 3-thienyl radical EtOCOO-
4844 iBuOCO- Cpro EtOCOO-
5171 tBuOCO- Cpro EtOCOO-
5155 iBuOCO- Isobutylene radical EtOCOO-
1788 tBuOCO- Isobutylene radical EtOCOO-
1767 tBuOCO- Isopropyl group EtOCOO-
1771 tBuOCO- Phenyl radical EtOCOO-
1866 tBuOCO- P-nitrophenyl radical EtOCOO-
2060 tBuOCO- Isopropyl group MeOCOO-
2092 tBuOCO- Phenyl radical MeOCOO-
2088 tBuOCO- P-nitrophenyl radical MeOCOO-
Example 3
Following the procedures described in example 1 and other procedures, the following specific taxanes of formula 14, wherein R is10As defined above, including R10Is R10aOCOO-，R10aIs (i) substituted or unsubstituted C1To C8Alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or notSubstituted C3To C8Alkenyl such as propenyl or straight, branched or cyclic butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C3To C8Alkynyl such as propynyl or straight or branched butynyl, pentynyl or hexynyl; (iv) (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaryl such as pyridyl, the substituents being as defined above or substituted hydrocarbyl. For example, R10Can be R10aOCOO-where R10aIs methyl, ethyl, or linear, branched or cyclic propyl.
Figure A0114240800391
X5 X3 R10
tBuOCO 2-furyl radical RaOCOO-
tBuOCO 3-furyl radical RaOCOO-
tBuOCO 2-thienyl radical RaOCOO-
tBuOCO 3-thienyl radical RaOCOO-
tBuOCO 2-pyridyl group RaOCOO-
tBuOCO 3-pyridyl group RaOCOO-
tBuOCO 4-pyridyl group RaOCOO-
tBuOCO Isobutylene radical RaOCOO-
tBuOCO Isopropyl group RaOCOO-
tBuOCO Cyclopropyl group RaOCOO-
tBuOCO Cyclobutyl radical RaOCOO-
tBuOCO Cyclopentyl group RaOCOO-
tBuOCO Phenyl radical RaOCOO-
Benzoyl radical 2-furyl radical RaOCOO-
Benzoyl radical 3-furyl radical RaOCOO-
Benzoyl radical 2-thienyl radical RaOCOO-
Benzoyl radical 3-thienyl radical RaOCOO-
Benzoyl radical 2-pyridyl group RaOCOO-
Benzoyl radical 3-pyridyl group RaOCOO-
Benzoyl radical 4-pyridyl group RaOCOO-
Benzoyl radical Isobutylene radical RaOCOO-
Benzoyl radical Isopropyl group RaOCOO-
Benzoyl radical Cyclopropyl group RaOCOO-
Benzoyl radical Cyclobutyl radical RaOCOO-
Benzoyl radical Cyclopentyl group RaOCOO-
Benzoyl radical Phenyl radical RaOCOO-
2-FuCO- 2-furyl radical RaOCOO-
2-FuCO- 3-furyl radical RaOCOO-
2-FuCO- 2-thienyl radical RaOCOO-
2-FuCO- 3-thienyl radical RaOCOO-
2-FuCO- 2-pyridyl group RaOCOO-
2-FuCO- 3-pyridyl group RaOCOO-
2-FuCO- 4-pyridyl group RaOCOO-
2-FuCO- Isobutylene radical RaOCOO-
2-FuCO- Isopropyl group RaOCOO-
2-FuCO- Cyclopropyl group RaOCOO-
2-FuCO- Cyclobutyl radical RaOCOO-
2-FuCO- Cyclopentyl group RaOCOO-
2-FuCO- Phenyl radical RaOCOO-
2-ThCO- 2-furyl radical RaOCOO-
2-ThCO- 3-furyl radical RaOCOO-
2-ThCO- 2-thienyl radical RaOCOO-
2-ThCO- 3-thienyl radical RaOCOO-
2-ThCO- 2-pyridyl group RaOCOO-
2-ThCO- 3-pyridyl group RaOCOO-
2-ThCO- 4-pyridyl group RaOCOO-
2-ThCO- Isobutylene radical RaOCOO-
2-ThCO- Isopropyl group RaOCOO-
2-ThCO- Cyclopropyl group RaOCOO-
2-ThCO- Cyclobutyl radical RaOCOO-
2-ThCO- Cyclopentyl group RaOCOO-
2-ThCO- Phenyl radical RaOCOO-
2-PyCO- 2-furyl radical RaOCOO-
2-PyCO- 3-furyl radical RaOCOO-
2-PyCO- 2-thienyl radical RaOCOO-
2-PyCO- 3-thienyl radical RaOCOO-
2-PyCO- 2-pyridyl group RaOCOO-
2-PyCO- 3-pyridyl group RaOCOO-
2-PyCO- 4-pyridyl group RaOCOO-
2-PyCO- Isobutylene radical RaOCOO-
2-PyCO- Isopropyl group RaOCOO-
2-PyCO- Cyclopropyl group RaOCOO-
2-PyCO- Cyclobutyl radical RaOCOO-
2-PyCO- Cyclopentyl group RaOCOO-
2-PyCO- Phenyl radical RaOCOO-
3PyCO- 2-furyl radical RaOCOO-
3-PyCO- 3-furyl radical RaOCOO-
3-PyCO- 2-thienyl radical RaOCOO-
3-PyCO- 3-thienyl radical RaOCOO-
3-PyCO- 2-pyridyl group RaOCOO-
3-PyCO- 3-pyridyl group RaOCOO-
3-PyCO- 4-pyridyl group RaOCOO-
3-PyCO- Isobutylene radical RaOCOO-
3-PyCO- Isopropyl group RaOCOO-
3-PyCO- Cyclopropyl group RaOCOO-
3-PyCO- Cyclobutyl radical RaOCOO-
3-PyCO- Cyclopentyl group RaOCOO-
3-PyCO- Phenyl radical RaOCOO-
4-PyCO- 2-furyl radical RaOCOO-
4-PyCO- 3-furyl radical RaOCOO-
4-PyCO- 2-thienyl radical RaOCOO-
4-PyCO- 3-thienyl radical RaOCOO-
4-PyCO- 2-pyridyl group RaOCOO-
4-PyCO- 3-pyridyl group RaOCOO-
4-PyCO- 4-pyridyl group RaOCOO-
4-PyCO- Isobutylene radical RaOCOO-
4-PyCO- Isopropyl group RaOCOO-
4-PyCO- Cyclopropyl group RaOCOO-
4-PyCO- Cyclobutyl radical RaOCOO-
4-PyCO- Cyclopentyl group RaOCOO-
4-PyCO- Phenyl radical RaOCOO-
C4H7CO- 2-furyl radical RaOCOO-
C4H7CO- 3-furyl radical RaOCOO-
C4H7CO- 2-thienyl radical RaOCOO-
C4H7CO- 3-thienyl radical RaOCOO-
C4H7CO- 2-pyridyl group RaOCOO-
C4H7CO- 3-pyridyl group RaOCOO-
C4H7CO- 4-pyridyl group RaOCOO-
C4H7CO- Isobutylene radical RaOCOO-
C4H7CO- Isopropyl group RaOCOO-
C4H7CO- Cyclopropyl group RaOCOO-
C4H7CO- Cyclobutyl radical RaOCOO-
C4H7CO- Cyclopentyl group RaOCOO-
C4H7CO- Phenyl radical RaOCOO-
EtOCO- 2-furyl radical RaOCOO-
EtOCO- 3-furyl radical RaOCOO-
EtOCO- 2-thienyl radical RaOCOO-
EtOCO- 3-thienyl radical RaOCOO-
EtOCO- 2-pyridyl group RaOCOO-
EtOCO- 3-pyridyl group RaOCOO-
EtOCO- 4-pyridyl group RaOCOO-
EtOCO- Isobutylene radical RaOCOO-
EtOCO- Isopropyl group RaOCOO-
EtOCO- Cyclopropyl group RaOCOO-
EtOCO- Cyclobutyl radical RaOCOO-
EtOCO- Cyclopentyl group RaOCOO-
EtOCO- Phenyl radical RaOCOO-
ibueCO- 2-furyl radical RaOCOO-
ibueCO- 3-furyl radical RaOCOO-
ibueCO- 2-thienyl radical RaOCOO-
ibueCO- 3-thienyl radical RaOCOO-
ibueCO- 2-pyridyl group RaOCOO-
ibueCO- 3-pyridyl group RaOCOO-
ibueCO- 4-pyridyl group RaOCOO-
ibueCO- Isobutylene radical RaOCOO-
ibueCO- Isopropyl group RaOCOO-
ibueCO- Cyclopropyl group RaOCOO-
ibueCO- Cyclobutyl radical RaOCOO-
ibueCO- Cyclopentyl group RaOCOO-
ibueCO- Phenyl radical RaOCOO-
iBuCO- 2-furyl radical RaOCOO-
iBuCO- 3-furyl radical RaOCOO-
iBuCO- 2-thienyl radical RaOCOO-
iBuCO- 3-thienyl radical RaOCOO-
iBuCO- 2-pyridyl group RaOCOO-
iBuCO- 3-pyridyl group RaOCOO-
iBuCO- 4-pyridyl group RaOCOO-
iBuCO- Isobutylene radical RaOCOO-
iBuCO- Isopropyl group RaOCOO-
iBuCO- Cyclopropyl group RaOCOO-
iBuCO- Cyclobutyl radical RaOCOO-
iBuCO- Cyclopentyl group RaOCOO-
iBuCO- Phenyl radical RaOCOO-
iBuOCO- 2-furyl radical RaOCOO-
iBuOCO- 3-furyl radical RaOCOO-
iBuOCO- 2-thienyl radical RaOCOO-
iBuOCO- 3-thienyl radical RaOCOO-
iBuOCO- 2-pyridyl group RaOCOO-
iBuOCO- 3-pyridyl group RaOCOO-
iBuOCO- 4-pyridyl group RaOCOO-
iBuOCO- Isobutylene radical RaOCOO-
iBuOCO- Isopropyl group RaOCOO-
iBuOCO- Cyclopropyl group RaOCOO-
iBuOCO- Cyclobutyl radical RaOCOO-
iBuOCO- Cyclopentyl group RaOCOO-
iBuOCO- Phenyl radical RaOCOO-
iPrOCO- 2-furyl radical RaOCOO-
iPrOCO- 3-furyl radical RaOCOO-
iPrOCO- 2-thienyl radical RaOCOO-
iPrOCO- 3-thienyl radical RaOCOO-
iPrOCO- 2-pyridyl group RaOCOO-
iPrOCO- 3-pyridyl group RaOCOO-
iPrOCO- 4-pyridyl group RaOCOO-
iPrOCO- Isobutylene radical RaOCOO-
iPrOCO- Isopropyl group RaOCOO-
iPrOCO- Cyclopropyl group RaOCOO-
iPrOCO- Cyclobutyl radical RaOCOO-
iPrOCO- Cyclopentyl group RaOCOO-
iPrOCO- Phenyl radical RaOCOO-
nPrOCO- 2-furyl radical RaOCOO-
nPrOCO- 3-furyl radical RaOCOO-
nPrOCO- 2-thienyl radical RaOCOO-
nPrOCO- 3-thienyl radical RaOCOO-
nPrOCO- 2-pyridyl group RaOCOO-
nPrOCO- 3-pyridyl group RaOCOO-
nPrOCO- 4-pyridyl group RaOCOO-
nPrOCO- Isobutylene radical RaOCOO-
nPrOCO- Isopropyl group RaOCOO-
nPrOCO- Cyclopropyl group RaOCOO-
nPrOCO- Cyclobutyl radical RaOCOO-
nPrOCO- Cyclopentyl group RaOCOO-
nPrOCO- Phenyl radical RaOCOO-
nPrCO- 2-furyl radical RaOCOO-
nPrCO- 3-furyl radical RaOCOO-
nPrCO- 2-thienyl radical RaOCOO-
nPrCO- 3-thienyl radical RaOCOO-
nPrCO- 2-pyridyl group RaOCOO-
nPrCO- 3-pyridyl group RaOCOO-
nPrCO- 4-pyridyl group RaOCOO-
nPrCO- Isobutylene radical RaOCOO-
nPrCO- Isopropyl group RaOCOO-
nPrCO- Cyclopropyl group RaOCOO-
nPrCO- Cyclobutyl radical RaOCOO-
nPrCO- Cyclopentyl group RaOCOO-
nPrCO- Phenyl radical RaOCOO-
Benzoyl radical Cyclopentyl group EtOCOO-
Benzoyl radical 3-furyl radical EtOCOO-
Benzoyl radical 3-thienyl radical EtOCOO-
Benzoyl radical 2-pyridyl group EtOCOO-
Benzoyl radical 3-pyridyl group EtOCOO-
Benzoyl radical 4-pyridyl group EtOCOO-
Benzoyl radical Isobutylene radical EtOCOO-
Benzoyl radical Isopropyl group EtOCOO-
Benzoyl radical Cyclopropyl group EtOCOO-
