HK1053472B - C10 carbonate substituted taxanes as antitumor agents - Google Patents
C10 carbonate substituted taxanes as antitumor agents Download PDFInfo
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Description
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:
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:
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):
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 R is in one embodiment of the invention9When 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)9bOC (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 group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, 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), butylA radical (linear, branched or cyclic), a pentyl radical (linear, branched or cyclic), or a hexyl radical (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) substituted or 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, R10aIs substituted 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, alkoxyAlkenyloxy, alkynyloxy, aryloxy, hydroxy, protected hydroxy, 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. Examples of preferred X5 substituents include-COX10，-COOX10or-CONX10Wherein 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 heterocyclic, alkoxy, alkenyloxy, alkyneOxy, aryloxy, hydroxyl, protected hydroxyl, 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):
wherein the content of the first and second substances,
R7is a hydroxyl group, and the 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, still more preferably a substituted or unsubstituted methyl, ethyl group, and 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 embodiment6Is selected from-COX10Wherein X is10Is phenyl, alkyl or heterocyclyl, more preferably phenyl. Alternatively, 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. In a more preferred embodiment, the taxane corresponding to 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.
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 a benzoyl group, an alkoxycarbonyl group, or a heterocyclylcarbonyl group, more 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 embodimentIn, 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 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 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.
Similarly, in taxane corresponding toIn a preferred embodiment of 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, 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 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 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 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 heterocyclylcarbonylMore preferably a benzoyl group, a tert-butoxycarbonyl group, or a tert-pentyloxycarbonyl group, still more preferably a tert-butoxycarbonyl group; 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, 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, 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 stereochemistryType, 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):
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:
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 adding a buffer at pH 8 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, in Reminciton’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 medicine 7 (7)Modern 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-dimethylacetamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidone, acetates such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl octanoate 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-derived PEG esters such as PEG-hydroxyoleate, and PEG-hydroxystearate, N-methylpyrrolidone, glycerol monostearate, and mixtures thereofPluronic 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., mixtures of saturated fatty acids such as caprylic acid, lauric acid, myristic acid, palmitic acid, and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid, and linoleic acid), 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 (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,hydrocarbons based on mixed aliphatic and aromatic 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 germ oil, sesame oil and peanut oil, and glycerides such as mono-, di-, tri-glycerides, animal oils such as fish oil, 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 essence; 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), handbook of pharmaceutical excipients (seeThe 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 prescriptions 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., 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: bioavailability of antitumor compounds, disorders to be treated, treatments in need thereofThe amount of treatment, 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 composition for parenteral administration is formulated by containing at least 20mg of the anti-neoplastic compound per square meter of the 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 the patient's body surface area in a single dose. 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 solution 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. 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 desired, the above emulsions or solutions for oral or parenteral administration 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 2 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 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 6 to 12 carbon atoms in the ring, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl. Phenyl and substituted phenyl are 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 acetyl; "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-furanylcarbonyl; "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 ℃ under 0.941 g (1.73 mmol) of 10-deacetylbaccatin III and 0.043 g (0.17 mmol) of 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 H13), 4.44(dd, J ═ 6.84, 10.37Hz, 1H, H7), 4.27(d, J ═ 8.27Hz, 1H, H20 α), 4.16 (J ═ 7.00, H, J ═ 2H, H2 Hz, H7), 4.00 (q ═ 7.00)3-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-).
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 are 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 nitrogen. 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 with 50 ml of ethyl acetate for 3 mm. 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-ethoxycarbonyl-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. Purifying the crude product by silica gel flash column chromatographyElution with 70% ethyl acetate/hexanes provided 0.411 g (100%) of 3 '-desmphenyl-3' - (2-thienyl) -10-ethoxycarbonyl-10-deacetyltaxotere (taxotere) as a solid.