Benzoyl radical Cyclobutyl radical EtOCOO-
Benzoyl radical Cyclopentyl group EtOCOO-
Benzoyl radical Phenyl radical EtOCOO-
2-FuCO- 3 furyl radical EtOCOO-
2-FuCO- 3-thienyl radical EtOCOO-
2-FuCO- 2-pyridyl group EtOCOO-
2-FuCO- 3-pyridyl group EtOCOO-
2-FuCO- 4-pyridyl group EtOCOO-
2-FuCO- Isobutylene radical EtOCOO-
2-FuCO- Isopropyl group EtOCOO-
2-FuCO- Cyclopropyl group EtOCOO-
2-FuCO- Cyclobutyl radical EtOCOO-
2-FuCO- Cyclopentyl group EtOCOO-
2-FuCO- Phenyl radical EtOCOO-
2-ThCO- 3-furyl radical EtOCOO-
2-ThCO- 3-thienyl radical EtOCOO-
2-ThCO- 2-pyridyl group EtOCOO-
2-ThCO- 3-pyridyl group EtOCOO-
2-ThCO- 4-pyridyl group EtOCOO-
2-ThCO- Isobutylene radical EtOCOO-
2-ThCO- Isopropyl group EtOCOO-
2-ThCO- Cyclopropyl group EtOCOO-
2-ThCO- Cyclobutyl radical EtOCOO-
2-ThCO- Cyclopentyl group EtOCOO-
2-ThCO- Phenyl radical EtOCOO-
2-PyCO- 2-furyl radical EtOCOO-
2-PyCO- 3-furyl radical EtOCOO-
2-PyCO- 3-thienyl radical EtOCOO-
2-PyCO- 2-pyridyl group EtOCOO-
2-PyCO- 3-pyridyl group EtOCOO-
2-PyCO- 4-pyridyl group EtOCOO-
2-PyCO- Isobutylene radical EtOCOO-
2-PyCO- Isopropyl group EtOCOO-
2-PyCO- Cyclopropyl group EtOCOO-
2-PyCO- Cyclobutyl radical EtOCOO-
2-PyCO- Cyclopentyl group EtOCOO-
2-PyCO- Phenyl radical EtOCOO-
3PyCO- 2-furyl radical EtOCOO-
3-PyCO- 3-furyl radical EtOCOO-
3-PyCO- 3-thienyl radical EtOCOO-
3-PyCO- 2-pyridyl group EtOCOO-
3-PyCO- 3-pyridyl group EtOCOO-
3-PyCO- 4-pyridyl group EtOCOO-
3-PyCO- Isobutylene radical EtOCOO-
3-PyCO- Isopropyl group EtOCOO-
3-PyCO- Cyclopropyl group EtOCOO-
3-PyCO- Cyclobutyl radical EtOCOO-
3-PyCO- Cyclopentyl group EtOCOO-
3-PyCO- Phenyl radical EtOCOO-
4-PyCO- 2-furyl radical EtOCOO-
4-PyCO- 3-furyl radical EtOCOO-
4-PyCO- 3-thienyl radical EtOCOO-
4-PyCO- 2-pyridyl group EtOCOO-
4-PyCO- 3-pyridyl group EtOCOO-
4-PyCO- 4-pyridyl group EtOCOO-
4-PyCO- Isobutylene radical EtOCOO-
4-PyCO- Isopropyl group EtOCOO-
4-PyCO- Cyclopropyl group EtOCOO-
4-PyCO- Cyclobutyl radical EtOCOO-
4-PyCO- Cyclopentyl group EtOCOO-
4-PyCO- Phenyl radical EtOCOO-
C4H7CO- 3-furyl radical EtOCOO-
C4H7CO- 3-thienyl radical EtOCOO-
C4H7CO- 2-pyridyl group EtOCOO-
C4H7CO- 3-pyridyl group EtOCOO-
C4H7CO- 4-pyridyl group EtOCOO-
C4H7CO- Isobutylene radical EtOCOO-
C4H7CO- Isopropyl group EtOCOO-
C4H7CO- Cyclopropyl group EtOCOO-
C4H7CO- Cyclobutyl radical EtOCOO-
C4H7CO- Cyclopentyl group EtOCOO-
C4H7CO- Phenyl radical EtOCOO-
EtOCO- 3-furyl radical EtOCOO-
EtOCO- 3-thienyl radical EtOCOO-
EtOCO- 2-pyridyl group EtOCOO-
EtOCO- 3-pyridyl group EtOCOO-
EtOCO- 4-pyridyl group EtOCOO-
EtOCO- Isobutylene radical EtOCOO-
EtOCO- Isopropyl group EtOCOO-
EtOCO- Cyclopropyl group EtOCOO-
EtOCO- Cyclobutyl radical EtOCOO-
EtOCO- Cyclopentyl group EtOCOO-
EtOCO- Phenyl radical EtOCOO-
ibueCO- 2-furyl radical EtOCOO-
ibueCO- 3-FuranFuryl group EtOCOO-
ibueCO- 2-thienyl radical EtOCOO-
ibueCO- 3-thienyl radical EtOCOO-
ibueCO- 2-pyridyl group EtOCOO-
ibueCO- 3-pyridyl group EtOCOO-
ibueCO- 4-pyridyl group EtOCOO-
ibueCO- Isobutylene radical EtOCOO-
ibueCO- Isopropyl group EtOCOO-
ibueCO- Cyclopropyl group EtOCOO-
ibueCO- Cyclobutyl radical EtOCOO-
ibueCO- Cyclopentyl group EtOCOO-
ibueCO- Phenyl radical EtOCOO-
iBuCO- 2-furyl radical EtOCOO-
iBuCO- 3-furyl radical EtOCOO-
iBuCO- 2-thienyl radical EtOCOO-
iBuCO- 3-thienyl radical EtOCOO-
iBuCO- 2-pyridyl group EtOCOO-
iBuCO- 3-pyridyl group EtOCOO-
iBuCO- 4-pyridyl group EtOCOO-
iBuCO- Isobutylene radical EtOCOO-
iBuCO- Isopropyl group EtOCOO-
iBuCO- Cyclopropyl group EtOCOO-
iBuCO- Cyclobutyl radical EtOCOO-
iBuCO- Cyclopentyl group EtOCOO-
iBuCO- Phenyl radical EtOCOO-
iBuOCO- 2-pyridyl group EtOCOO-
iBuOCO- 3-pyridyl group EtOCOO-
iBuOCO- 4-pyridyl group EtOCOO-
iBuOCO- Isopropyl group EtOCOO-
iBuOCO- Cyclobutyl radical EtOCOO-
iBuOCO- Cyclopentyl group EtOCOO-
iBuOCO- Phenyl radical EtOCOO-
iPrOCO- 3-furyl radical EtOCOO-
iPrOCO- 3-thienyl radical EtOCOO-
iPrOCO- 2-pyridyl group EtOCOO-
iPrOCO- 3-pyridyl group EtOCOO-
iPrOCO- 4-pyridyl group EtOCOO-
iPrOCO- Isobutylene radical EtOCOO-
iPrOCO- Isopropyl group EtOCOO-
iPrOCO- Cyclopropyl group EtOCOO-
iPrOCO- Cyclobutyl radical EtOCOO-
iPrOCO- Cyclopentyl group EtOCOO-
iPrOCO- Phenyl radical EtOCOO-
nPrOCO- 2-furyl radical EtOCOO-
nPrOCO- 3-furyl radical EtOCOO-
nPrOCO- 2-thienyl radical EtOCOO-
nPrOCO- 3-thienyl radical EtOCOO-
nPrOCO- 2-pyridyl group EtOCOO-
nPrOCO- 3-pyridyl group EtOCOO-
nPrOCO- 4-pyridyl group EtOCOO-
nPrOCO- Isobutylene radical EtOCOO-
nPrOCO- Isopropyl group EtOCOO-
nPrOCO- Cyclopropyl group EtOCOO-
nPrOCO- Cyclobutyl radical EtOCOO-
nPrOCO- Cyclopentyl group EtOCOO-
nPrOCO- Phenyl radical EtOCOO-
nPrCO- 3-furyl radical EtOCOO-
nPrCO- 3-thienyl radical EtOCOO-
nPrCO- 2-pyridyl group EtOCOO-
nPrCO- 3-pyridyl group EtOCOO-
nPrCO- 4-pyridyl group EtOCOO-
nPrCO- Isobutylene radical EtOCOO-
nPrCO- Isopropyl group EtOCOO-
nPrCO- Cyclopropyl group EtOCOO-
nPrCO- Cyclobutyl radical EtOCOO-
nPrCO- Cyclopentyl group EtOCOO-
nPrCO- Phenyl radical EtOCOO-
tBuOCO Cyclopropyl group MeOCOO-
tBuOCO Cyclopentyl group MeOCOO-
Benzoyl radical 2-furyl radical MeOCOO-
Benzoyl radical 3-furyl radical MeOCOO-
Benzoyl radical 2-thienyl radical MeOCOO-
Benzoyl radical 3-thienyl radical MeOCOO-
Benzoyl radical 2-pyridyl group MeOCOO-
Benzoyl radical 3-pyridyl group MeOCOO-
Benzoyl radical 4-pyridyl group MeOCOO-
Benzoyl radical Isobutylene radical MeOCOO-
Benzoyl radical Isopropyl group MeOCOO-
Benzoyl radical Cyclopropyl group MeOCOO-
Benzoyl radical Ring DBase of MeOCOO-
Benzoyl radical Cyclopentyl group MeOCOO-
Benzoyl radical Phenyl radical MeOCOO-
2-FuCO- 2-furyl radical MeOCOO-
2-FuCO- 3-furyl radical MeOCOO-
2-FuCO- 2-thienyl radical MeOCOO-
2-FuCO- 3-thienyl radical MeOCOO-
2-FuCO- 2-pyridyl group MeOCOO-
2-FuCO- 3-pyridyl group MeOCOO-
2-FuCO- 4-pyridyl group MeOCOO-
2-FuCO- Isobutylene radical MeOCOO-
2-FuCO- Isopropyl group MeOCOO-
2-FuCO- Cyclopropyl group MeOCOO-
2-FuCO- Cyclobutyl radical MeOCOO-
2-FuCO- Cyclopentyl group MeOCOO-
2-FuCO- Phenyl radical MeOCOO-
2-ThCO- 2-furyl radical MeOCOO-
2-ThCO- 3-furyl radical MeOCOO-
2-ThCO- 2-thienyl radical MeOCOO-
2-ThCO- 3-thienyl radical MeOCOO-
2-ThCO- 2-pyridyl group MeOCOO-
2-ThCO- 3-pyridyl group MeOCOO-
2-ThCO- 4-pyridyl group MeOCOO-
2-ThCO- Isobutylene radical MeOCOO-
2-ThCO- Isopropyl group MeOCOO-
2-ThCO- Cyclopropyl group MeOCOO-
2-ThCO- Cyclobutyl radical MeOCOO-
2-ThCO- Cyclopentyl group MeOCOO-
2-ThCO- Phenyl radical MeOCOO-
2-PyCO- 2-furyl radical MeOCOO-
2-PyCO- 3-furyl radical MeOCOO-
2-PyCO- 2-thienyl radical MeOCOO-
2-PyCO- 3-thienyl radical MeOCOO-
2-PyCO- 2-pyridyl group MeOCOO-
2-PyCO- 3-pyridyl group MeOCOO-
2-PyCO- 4-pyridyl group MeOCOO-
2-PyCO- Isobutylene radical MeOCOO-
2-PyCO- Isopropyl group MeOCOO-
2-PyCO- Cyclopropyl group MeOCOO-
2-PyCO- Cyclobutyl radical MeOCOO-
2-PyCO- Cyclopentyl group MeOCOO-
2-PyCO- Phenyl radical MeOCOO-
3PyCO- 2-furyl radical MeOCOO-
3-PyCO- 3-furyl radical MeOCOO-
3-PyCO- 2-thienyl radical MeOCOO-
3-PyCO- 3-thienyl radical MeOCOO-
3-PyCO- 2-pyridyl group MeOCOO-
3-PyCO- 3-pyridyl group MeOCOO-
3-PyCO- 4-pyridyl group MeOCOO-
3-PyCO- Isobutylene radical MeOCOO-
3-PyCO- Isopropyl group MeOCOO-
3-PyCO- Cyclopropyl group MeOCOO-
3-PyCO- Cyclobutyl radical MeOCOO-
3-PyCO- Cyclopentyl group MeOCOO-
3-PyCO- Phenyl radical MeOCOO-
4-PyCO- 2-furyl radical MeOCOO-
4-PyCO- 3-furyl radical MeOCOO-
4-PyCO- 2-thienyl radical MeOCOO-
4-PyCO- 3-thienyl radical MeOCOO-
4-PyCO- 2-pyridyl group MeOCOO-
4-PyCO- 3-pyridyl group MeOCOO-
4-PyCO- 4-pyridyl group MeOCOO-
4-PyCO- Isobutylene radical MeOCOO-
4-PyCO- Isopropyl group MeOCOO-
4-PyCO- Cyclopropyl group MeOCOO-
4-PyCO- Cyclobutyl radical MeOCOO-
4-PyCO- Cyclopentyl group MeOCOO-
4-PyCO- Phenyl radical MeOCOO-
C4H7CO- 2-furyl radical MeOCOO-
C4H7CO- 3-furyl radical MeOCOO-
C4H7CO- 2-thienyl radical MeOCOO-
C4H7CO- 3-thienyl radical MeOCOO-
C4H7CO- 2-pyridyl group MeOCOO-
C4H7CO- 3-pyridyl group MeOCOO-
C4H7CO- 4-pyridyl group MeOCOO-
C4H7CO- Isobutylene radical MeOCOO-
C4H7CO- Isopropyl group MeOCOO-
C4H7CO- Cyclopropyl group MeOCOO-