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)
| i proton | δ(ppm) | Peak shape | J(Hz) |
| 1OH | 1.68 | s | |
| 2 | 5.68 | d | H3(7.0) |
| 3 | 3.80 | d | H3(7.0) |
| 4Ac | 2.38 | s | |
| 5 | 4.95 | dd | H6β(2.0)，H6β(9.8) |
| 6α | 2.56 | ddd | H7(6.6)，H5(9.8)，H6β(14.65) |
| 6β | 1.89 | ddd | H5(2.0)，H7(10.9)，H6α(14.65) |
| 7 | 4.40 | ddd | C7OH(4.2)，H6α(6.6)，H6β(10.9) |
| 7OH | 2.50 | d | H7(4.2) |
| 10 | 6.12 | s | |
| 13 | 6.25 | t | H14α(9.1)，H14β(9.1) |
| 14α | 2.35 | dd | H13(9.1)，H14β(14.2) |
| 14β | 2.34 | dd | H13(9.1)，H14α(14.2) |
| 16Me | 1.17 | s | |
| 17Me | 1.26 | s | |
| 18Me | 1.90 | s | |
| 19Me | 1.70 | s | |
| 20α | 4.31 | d | H20β(8.6) |
| 20β | 4.19 | d | H20α(8.6) |
| 2′ | 4.64 | dd | C2′OH(5.5)，H3′(2.0) |
| 2′OH | 3.38 | d | H3′(5.5) |
| 3′ | 5.51 | brd | NH(9.5) |
| NH | 5.28 | d | H3′(9.5) |
| 3' (2-thienyl), H3 ″ | 7.29 | dd | 3 '(2-thienyl), H5' (1.1), 3 '(2-thienyl), H3' (5.1) |
| 3' (2-thienyl), H4 ″ | 7.02 | dd | 3 '(2-thienyl), H5' (3.6), 3 '(2-thienyl), H3' (5.1) |
| 3' (2-thienyl), H5 ″ | 7.09 | d | 3 '(2-thienyl), H4' (3.6) |
| Boc | 1.34 | s | |
| Benzoic 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 unsubstituted 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 substituent may be a group as defined above, or may be a substituted hydrocarbon group. For example, R10Can be R10aOCOO-where R10aIs methyl, ethyl, or linear, branched or cyclic propyl.
| 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- | CyclopentanBase of | 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-furyl radical | 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- |
| i8uOCO- | 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 | Cyclobutyl radical | 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- | Benzene and its derivativesBase of | 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 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 unsubstituted, 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., t-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. Preference is given toOr heterocyclyl is substituted or unsubstituted furyl, thienyl or pyridyl, 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, thienyl, 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) of (a) may be a hydroxyl group or any heteroatom containing substituent selected from the group consisting of heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, aryloxy group, hydroxyl group, protected hydroxyl group, keto group, acyloxy group, nitro group, amino group, amide group, mercapto group, ketal group, acetal group, ester group and ether group, but is not a phosphorus containing substituent.
| 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 substitutedC2-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 | Optionally 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 | Optionally substituted 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 | Optionally substituted 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 ringsBase of | 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 | ＜10 |
| 3155 | ＜1 |
| 3181 | ＜1 |
| 3243 | ＜1 |
| 3300 | ＜10 |
| 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 Gremophor * 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.
Claims (108)
1. A taxane having the formula:
wherein:
R2is C1-20An acyloxy group;
R7is a hydroxyl group;
R9is keto, hydroxy, or C1-20An acyloxy group;
R10is a carbonate;
R14is hydrogen or hydroxy;
X3is a heterocyclic group;
X5is-COX10，-COOX10or-CONHX10；
X10Is substituted or unsubstituted C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl or phenyl, the substituents being selected from halogen, heterocyclyl, C1-8Alkoxy radical, C2-8Alkenyloxy radical, C2-8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-20Acyl radical, C1-20Acyloxy, nitro, amino, C1-20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, the aromatic group being an unsubstituted or substituted monocyclic or bicyclic carbocyclic aromatic group containing 6 to 12 carbon atoms in the ring; or X10Is a heterocyclic group; and is
Ac is an acetyl group, and the content of Ac is,
said heterocyclyl group is an unsubstituted or substituted, fully saturated or unsaturated, monocyclic or bicyclic aromatic or nonaromatic radical having at least one heteroatom in at least one ring and 5 or 6 atoms in each ring, the substituents of said heterocyclyl group being selected from C1-C20Hydrocarbyl, substituted C1-C20Hydrocarbyl, keto, hydroxy, protected hydroxy, C1-20Acyl radical, C1-20Acyloxy, C1-8Alkoxy radical, C2-8Alkenyloxy radical, C2-8Alkynyloxy, aryloxy, halogen, C1-20Amide groups, amino groups, nitro groups, cyano groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
2. The taxane of claim 1 wherein R10Is R10aOCOO-, and R10aIs substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, oxo,C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
3. The taxane of claim 2 wherein X3Is furyl, thienyl or pyridyl.
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 or pyridyl.