C4H7CO- Cyclobutyl radical MeOCOO-
C4H7CO- Cyclopentyl group MeOCOO-
C4H7CO- Phenyl radical MeOCOO-
EtOCO- 2-furyl radical MeOCOO-
EtOCO- 3-furyl radical MeOCOO-
EtOCO- 2-thienyl radical MeOCOO-
EtOCO- 3-thienyl radical MeOCOO-
EtOCO- 2-pyridyl group MeOCOO-
EtOCO- 3-pyridyl group MeOCOO-
EtOCO- 4-pyridyl group MeOCOO-
EtOCO- Isobutylene radical MeOCOO-
EtOCO- Isopropyl group MeOCOO-
EtOCO- Cyclopropyl group MeOCOO-
EtOCO- Cyclobutyl radical MeOCOO-
EtOCO- Cyclopentyl group MeOCOO-
EtOCO- Phenyl radical MeOCOO-
ibueCO- 2-furyl radical MeOCOO-
ibueCO- 3-furyl radical MeOCOO-
ibueCO- 2-thienyl radical MeOCOO-
ibueCO- 3-thienyl radical MeOCOO-
ibueCO- 2-pyridyl group MeOCOO-
ibueCO- 3-pyridyl group MeOCOO-
ibueCO- 4-pyridyl group MeOCOO-
ibueCO- Isobutylene radical MeOCOO-
ibueCO- Isopropyl group MeOCOO-
ibueCO- Cyclopropyl group MeOCOO-
ibueCO- Cyclobutyl radical MeOCOO-
ibueCO- Cyclopentyl group MeOCOO-
ibueCO- Phenyl radical MeOCOO-
iBuCO- 2-furyl radical MeOCOO-
iBuCO- 3-furyl radical MeOCOO-
iBuCO- 2-thienyl radical MeOCOO-
iBuCO- 3-thienyl radical MeOCOO-
iBuCO- 2-pyridyl group MeOCOO-
iBuCO- 3-pyridyl group MeOCOO-
iBuCO- 4-pyridyl group MeOCOO-
iBuCO- Isobutylene radical MeOCOO-
iBuCO- Isopropyl group MeOCOO-
iBuCO- Cyclopropyl group MeOCOO-
iBuCO- Cyclobutyl radical MeOCOO-
iBuCO- Cyclopentyl group MeOCOO-
iBuCO- Phenyl radical MeOCOO-
iBuOCO- 2-furyl radical MeOCOO-
iBuOCO- 3-furyl radical MeOCOO-
iBuOCO- 2-thienyl radical MeOCOO-
iBuOCO- 3-thienyl radical MeOCOO-
iBuOCO- 2-pyridyl group MeOCOO-
iBuOCO- 3-pyridyl group MeOCOO-
iBuOCO- 4-pyridyl group MeOCOO-
iBuOCO- Isobutylene radical MeOCOO-
iBuOCO- Isopropyl group MeOCOO-
iBuOCO- Cyclopropyl group MeOCOO-
iBuOCO- Cyclobutyl radical MeOCOO-
iBuOCO- Cyclopentyl group MeOCOO-
iBuOCO- Phenyl radical MeOCOO-
iPrOCO- 2-furyl radical MeOCOO-
iPrOCO- 3-furyl radical MeOCOO-
iPrOCO- 2-thienyl radical MeOCOO-
iPrOCO- 3-thienyl radical MeOCOO-
iPrOCO- 2-pyridyl group MeOCOO-
iPrOCO- 3-pyridyl group MeOCOO-
iPrOCO- 4-pyridyl group MeOCOO-
iPrOCO- Isobutylene radical MeOCOO-
iPrOCO- Isopropyl group MeOCOO-
iPrOCO- Cyclopropyl group MeOCOO-
iPrOCO- Cyclobutyl radical MeOCOO-
iPrOCO- Cyclopentyl group MeOCOO-
iPrOCO- Phenyl radical MeOCOO-
nPrOCO- 2-furyl radical MeOCOO-
nPrOCO- 3-furyl radical MeOCOO-
nPrOCO- 2-thienyl radical MeOCOO-
nPrOCO- 3-thienyl radical MeOCOO-
nPrOCO- 2-pyridyl group MeOCOO-
nPrOCO- 3-pyridyl group MeOCOO-
nPrOCO- 4-pyridyl group MeOCOO-
nPrOCO- Isobutylene radical MeOCOO-
nPrOCO- Isopropyl group MeOCOO-
nPrOCO- Cyclopropyl group MeOCOO-
nPrOCO- Cyclobutyl radical MeOCOO-
nPrOCO- Cyclopentyl group MeOCOO-
nPrOCO- Phenyl radical MeOCOO-
nPrCO- 2-furyl radical MeOCOO-
nPrCO- 3-furyl radical MeOCOO-
nPrCO- 2-thienyl radical MeOCOO-
nPrCO- 3-thienyl radical MeOCOO-
nPrCO- 2-pyridyl group MeOCOO-
nPrCO- 3-pyridyl group MeOCOO-
nPrCO- 4-pyridyl group MeOCOO-
nPrCO- Isobutylene radical MeOCOO-
nPrCO- Isopropyl group MeOCOO-
nPrCO- Cyclopropyl group MeOCOO-
nPrCO- Cyclobutyl radical MeOCOO-
nPrCO- Cyclopentyl group MeOCOO-
nPrCO- Phenyl radical MeOCOO-
Example 4
Following the procedures described in example 1, and others, the following specific taxanes of formula 15, R in the series of compounds (i.e., the series "A" through "K" compounds), can be prepared7Is hydroxy, R10As previously defined, comprising R10Is R10Is R10aOCOO-，R10aIs (i) substituted or unsubstituted, preferably unsubstituted, C2To C8Alkyl (linear, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, preferably less than human C2To C8Alkenyl (linear, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C2To C8Alkynyl (linear, branched or cyclic), such as ethynyl, propynyl, butynyl, pentynyl or hexynyl; (iv) substituted or unsubstituted, preferably unsubstituted, phenyl; or (v) a substituted or unsubstituted, preferably unsubstituted, heteroaryl group such as furyl, thienyl, or pyridyl.
In the "A" series of compounds, X10Are groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Is substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., t-butyl), R7And R10Each having a beta stereochemical configuration.
In the "B" series of compounds, X10And R2aAre groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2aPreferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl, R7And R10Each having a beta stereochemical configuration.
In the "C" series of compounds, X10And R9aAre groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9aPreferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl, R7，R9And R10Each having a beta stereochemical configuration.
In the "D" and "E" series of compounds, X10Are groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R7，R9(series D only) and R10Each having a beta stereochemical configuration.
In the "F" series of compounds, X10，R2aAnd R9aAre groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2aPreferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl, R7，R9And R10Each having a beta stereochemical configuration.
In the "G" series of compounds, X10And R2aAre groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2aPreferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl, R7，R9And R10Each having a beta stereochemical configuration.
In the "H" series of compounds, X10Are groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2aPreferably substituted or unsubstituted furyl, thiaThienyl, pyridyl, phenyl, or lower alkyl, R7And R10Each having a beta stereochemical configuration.
In the "I" series of compounds, X10And R2aAre groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2aPreferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl, R7And R10Each having a beta stereochemical configuration.
In the "J" series of compounds, X10And R2aAre groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2aPreferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl, R7，R9And R10Each having a beta stereochemical configuration.
In the "K" series of compounds, X10，R2aAnd R9aAre groups as defined above or other groups. Preferably, the heterocyclic group is a substituted or unsubstituted furyl, thienyl or pyridyl group, X10Preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2aPreferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl, or lower alkyl, R7，R9And R10Each having a beta stereochemical configuration.
X3，X5，R2，R9And R10The substituent(s) may be hydroxyl or any heteroatom containing substituent selected from the group consisting of heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, hydroxylProtected hydroxyl, keto, acyloxy, nitro, amino, amide, mercapto, ketal, acetal, ester and ether groups, but not phosphorus containing substituents.
Figure A0114240800521
Group of X5 X3 R10 R2 R9 R14
A1 -COOX10 Heterocyclic radical R10aOCOO- C6H5COO- O H
A2 -COX10 Heterocyclic radical R10aOCOO- C6H5COO- O H
A3 -CONHX10 Heterocyclic radical R10aOCOO- C6H5COO- O H
A4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- O H
A5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- O H
A6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- O H
A7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- O H
A8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- O H
A9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- O H
A10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- O H
A11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- O H
A12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- O H
B1 -COOX10 Heterocyclic radical R10aOCOO- R2aCOO- O H
B2 -COX10 Heterocyclic radical R10aOCOO- R2aCOO- O H
B3 -CONHX10 Heterocyclic radical R10aOCOO- R2aCOO- O H
B4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- O H
B5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- O H
B6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- O H
B7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- O H
B8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- O H
B9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- O H
B10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- O H
B11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- O H
B12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- O H
C1 -COOX10 Heterocyclic radical R10aOCOO- C6H5COO- R9aCOO- H
C2 -COX10 Heterocyclic radical R10aOCOO- C6H5COO- R9aCOO- H
C3 -CONHX10 Heterocyclic radical R10aOCOO- C6H5COO- R9aCOO- H
C4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- R9aCOO- H
C5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- R9aCOO- H
C6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- R9aCOO- H
C7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- R9aCOO- H
C8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- R9aCOO- H
C9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- R9aCOO- H
C10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- R9aCOO- H
C11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- R9aCOO- H
C12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- R9aCOO- H
D1 -COOX10 Heterocyclic radical R10aOCOO- C6H5COO- OH H
D2 -COX10 Heterocyclic radical R10aOCOO- C6H5COO- OH H
D3 -CONHX10 Heterocyclic radical R10aOCOO- C6H5COO- OH H
D4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- OH H
D5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- OH H
D6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- OH H
D7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- OH H
D8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- OH H
D9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- OH H
D10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- OH H
D11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- OH H
D12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- OH H
E1 -COOX10 Heterocyclic radical R10aOCOO- C6H5COO- O OH
E2 -COX10 Heterocyclic radical R10aOCOO- C6H5COO- O OH
E3 -CONHX10 Heterocyclic radical R10aOCOO- C6H5COO- O OH
E4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- O OH
E5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- O OH
E6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- O OH
E7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- O OH
E8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- O OH
E9 -CONHX10 SelectingOptionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- O OH
E10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- O OH
E11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- O OH
E12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- O OH
F1 -COOX10 Heterocyclic radical R10aOCOO- R2aCOO- R9aCOO- H
F2 -COX10 Heterocyclic radical R10aOCOO- R2aCOO- R9aCOO- H
F3 -CONHX10 Heterocyclic radical R10aOCOO- R2aCOO- R9aCOO- H
F4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- R9aCOO- H
F5 -COX10 Selectively getSubstituted C2-C8Alkyl radical R10aOCOO- R2aCOO- R9aCOO- H
F6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- R9aCOO- H
F7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- R9aCOO- H
F8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- R9aCOO- H
F9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- R9aCOO- H
F10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- R9aCOO- H
F11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- R9aCOO- H
F12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- R9aCOO- H
G1 -COOX10 Heterocyclic radical R10aOCOO- R2aCOO- OH H
G2 -COX10 Heterocyclic radical R10aOCOO- R2aCOO- OH H
G3 -CONHX10 Heterocyclic radical R10aOCOO- R2aCOO- OH H
G4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- OH H
G5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- OH H
G6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- OH H
G7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- OH H
G8 -COX10 SelectingSubstituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- OH H
G9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- OH H
G10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- OH H
G11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- OH H
G12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- OH H
H1 -COOX10 Heterocyclic radical R10aOCOO- C6H5COO- OH OH
H2 -COX10 Heterocyclic radical R10aOCOO- C6H5COO- OH OH
H3 -CONHX10 Heterocyclic radical R10aOCOO- C6H5COO- OH OH
H4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- OH OH
H5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- OH OH
H6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- C6H5COO- OH OH
H7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- OH OH
H8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- OH OH
H9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- C6H5COO- OH OH
H10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- OH OH
H11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- OH OH
H12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- C6H5COO- OH OH
I1 -COOX10 Heterocyclic radical R10aOCOO- R2aCOO- O OH
I2 -COX10 Heterocyclic radical R10aOCOO- R2aCOO- O OH
I3 -CONHX10 Heterocyclic radical R10aOCOO- R2aCOO- O OH
I4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- O OH
I5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- O OH
I6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- O OH
I7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- O OH
I8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- O OH
I9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- O OH
I10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- O OH
I11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- O OH
I12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- O OH
J1 -COOX10 Heterocyclic radical R10aOCOO- R2aCOO- OH OH
J2 -COX10 Heterocyclic radical R10aOCOO- R2aCOO- OH OH
J3 -CONHX10 Heterocyclic radical R10aOCOO- R2aCOO- OH OH
J4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- OH OH
J5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- OH OH
J6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- OH OH
J7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- OH OH
J8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- OH OH
J9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- OH OH
J10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- OH OH
J11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- OH OH
J12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- OH OH
K1 -COOX10 Heterocyclic radical R10aOCOO- R2aCOO- R9aCOO- OH
K2 -COX10 Heterocyclic radical R10aOCOO- R2aCOO- R9aCOO- OH
K3 -CONHX10 Heterocyclic radical R10aOCOO- R2aCOO- R9aCOO- OH
K4 -COOX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K5 -COX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K6 -CONHX10 Optionally substituted C2-C8Alkyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K7 -COOX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K8 -COX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K9 -CONHX10 Optionally substituted C2-C8Alkenyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K10 -COOX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K11 -COX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- R9aCOO- OH
K12 -CONHX10 Optionally substituted C2-C8Alkynyl radical R10aOCOO- R2aCOO- R9aCOO- OH
Example 5
Measurement of in vitro cytotoxicity by cell colony formation assay
Four hundred cells (HCT116) were plated in 60 mm petri dishes containing 2.7 ml of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/ml penicillin and 100 mg/ml streptomycin). CO at 37 deg.C2These cells were cultured in an incubator for 5 hours and allowed to adsorb to the bottom of a petri dish. The compound described in example 2 was prepared in medium at ten times the final concentration, and then 0.3 ml of the above solution was added to 2.7 ml of medium in a petri dish. The cells were then incubated with the drug at 37 ℃ for 72 hours. After the incubation was completed, the drug-containing medium was decanted, the dishes were rinsed with 4 ml of Hank's Balance Salt Solution (HBSS), 5 ml of fresh medium was added, and the dishes were placed in the incubator again for colony formation. After 7 days of culture, cell colonies were counted using a colony counter. Cell viability was calculated and the ID50 value (concentration of drug that results in 50% inhibition of colony formation) was determined for each test compound.