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 or pyridyl.
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 or 4-pyridyl.
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 or 4-pyridyl.
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 or 4-pyridyl.
19. The taxane of claim 17 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
20. Violet according to claim 2A taxane of which 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 or 4-pyridyl.
22. The taxane of claim 20 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
23. The taxane of claim 1 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 or 4-pyridyl.
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 or 4-pyridyl.
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 or 4-pyridyl.
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 or 4-pyridyl.
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 X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
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 or 4-pyridyl.
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 or 4-pyridyl.
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 or 4-pyridyl.
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 or 4-pyridyl.
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 R2Is benzoyloxy.
51. The taxane of claim 50 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
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, and 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 or 4-pyridyl.
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 or 4-pyridyl.
58. A taxane having the formula:
wherein:
R2is benzoyloxy;
R7is a hydroxyl group;
R10is R10aOCOO-；
X3Is a heterocyclic group;
X5is-COX10，-COOX10or-CONHX10；
X10Is substituted or unsubstituted C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl or phenyl, the substituents being selected from halogen, heterocyclyl, C1-8Alkoxy radical, C2-8Alkenyloxy radical, C2-8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-20Acyl radical, C1-20Acyloxy, nitro, amino, C1-20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or X10Is a heterocycle, said aryl group being an unsubstituted or substituted monocyclic or bicyclic carbocyclic aryl group containing from 6 to 12 carbon atoms in the ring; and is
R10aIs C1-20Hydrocarbyl, substituted C1-20A hydrocarbon group, the substituent being selected from the group consisting of halogen, heterocyclic group, C1-8Alkoxy radical, C2-8Alkenyloxy radical, C2-8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-20Acyl radical, C1-20Acyloxy, nitro, amino, C1-20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or R10aIs a heterocyclic group; and is
Ac is an acetyl group, and the content of Ac is,
said heterocyclyl group is an unsubstituted or substituted, fully saturated or unsaturated, monocyclic or bicyclic aromatic or nonaromatic radical having at least one heteroatom in at least one ring and 5 or 6 atoms in each ring, the substituents of said heterocyclyl group being selected from C1-C20Hydrocarbyl, substituted C1-C20Hydrocarbyl, keto, hydroxy, protected hydroxy, C1-20Acyl radical, C1-20Acyloxy, C1-8Alkoxy radical, C2-8Alkenyloxy radical, C2-8Alkynyloxy, aryloxy, halogen, C1-20Amide groups, amino groups, nitro groups, cyano groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
59. The taxane of claim 58 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
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, the substituent is selected from C1-C20Hydrocarbyl, halogen, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or X10Is 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, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
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 R10Is methyl or ethyl.
65. The taxane of claim 64 wherein X3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
66. The taxane of claim 65 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, the substituent is selected from C1-C20Hydrocarbyl, halogen, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or X10Is 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, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
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, the substituent is selected from C1-C20Hydrocarbyl, halogen, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or X10Is 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, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
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 pyridyl group.
72. The taxane of claim 71 wherein X5is-COX10And X10Is substituted or unsubstituted phenyl, the substituent is selected from C1-C20Hydrocarbyl, halogen, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or X10Is 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, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
73. The taxane of claim 71 wherein X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
74. The taxane of claim 58 wherein X3 is furyl or thienyl, R10aIs ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
75. The taxane of claim 58 wherein X3Is 2-furyl or 2-thienyl, R10aIs ethyl, and X5is-COOX10And X10Is a tert-butyl group.
76. The taxane of claim 58 wherein X3Is pyridyl, R10aIs methyl or ethyl，X5is-COOX10And X10Is a tert-butyl group.
77. A pharmaceutical composition comprising a taxane according to claim 1 and at least one pharmaceutically acceptable, inert or physiologically active diluent or adjuvant.