Compound (I) In vitro ID50(nm) HCT116
Paclitaxel 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
Example 6
Preparation of oral solutions
Solution 1: anti-tumor compound 1771 is dissolved in ethanol to form a solution containing 145 mg of compound per ml of solution. An equivalent volume of Cremophor  EL solution was added with stirring to give a solution containing 72.5 mg of compound 1771 per ml. The solution was diluted with 9 parts by weight of saline to obtain a pharmaceutically acceptable solution for patient administration.
Solution 2: antitumor compound 1781 was dissolved in ethanol to form a solution containing 98 mg of compound per ml of solution. An equivalent volume of Cremophor  EL solution was added with stirring to give a solution containing 49 mg of compound 1781 per ml. The solution was diluted with 9 parts by weight of saline to obtain a pharmaceutically acceptable solution for patient administration.
Example 7
Preparation of oral suspensions
Oral compositions of the anti-tumor compound were prepared by suspending 25mg of the micronized compound in a deionized water carrier containing 1% carboxymethylcellulose (CMC).
Example 8
Preparation of oral tablets
The antitumor compound (100 mg) was dissolved in dichloroethane (2 ml) and CRemophor  EL (100 mg) was added. The methylene chloride was evaporated in vacuo to form a glass. Microcrystalline cellulose (600 mg) was added to the glass and mixed to form a powder that could be compressed into tablets.
Example 9
Preparation of emulsion for parenteral administration
Emulsion 1: the antitumor compound was dissolved in 100% ethanol to form a solution containing 40 mg of the compound per ml of solution. 19 parts by weight of Liposon  II (2%) were added with stirring to give a parenteral emulsion containing 2mg of the compound per ml.
Emulsion 2: the antitumor compound was dissolved in 100% ethanol to form a solution containing 40 mg of the compound per ml of solution. 19 parts by weight of Liposon  III (2%) were added with stirring to give a parenteral emulsion containing 2mg of the compound per ml.
Emulsion 3: the antitumor compound was dissolved in 100% ethanol to form a solution containing 40 mg of the compound per ml of solution. 9 parts by weight of Liposon  III (2%) were added with stirring to give a parenteral emulsion containing 4mg of the compound per ml.
Example 10
Preparation of parenteral solutions containing the compounds
Solution 1: the antitumor compound was dissolved in 100% ethanol to form a solution containing 140 mg of the compound per ml of solution. An equivalent volume of Cremophor  EL solution was added with stirring and diluted with 9 parts by weight of normal saline to give a parenteral solution containing 7mg of the compound per ml.
Solution 2: the antitumor compound was dissolved in 100% ethanol to form a solution containing 140 mg of the compound per ml of solution. An equivalent volume of Cremophor  EL solution was added with stirring and diluted with 4 parts by weight of normal saline to give a parenteral solution containing 11.7 mg of the compound per ml.
Solution 3: the antitumor compound was dissolved in 100% ethanol to form a solution containing 140 mg of the compound per ml of solution. An equivalent volume of Cremophor  EL solution was added with stirring and diluted with 2.33 parts by weight of normal saline to give a parenteral solution containing 16.2 mg of the compound per ml.
Example 11
In vivo activity of antitumor compounds on human lung cancer xenografts
The following vectors were used: 10% ethanol, 10% Cremophor and 80% isotonic saline, and the anti-tumor compound 1755 was formulated into an intravenous injection. Antitumor compound 1755 used in this assay was formulated as described in example 10, solution 2. Paclitaxel (paclitaxel, Bristol Meyers Squibb) used as a control was a commercially available drug.
Two lung tumors used for the study were xenografted with SK-MES carcinoma, which is very sensitive to paclitaxel, and NCI-H1299(H1299) carcinoma, which is more resistant to paclitaxel than SK-MES tumors.
The first day, female NCr-nude mice (1 mm each) will have SK-MES carcinoma or H1299 carcinoma3Human lung cancer fragments implanted subcutaneously ventrally) were grouped by gender pairing, with six mice per group, and the mean tumor size ranged from 241-244 mg. The processing group comprises: vehicle treated (group 1); paclitaxel treated (group 2); and treatment with anti-tumor compound 1755 (group 3).
Animals in the paclitaxel treated group and the anti-tumor compound 1755 treated group were injected intravenously at the Maximum Tolerated Dose (MTD) of each compound, and half the dose was given at one hour intervals on the qd x 1 schedule. The MTD of anti-tumor compound 1755 was calculated from the single dose data of the intravenous injection of these compounds in early mice. Paclitaxel itself was administered at an isolated i.v. dose of 36 mg/kg, 18 mg/kg before and after one hour, respectively. Vehicle control animals were dosed twice in half the total amount around one hour. The assay study was terminated on day 60.
The results are summarized in Table 1, including the mean number of days alive (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The average day of survival refers to the number of days after the SKMES tumor size reached 1.5 grams and the animal died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 1.5 grams at the end of the study, resulting in "stable disease".
The tumor scoring system designed below provides a more quantitative range for evaluating the efficacy (potential therapeutic efficacy) of antineoplastic agents in treating xenogeneic colonization of different human solid tumors. At the end of the study, each mouse studied gave a score of 1 to 10. The scores are summarized as follows:
description of the Scoring
< 1 serious toxicity
2-3 tumors were extreme but significant tumor growth delays occurred
4-6 obvious inhibition of tumor growth (stable disease condition)
7-9 partial tumor shrinkage (partial response)
10 complete reaction (score)
The scores for each mouse were averaged to obtain the average score for each treatment group. The tumor scoring system provides a better way to compare different anti-tumor compounds by quantifying the treatment results (complete response vs partial response).
TABLE 1
Group of MDS(n) Number of poisonous death Number of survivors Complete reaction Partial reaction Stable state of illness Average score
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
MDS values were calculated from vehicle treated controls for 12.2 days. Paclitaxel (36 mg/kg; group 2) produced only an increase in survival of no more than 30% (MDS 16.0 days) compared to vehicle control group, and no tumor reduction was recorded. In contrast, anti-tumor compound 1755 has high activity. Anti-tumor compound 1755(49 mg/kg; group 4) produced five complete responses and survived significantly longer than vehicle or paclitaxel treated control animals. Anti-tumor compound 1755 was well tolerated.
In the H1299 trial, on day one, mice were divided into six groups by gender pairing, with six mice in each group and the mean tumor size ranged from 229-233 mg. The H1299 test was carried out in the same way as the SK-MES test. MDS values were calculated from vehicle treated control 1 group to be 24.5. Paclitaxel (36 mg/kg; group 2) was inactive in the H1299 model compared to the vehicle control group, and five animals produced only a survival increase of no more than 10% (MDS 27.0 days) compared to the vehicle control group (no statistical significance). One partial response was observed in paclitaxel treatment.
TABLE 2
Group of MDS(n) Number of poisonous death Number of survivors Complete reaction Partial reaction Stable state of illness Average score
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
Antitumor compound 1755(49 mg/kg; group 4) had significant therapeutic benefit against paclitaxel-null H1299 tumors, producing three complete responses in the H1299 assay. The survival time of other mice treated with this compound was significantly increased compared to vehicle-treated or paclitaxel-treated animals.
In the H1299 toxicity test, two mice in the anti-tumor compound 1755 treated group died. Since the dose and dosing schedule of the three compounds was the same as in the SK-MES assay, the side effects experienced by nude mice are likely not due to systemic drug toxicity. One explanation is the extreme response of the H1299 tumor to anti-tumor compound 1755, which includes the release of toxic substances from the tumor of the host mouse by the compound causing tumor masses and interstitial necrosis and hemorrhage.
Anti-tumor compound 1755 was effective for late (upstaged) (250mg) human lung cancer xenografts when administered as a single dose bolus.
Example 12
In vivo evaluation of DU145 human prostate cancer xenografts with anti-tumor compounds
The following vectors were used: 5% ethanol, 5% Cremophor and 90% isotonic saline, the antitumor compound was formulated as described in solution 1 of example 10. Paclitaxel (paclitaxel, Bristol meyers squibb) was used as a control as a commercially available drug. The dose volume was 0.3 ml per 20g mouse.
Male NCr-nude mice (1 mm each)3DU145 human prostate cancer fragments were implanted subcutaneously ventrally) into groups of five mice each. The mean tumor size for the DU145 group ranged from 223-228 mg. Dosing began on the first day. The anti-tumor compounds were injected intravenously on a qd x 1 schedule at the Maximum Tolerated Dose (MTD) appropriate for each agent. Paclitaxel was injected intravenously twice (24 mg/kg total dose) on a qd x 1 schedule at 12 mg/kg doses each around one hour. Paclitaxel was also administered i.p. on a qd x 5 schedule at a dose of 18 mg/kg per day. Control group 1 mice were injected intravenously with vehicle on a qd x 1 schedule. The assay study was performed on day 91. The treatment groups are shown in Table 3.
TABLE 3
Group of Compound (I) Mg/kg Route of administration Administration regimen
1 Excipient --- 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 results are summarized in Table 4, including mean days to live (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The mean survival days refer to the days after the tumor size reached 1.5 grams and the animals died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 1.5 grams at the end of the study, resulting in "stable disease".
TABLE 4
Group of MDS(n) Number of poisonous death Number of survivors Complete reaction Partial reaction Stable state of illness Average score
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
Three of the five mice treated with vehicle (group 1) had progressively larger DU145 tumors. MDS values for these mice were 34.3 days (calculated). One mouse in group 1 died for no reason evident at day 40, and the tumor of another mouse in group 1 slowly shrunk in size from 220 mg at the beginning of pairing until the tumor became less apparent at day 71. The latter example is likely to pick an inappropriate lesion.
Three of five animals dosed with 24 mg/kg (i.v.; qd × 1) paclitaxel (group 2) had steadily increased prostate tumors, MDS ═ 37.4 days, reaching an end value of 1.5 grams. It was 9% higher than the survival rate of the control group of group 1, with no statistically significant difference (p ═ 0.82; unpaired t-test). One animal in group 2 died on day 32, likely due to drug side effects; the fifth mouse in group 2 had no tumor increase in the 91 day study; the tumor size at day 91 was the same as day 6 (196 mg). Paclitaxel administered i.p. according to the qd x 5 schedule at a dose of 18 mg/kg per day is highly toxic. All five mice died from drug-related side effects and included significant weight loss (over 20%).
Anti-tumor compound 1781 the mortality rate was greater than 40% at the dose of five animals treated with each compound. At this dose the anti-tumor compound is 100% lethal. The compound reduces body weight by 20% before causing death in the animal.
Example 13
In vivo evaluation of A2780 human ovarian cancer xenografts with anti-tumor compounds
The following vectors were used: 5% ethanol, 5% Cremophor and 90% isotonic saline, the antitumor compound was formulated as described in solution 1 of example 10. Paclitaxel (paclitaxel, Bristol MeyersQuibb) and Taxotere (docetaxel; Rhonen-Poulenc Rorer) were used as controls as commercially available drugs. The dose volume was 0.3 ml per 20g mouse.
The first day, female NCr-nude mice (1 mm will be used)3A2780 human melanoma fragment was implanted subcutaneously ventrally) into groups of five mice each, but the Taxotere-treated group included six mice. Group A2780 has a size range of 237-243 mg. Dosing began on the first day. The antitumor compounds were injected intravenously on a qd x 1 schedule (compounds administered alone) at the Maximum Tolerated Dose (MTD) appropriate for each agent. Paclitaxel was injected intravenously twice (24 mg/kg total dose) at a dose of 12 mg/kg on a qd x 1 schedule. Paclitaxel was also administered i.p. on a qd x 5 schedule at a dose of 15 mg/kg per day. Taxotere was injected intravenously at a dose of 70 mg/kg on a qd x 1 schedule. Control group 1 mice were injected intravenously with vehicle on a qd x 1 schedule. The assay study was terminated on day 60. The treatment groups are detailed in table 5.
TABLE 5
Group of Compound (I) Mg/kg Route of administration Administration regimen
1 Excipient --- 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 results are summarized in Table 6, including mean days to live (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The mean survival days refer to the days after the tumor size reached 2.0 grams and the animals died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 2.0 grams at the end of the study, resulting in "stable disease".
TABLE 6
Group of MDS(n) Number of poisonous death Number of survivors Complete reaction Partial reaction Stable state of illness Average score
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
Five mice in group 1 treated with vehicle had progressively larger ovarian tumors reaching an end of 2.0 grams of MDS values of 11.7 days. Thus, ovarian cancer xenografts are rapidly growing tumors that require a relatively short time to kill the host.
Paclitaxel (group 2) dosed on the qd x 1 schedule in this assay showed modest activity. The MDS score for group 2 was 21.9 days, which was 87% longer than the survival time of the control animals in group 1, which was not evident (p 0.13; unpaired t-test). Stable disease was recorded for 61 days in one animal in group 2. Paclitaxel (group 3) dosed i.p. on the qd x 5 schedule and at 15 mg/kg dose showed high toxicity. Four mice died of drug side effects.
In this test, taxotere (70 mg/kg; i.v.; qd x 1) showed higher activity than paclitaxel. Five mice in group 5 had an MDS score of 27.4 days, a 134% longer survival time than the control animals in group 1, with clear statistical significance (p 0.007; unpaired t-test).
An anti-tumor compound (1781) produces at least one complete response or partial response (total response rate of at least 20%) in mice with A2780 ovarian cancer. Compound 1781 produced 2 partial responses in five treated mice.
On day 11, the anti-tumor compound 1781 treated group resulted in a maximum average weight loss of 3% to 19%, after which the animals rebounded in weight. The side effects of anti-tumor compound 1781 were well within the NCI acceptable range, indicating that the MTD dose was appropriate for the animals in the a2780 assay.
Example 14
In vivo activity of antitumor compounds on A375 human melanoma xenograft
The following vectors were used: 5% ethanol, 5% Cremophor and 90% isotonic saline, the antitumor compound was formulated as described in solution 1 of example 10. Paclitaxel (paclitaxel, Bristol MeyersQuibb) and Taxotere (docetaxel; Rhonen-Poulenc Rorer) were used as controls as commercially available drugs. The dose volume was 0.3 ml per 20g mouse.
Female NCr-nude mice (1 mm each)3A375 human melanoma fragment was implanted subcutaneously ventrally) into treatment groups of six mice each, but the Taxotere treatment group included seven mice. The mean size range for the tumor group was 206-212 mg. Dosing began on the first day. The antitumor compounds were injected intravenously on a qd x 1 schedule (compounds administered alone) at the Maximum Tolerated Dose (MTD) appropriate for each agent. Paclitaxel was injected intravenously twice (24 mg/kg total dose) at a dose of 12 mg/kg on a qd x 1 schedule. Paclitaxel was also administered i.p. on a qd x 5 schedule at a dose of 18 mg/kg per day. Taxotere was injected intravenously at a dose of 70 mg/kg on a qd x 1 schedule. Control group 1 mice were injected intravenously with vehicle on a qd x 1 schedule. The assay study was terminated on day 60. The treatment groups are shown in Table 7.
TABLE 7
Group of Compound (I) Mg/kg Route of administration Administration regimen
1 Excipient --- i.v. qd×1
2 Paclitaxel 24 i.v. qd×1
3 Paclitaxel 18 i.p. qd×5
4 1781 72.6 i.p. qd×1
5 Taxotere 70 i.v. qd×1
The results are summarized in Table 8, including mean days to live (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The mean survival days refer to the days after the tumor size reached 2.0 grams and the animals died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 2.0 grams at the end of the study, resulting in "stable disease".
TABLE 8
Group of MDS(n) Number of poisonous death Number of survivors Complete reaction Partial reaction Stable state of illness Average score
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
All six mice treated with vehicle (group 1) had a375 melanoma xenografts that rapidly continued to increase. MDS values reached the end of 2.0 grams for 14.4 days.
Paclitaxel animals dosed i.v. with qd x 1 schedule (24 mg/kg; group 2) in this trial showed modest activity, suitable for use as chemotherapeutic drugs. MDS values were 18.1 days, which increased survival by 26% over control animals of group 1. This elongation was statistically significant (p ═ 0.016; unpaired t-test). Paclitaxel groups administered on a qd x 5 schedule (18 mg/kg; i.p.) showed high toxicity in mice.
Taxotere administered at 70 mg/kg i.v. (qd x 1; group 5) produced MDS values of 21.5 days, which were 49% longer than survival in control animals of group 1, p 0.0001 (unpaired t-test).
The anti-tumor compound 1781 resulted in five toxic deaths in six mice. These compounds resulted in an average body weight loss of 20-30%.
Example 15
In vivo Activity of anti-tumor Compounds on human Panc-1 pancreatic cancer
The following vectors were used: 5% ethanol, 5% Cremophor and 90% isotonic saline, the antitumor compound was formulated as described in solution 1 of example 10. Paclitaxel (paclitaxel, Bristol meyers squibb) was used as a control as a commercially available drug. The dose volume was 0.3 ml per 20g mouse.
Female NCr-nude mice (1 mm each)3Panc-1 pancreatic cancer fragments were implanted subcutaneously ventrally) into treatment groups of six mice each. Panc-1 pancreatic cancer tumor groupThe average size range was 192-. Dosing began on the first day. The antitumor compounds were injected intravenously on a qd x 1 schedule (compounds administered alone) at the Maximum Tolerated Dose (MTD) appropriate for each agent. Paclitaxel was injected intravenously twice (24 mg/kg total dose) at a dose of 12 mg/kg on a qd x 1 schedule. Paclitaxel was also administered i.p. on a qd x 5 schedule at a dose of 15 mg/kg per day. Control group 1 mice were injected intravenously with vehicle on a qd x 1 schedule. The study was ended on day 63. The treatment groups are shown in Table 9.