78. The pharmaceutical composition of claim 77, wherein X of the taxane is3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
79. The pharmaceutical composition of claim 78 wherein X of the taxane is5is-COX10And X10Is substituted or unsubstituted phenyl, and the substituent is selected from alkyl, halogen and C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or X10Is 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, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
80. The pharmaceutical composition of claim 78 wherein X of the taxane is5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
81. The pharmaceutical composition of claim 77, wherein R of the taxane is10aIs methyl, ethyl or propyl.
82. The pharmaceutical composition of claim 81 wherein X of the taxane is3Is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
83. The pharmaceutical composition of claim 82, wherein X of the taxane is5is-COX10And X10Is substituted or unsubstituted phenyl, and the substituent is selected from alkyl, halogen and C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups, or X10Is 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, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy radicalNitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
84. The pharmaceutical composition of claim 82, wherein X of the taxane is5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
85. The pharmaceutical composition of claim 78 wherein X of the taxane is3Is 2-furyl, 3-furyl, 2-thienyl or 3-thienyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
86. The pharmaceutical composition of claim 78 wherein X of the taxane is3Is 2-furyl or 3-furyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
87. The pharmaceutical composition of claim 78 wherein X of the taxane is3Is 2-thienyl or 3-thienyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
88. The pharmaceutical composition of claim 78 wherein X of the taxane is3Is 2-pyridyl, 3-pyridyl or 4-pyridyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
89. The pharmaceutical composition of claim 78Wherein X of taxane3Is 2-furyl or 2-thienyl, R10aIs methyl, X5is-COOX10And X10Is a tert-butyl group.
90. The pharmaceutical composition of claim 78 wherein X of the taxane is3Is 2-furyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
91. The pharmaceutical composition of claim 78 wherein X of the taxane is3Is 2-thienyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
92. A pharmaceutical composition comprising the taxane of claim 58 and at least one pharmaceutically acceptable, inert or physiologically active diluent or adjuvant.
93. A pharmaceutical composition comprising the taxane of claim 61 and at least one pharmaceutically acceptable, inert or physiologically active diluent or adjuvant.
94. A composition for oral administration comprising the taxane of claim 1 and at least one pharmaceutically acceptable carrier.
95. The composition of claim 94 wherein R of the taxane is10Is R10aOCOO-, and X10aIs substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20Acyl radical, C1-C20Acyloxy, nitro, amino, C1-C20Amides of carboxylic acidsRadicals, nitrile groups, mercapto groups, ketals, acetals, ester groups and ether groups.
96. The composition of claim 95 wherein X of the taxane is3Is phenyl, isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
97. The composition of claim 96, wherein X of the taxane is5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
98. The composition of claim 97 wherein R of the taxane10aIs methyl, ethyl or propyl.
99. The composition of claim 98 wherein X of the taxane is3Is 2-pyridyl, 3-pyridyl or 4-pyridyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
100. The composition of claim 99 wherein X of the taxane is3Is 2-furyl or 2-thienyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
101. A pharmaceutical composition comprising the taxane of claim 8 and at least one pharmaceutically acceptable carrier.
102. Use of a composition comprising the taxane of claim 1 and at least one pharmaceutically acceptable carrier in the manufacture of a medicament for inhibiting tumor development in a mammal.
103. The use of claim 102, which isR of taxane10Is R10aOCOO-, and X10aIs substituted or unsubstituted C1-C8Alkyl radical, C2-C8Alkenyl or C2-C8Alkynyl, said substituents being selected from halogen, heterocyclyl, C1-C8Alkoxy radical, C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, aryloxy, hydroxy, protected hydroxy, keto, C1-C20 acyl group, C1-C20Acyloxy, nitro, amino, C1-C20Amide groups, nitrile groups, mercapto groups, ketals, acetals, ester groups, and ether groups.
104. The use of claim 103, wherein X of the taxane is3Is phenyl, isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
105. The use of claim 104, wherein X of the taxane is5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
106. The use of claim 105, wherein R of the taxane10aIs methyl, ethyl or propyl.
107. The use of claim 106, wherein X of the taxane is3Is 2-pyridyl, 3-pyridyl or 4-pyridyl, R10aIs methyl or ethyl, and X5is-COX10And X10Is phenyl, or X5is-COOX10And X10Is a tert-butyl group.
108. The use of claim 102, wherein X3 of the taxane is 2-furyl or 2-thienyl, R10aIs ethyl, X5is-COOX10And X10Is a tert-butyl group.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17968400P | 2000-02-02 | 2000-02-02 | |
| US60/179,684 | 2000-02-02 | ||
| PCT/US2001/003588 WO2001057031A1 (en) | 2000-02-02 | 2001-02-02 | C10 carbonate substituted taxanes as antitumor agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1053472A1 HK1053472A1 (en) | 2003-10-24 |
| HK1053472B true HK1053472B (en) | 2005-05-13 |
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