TABLE 9
Group of Compound (I) Mg/kg Route of administration Administration regimen
1 Excipient --- i.v. qd×1
2 Paclitaxel 24 i.v. qd×1
3 Paclitaxel 15 i.p. qd×5
4 1781 60 i.v. qd×1
The results are summarized in Table 10, including mean days to live (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The mean survival days refer to the days after the tumor size reached 1.5 grams and the animals died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 1.5 grams at the end of the study, resulting in "stable disease".
Watch 10
Group of MDS(n) Number of poisonous death Number of survivors Complete reaction Partial reaction Stable state of illness Average score
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
MDS calcd for Panc-1 tumors of vehicle-treated (group 1) mice to reach an endpoint of 1.5 grams was 23.0 days. One tumor in the control group did not grow and it is likely that an inappropriate tumor specimen was selected.
Paclitaxel (group 2) injected intravenously at a dose of 24 mg/kg (qd × 1) produced one stable disease and 34.7 days of MDS in four additional mice (clearly different from the group 1 control group; p ═ 0.038; unpaired t-tests). At this dose the next mouse died from the toxicity of paclitaxel. Paclitaxel administered at a dose of 15 mg/kg (qd x 5) i.p. resulted in four toxic deaths in six mice.
Anti-tumor compound 1781 produced a total response rate of 66.7%. Anti-tumor compound 1781 was well tolerated, did not result in death of the animals, and resulted in only a minor group average weight loss. Thus, the compound may be administered within the appropriate MTD dosage range.
Example 16
In vivo activity of antitumor Compounds against human VM46 Colon cancer
The following vectors were used: 5% ethanol, 5% Cremophor and 90% isotonic saline, the antitumor compound was formulated as described in solution 1 of example 10. Paclitaxel (paclitaxel, Bristol MeyersQuibb) and Taxotere (docetaxel; Rhonen-Poulenc Rorer) were used as controls as commercially available drugs. The dose volume was 0.3 ml per 20g mouse.
Female NCr-nude mice (1 mm each)3Human VM46 colon cancer fragment was implanted subcutaneously ventrally) into treatment groups of six mice each. The mean size range for the VM46 colon tumor group was 181-188 mg. Dosing began on the first day. The anti-tumor compounds were injected intravenously on a qd x 1 schedule (compounds administered alone) at the Maximum Tolerated Dose (MTD) appropriate for the estimation of each agent. Paclitaxel was injected intravenously twice (24 mg/kg total dose) at a dose of 12 mg/kg on a qd x 1 schedule. Paclitaxel was also administered i.p. on a qd x 5 schedule at a dose of 15 mg/kg per day. Taxotere was injected intravenously at a dose of 70 mg/kg on a qd x 1 schedule. Control group 1 mice were injected intravenously with vehicle on a qd x 1 schedule. The study was terminated on day 64. The treatment groups are shown in Table 11.
TABLE 11
Group of Compound (I) Mg/kg Route of administration Administration regimen
1 Excipient --- i.v. qd×1
2 Paclitaxel 24 i.v. qd×1
3 Paclitaxel 15 i.p. qd×5
4 1781 60 i.v. qd×1
5 Taxotere 70 i.v. qd×1
The results are summarized in Table 12, including mean days to live (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The mean survival days refer to the days after the tumor size reached 1.5 grams and the animals died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 1.5 grams at the end of the study, resulting in "stable disease".
TABLE 12
Group of MDS(n) Number of poisonous death Complete reaction Partial reaction Stable state of illness Average score
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
Colon tumors of all six mice treated with vehicle (group 1) continued to grow, with MDS calculations reaching an endpoint of 1.5 grams for 31.0 days.
Paclitaxel (group 2) administered at a dose of 24 mg/kg (i.v.; qd × 1) produced a partial response, one stable disease, and 43.3 days of MDS in four additional mice (no significant difference from the control group; p ═ 0.086; unpaired t-test). Paclitaxel administered at a 15 mg/kg dose (qd x 5) i.p. showed high toxicity, resulting in three toxic deaths in six treated mice. In this test Taxotere showed higher activity, yielding MDS values of 45.3 days (statistically significant, p ═ 0.05; unpaired t-test).
The reaction rate of the anti-tumor compound 1781 is 16.7%. Anti-tumor compound 1781 resulted in a survival time that was 11 to 20 days longer than 31.0 days of MDS as calculated from the control group. Anti-tumor compound 1781 was well tolerated without causing toxic death, with a maximum group average weight loss of 3-14% on day 8.
Example 17
In vivo activity of anti-tumor compound 1755 in human SKMES lung cancer xenograft by oral administration
Antitumor compound 1755 was formulated as described in example 6, solution 1, in the following vehicle: 5% ethanol, 5% Cremophor and 90% isotonic saline. To investigate the activity of the antitumor compound on the xenograft of human SKMES lung carcinoma, the compound was administered orally in the form of single-dose bolus.
Female Nu/Nu-nude mice (6-8 weeks old, 1mm old)3Human SKMES lung cancer fragment was implanted ventrally subcutaneously) into 4 treatment groups of six mice each. The SKMES size and group SKMES mean size ranges from 126 ℃ 448 mg and 238 ℃ 241 mg, respectively. The processing group comprises: treatment-free group (group 1), vehicle treatmentGroup (2), paclitaxel (40 mg/kg; group 3), and anti-tumor compound 1755(49 mg/kg; group 4). The first day starts dosing with a single dose of bolus and the study ends on day 60.
The results are summarized in Table 13, including mean days to live (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The mean survival days refer to the days after the SKMES tumor size reached 2.0 grams and the animals died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 2.0 grams at the end of the study, resulting in "stable disease".
Watch 13
Group of MDS(n) Number of poisonous death Number of survivors Complete reaction Partial reaction Stable state of illness 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
Antitumor compound 1755 has high activity when administered orally in a single dose. The total reaction rate was 100%, four cases were completely reacted, and two cases were partially reacted. The total response rate is the percentage of animals evaluated (including animals lethal due to handling or toxicity) that produced a complete response or partial response at the end of the study.
Example 18
In vivo activity of orally administered antitumor compounds against xenogeneic transplantation of human MX-1 breast cancer
In this experiment, to investigate the activity of the dosage form on xenotransplantation of human MX-1 breast cancer, the compound was administered orally. The antitumor compounds were formulated in the following vehicles: 90% saline, 5% Cremophor, 5% ethanol. Anti-tumor compound 1771 was formulated as described in example 6, solution 1. Antitumor compound 1781 was formulated as described in example 6, solution 2.
Female Nu/Nu mice (11-12 weeks old, 1 mm)3Human MX-1 breast cancer fragments implanted ventrally and subcutaneously) were divided into one control group (n-10) and two treatment groups (n-6) (group tumors mean size range 47-49 mg). The treatment groups are detailed in table 14. All treatment groups began on day one with a single bolus dose and ended on day 60.
The results are summarized in Table 14, including mean days to live (MDS), number of toxic deaths, number of survivors, number of complete or partial responses, and number of stable disease. The mean survival days refer to the days after MX-1 tumor size reached 1.5 grams and the animals died. Complete response is obtained if the presence of the tumor is not already apparent at the end of the study. If the tumor shrinks to a level less than the first day of the study, a partial response is obtained. Drug treatment limited tumor growth to less than 1.5 grams at the end of the study, resulting in "stable disease".
TABLE 14
Group of Antitumor compounds Dosage (mg/kg) Average survival days (n) Maximum weight reduction Number of poisonous death Complete reaction Partial reaction Stable state of illness
1 Excipient 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
The tumor compounds evaluated showed activity over a wide range of tolerated doses in the MX-1 human breast cancer xenograft model. Anti-tumor compound 1771 caused four out of six animals treated to completely stop their growth, and at the end of the experiment, the survival time of the other two was significantly increased compared to the control mice. The response shown by anti-tumor compound 1781 was characterized by a significant increase in survival time compared to control mice.
In addition to assessing survival time and tumor shrinkage response, the effect on blood cell populations was also determined. The main effect of these anti-tumor compounds on the blood cell population is a significant decrease in the number of neutrophils. Furthermore, for each anti-tumor compound, the reduction of neutrophils is correlated with the loss of monocytes. These anti-tumor compounds did not affect the general white blood cell count, lymphocytes, and platelets. There is a certain relationship between the antitumor activity and the number of neutrophils. In general, toxicity (as measured by neutrophil loss) and weight loss are associated with activity. Importantly, the toxicity observed with the very active anti-neoplastic compound is easily controlled and transformed; within just a few days, both neutrophil numbers and body weight rebound from low points. Table 15 summarizes the weight loss at day 4, the neutrophil and monocyte measurements, and the tumor weight reduction calculated at day 18:
watch 15
Group of Antitumor compounds Dosage (mg/kg) Weight (mg) % reduction rate Neutrophils (K/uL) % reduction rate Mononuclear cells (K/. mu.L) % reduction rate
1 Excipient 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. A taxane having the formula:
Figure A0114240800021
wherein:
R2is acyloxy;
R7is a hydroxyl group;
R9is a keto, hydroxyl, or acyloxy group;
R10is a carbonate;
R14is hydrogen or hydroxy;
X3is a substituted or unsubstituted alkyl, alkenyl, alkynyl or heterocyclyl group, wherein the alkyl group contains at least two carbon atoms;
X5is-COX10，-COOX10or-CONHX10；
X10Is a hydrocarbyl, substituted hydrocarbyl, or heterocyclic ring; and is
Ac is acetyl.
2. The taxane of claim 1 wherein R10Is R10aOCOO-, and R10aIs substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
3. The taxane of claim 2 wherein X3Is furyl, thienyl, pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
4. The taxane of claim 2 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
5. The taxane of claim 2 wherein R14Is hydrogen.
6. The taxane of claim 5 wherein X3Is furyl, thienyl, pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
7. The taxane of claim 5 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
8. The taxane of claim 2 wherein R2Is benzoyloxy.
9. The taxane of claim 8 wherein X3Is furyl, thienyl, pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
10. The taxane of claim 8 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
11. The taxane of claim 2 wherein R14Is hydrogen, and R9Is a keto group.
12. The taxane of claim 11 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C3-C8Alkynyl.
13. The taxane of claim 11 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
14. The taxane of claim 2 wherein R2Is benzoyloxy and R9Is a keto group.
15. The taxane of claim 14 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
16. The taxane of claim 14 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
17. The taxane of claim 2 wherein R14Is hydrogen and R2Is benzoyloxy.
18. The taxane of claim 17 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
19. The taxane of claim 17 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
20. The taxane of claim 2 wherein R14Is hydrogen, R9Is a keto group, and R2Is benzoyloxy.
21. The taxane of claim 20 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
22. The taxane of claim 20 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
23. The taxus species of claim 1Alkane, wherein R10Is R10aOCOO-, and R10aIs C1-C8An alkyl group.
24. The taxane of claim 23 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
25. The taxane of claim 23 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
26. The taxane of claim 23 wherein R14Is hydrogen.
27. The taxane of claim 26 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
28. The taxane of claim 26 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
29. The taxane of claim 23 wherein R2Is benzoyloxy.
30. The taxane of claim 29 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
31. The taxane of claim 29 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
32. The taxane of claim 23 wherein R14Is hydrogen, R9Is a keto group, and R2Is benzoyloxy.
33. The taxane of claim 32 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
34. The taxane of claim 32 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
35. The taxane of claim 1 wherein R10Is R10aOCOO-, and R10aIs methyl or ethyl.
36. The taxane of claim 35 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
37. The taxane of claim 35 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
38. The taxane of claim 35 wherein R14Is hydrogen.
39. The taxane of claim 38 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
40. The taxane of claim 38 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
41. The taxane of claim 35 wherein R2Is benzoyloxy.
42. The taxane of claim 41 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
43. The taxane of claim 41 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
44. The taxane of claim 35 wherein R14Is hydrogen and R9Is a keto group.
45. The taxane of claim 44 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
46. The taxane of claim 44 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
47. The taxane of claim 35 wherein R2Is benzoyloxy and R9Is a keto group.
48. The taxane of claim 47 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
49. The taxane of claim 47 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
50. The taxane of claim 35 wherein R14Is hydrogen. And R is2Is benzoyloxy.
51. The taxane of claim 50 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
52. The taxane of claim 50 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
53. The taxane of claim 35 wherein R14Is hydrogen, R9Is a keto group, and R2Is benzoyloxy.
54. The taxane of claim 53 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
55. The taxane of claim 53 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
56. The taxane of claim 53 wherein X5is-COOX10And X10Is a tert-butyl group.
57. The taxane of claim 56 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
58. A taxane having the formula:
wherein:
R2is benzoyloxy;
R7is a hydroxyl group;
R10is R10aOCOO-；
X3Is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclyl; wherein the alkyl group contains at least two carbon atoms;
X5is-COX10，-COOX10or-CONHX10；
X10Is a hydrocarbyl, substituted hydrocarbyl, or heterocyclic ring; and is
R10aIs a hydrocarbyl, substituted hydrocarbyl, or heterocyclic group; and is
Ac is acetyl.
59. The taxane of claim 58 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
60. The taxane of claim 59 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
61. The taxane of claim 58 wherein X3Is furyl or thienyl.
62. The taxane of claim 61 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
63. The taxane of claim 61 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
64. The taxane of claim 58 wherein R10aIs methyl or ethyl.
65. The taxane of claim 64 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
66. The taxane of claim 65 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
67. The taxane of claim 65 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
68. The taxane of claim 64 wherein X3Is furyl or thienyl.
69. The taxane of claim 68 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
70. The taxane of claim 68 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
71. The taxane of claim 64 wherein X3Is a cycloalkyl group.
72. The taxane of claim 71 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridoyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
73. The taxane of claim 71 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
74. The taxane of claim 64 wherein X3Is an isobutenyl group.
75. The taxane of claim 74 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl radicalOr C2-C8Alkynyl.
76. The taxane of claim 74 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
77. The taxane of claim 58 wherein X3Is furyl or thienyl, R10aIs ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
78. The taxane of claim 58 wherein X3Is 2-furyl or 2-thienyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
79. The taxane of claim 58 wherein X3Is isobutenyl, and X5is-COOX10And X10Is a tert-butyl group.
80. The taxane of claim 58 wherein X3Is cycloalkyl, R10aIs methyl or ethyl, X5is-COOX10And X10Is a tert-butyl group.
81. A taxane having the formula:
wherein:
R2is benzoyl;
R7is a hydroxyl group;
R10is R10aOCOO-；
X3Is cycloalkyl, alkenyl, alkynyl, phenyl or heterocyclyl;
X5is-COX10，-COOX10or-CONHX10；
X10Is a hydrocarbyl, substituted hydrocarbyl, or heterocyclic ring; and is
R10aIs alkyl, alkenyl, alkynyl, phenyl or heterocyclic radical, wherein the alkyl contains at least two carbon atoms;
and is
Ac is acetyl.
82. The taxane of claim 81 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
83. The taxane of claim 82 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
84. The taxane of claim 82 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
85. The taxane of claim 81 wherein X3Is furyl or thienyl.
86. The taxane of claim 85 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
87. The taxane of claim 85 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
88. The taxane of claim 81 wherein X3Is phenyl.
89. The taxane of claim 88 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
90. The taxane of claim 88 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
91. The taxane of claim 81 wherein X3Is an isobutenyl group.
92. The taxane of claim 91 wherein X5is-COX10And X10To substituteOr unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
93. The taxane of claim 91 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
94. The taxane of claim 81 wherein R10aIs ethyl.
95. The taxane of claim 94 wherein X3Is 2-furyl group, 3-furyl group. 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
96. The taxane of claim 94 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
97. The taxane of claim 94 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
98. The taxane of claim 94 wherein X3Is furyl or thienyl.
99. The taxane of claim 98 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
100. The taxane of claim 98 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
101. The taxane of claim 98 wherein X5is-COOX10And X10Is a tert-butyl group.
102. A pharmaceutical composition comprising a taxane according to claim 1 and at least one pharmaceutically acceptable, inert or physiologically active diluent or adjuvant.
103. The pharmaceutical composition of claim 102, wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
104. The pharmaceutical composition of claim 103, wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
105. The pharmaceutical composition of claim 103, wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
106. The pharmaceutical composition of claim 102, wherein R10aIs methyl, ethyl or propyl.
107. The pharmaceutical composition of claim 106, wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
108. The pharmaceutical composition of claim 107, wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, or X5is-COOX10And X10Is substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
109. Claim 107 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
110. The pharmaceutical composition of claim 103, wherein X3Is furyl or thienyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
111. The pharmaceutical composition of claim 103, wherein X3Is substituted or unsubstituted furyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
112. The pharmaceutical composition of claim 103, wherein X3Is substituted or unsubstituted thienyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
113. The pharmaceutical composition of claim 103, wherein X3Is isobutenyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
114. The pharmaceutical composition of claim 103, wherein X3Is alkyl, R10aIs methyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
115. The medicament of claim 103Composition of matter, wherein X3Is 2-furyl or 2-thienyl, R10aIs methyl, X5is-COOX10And X10Is a tert-butyl group.
116. The pharmaceutical composition of claim 103, wherein X3Is 2-furyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
117. The pharmaceutical composition of claim 103, wherein X3Is 2-thienyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
118. The pharmaceutical composition of claim 103, wherein X3Is isobutenyl, X5is-COOX10And X10Is a tert-butyl group.
119. The pharmaceutical composition of claim 103, wherein X3Is cycloalkyl, R10aIs methyl, X5is-COOX10And X10Is a tert-butyl group.
120. A pharmaceutical composition comprising the taxane of claim 58 and at least one pharmaceutically acceptable, inert or physiologically active diluent or adjuvant.
121. A pharmaceutical composition comprising the taxane of claim 61 and at least one pharmaceutically acceptable, inert or physiologically active diluent or adjuvant.
122. A composition for oral administration comprising the taxane of claim 1 and at least one pharmaceutically acceptable carrier.
123. The composition of claim 122, wherein R10Is R10aOCOO-, and R10aIs substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
124. The composition of claim 123, wherein X3Is phenyl, isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
125. The composition of claim 124, wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
126. The composition of claim 125, wherein R10aIs methyl, ethyl or propyl.
127. The composition of claim 126, wherein X3Is isobutenyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
128. The composition of claim 127, wherein X3Is 2-furyl or 2-thienyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
129. The composition of claim 127, wherein X3Is isobutenyl, X5is-COOX10，R10aIs ethyl, and X10Is a tert-butyl group.
130. The composition of claim 122, wherein X3Is a phenyl group, and the phenyl group,R10ais ethyl, X5is-COOX10And X10Is a tert-butyl group.
131. A pharmaceutical composition comprising the taxane of claim 92 and at least one pharmaceutically acceptable carrier.
132. A method of inhibiting tumor development in a mammal, the method comprising orally administering a therapeutically effective amount of a composition comprising the taxane of claim 122 and at least one pharmaceutically acceptable carrier.
133. The method of claim 132, wherein R10Is R10aOCOO-, and R10aIs substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
134. The method of claim 133, wherein X3Is phenyl, isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl.
135. The method of claim 134, wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
136. The method of claim 135, wherein R10aIs methyl, ethyl or propyl.
137. The method of claim 136, wherein X3Is isobutenyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is tert butylAnd (4) a base.
138. The method of claim 137, wherein X3Is isobutenyl, X5is-COOX10，R10aIs ethyl and X10Is a tert-butyl group.
139. The method of claim 132, wherein X3Is 2-furyl or 2-thienyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
140. The method of claim 132, wherein X3Is phenyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
141. A method of inhibiting tumor growth in a mammal, the method comprising orally administering a therapeutically effective amount of a composition comprising the taxane of claim 92 and at least one pharmaceutically acceptable carrier.
CNA011424087A 2001-08-06 2001-08-06 C10 ester carbonate substituted taxadane Pending CN1491947A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
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

Cited By (1)

* Cited by examiner, † Cited by third party
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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