KR20030012507A - C10 Carbonate Substituted Taxanes - Google Patents

Abstract

PURPOSE: C10 carbonate substituted taxane is provided which characteristically shows improved antitumor activity. CONSTITUTION: C10 carbonate substituted taxane having the formula 1 are provided, wherein R2 is acyloxy; R7 is hydroxy; R9 is keto, hydroxy or acyloxy; R10 is carbonate; R14 is hydrido or hydroxy; X3 is substituted or unsubstituted alkyl wherein alkyl contains 2 or more carbons, alkenyl, alkynyl, or heterocyclo; X5 is -COX10, -COOX10 or -CONHX10, wherein X10 is hydrocarbyl, substituted hydrocarbyl or heterocyclo; and Ac is acetyl.

Description

C10 Carbonate Substituted Taxanes

The present invention relates to novel taxanes with unexpected utility as antitumor agents.

Taxane compounds of terpenes, including baccatin III and taxol, have been of considerable interest in the biology and chemistry fields. Taxol is itself used as a chemotherapeutic agent for cancer and has a wide range of tumor suppressor activity. Taxol has a 2R, 3S configuration, and the structural formula is:

Wherein Ac is acetyl

Colin et al. Reported in US Pat. No. 4,814,470 that certain taxol analogs have significantly higher activity than taxol. One of these analogs, a compound called docetaxel, has the following structural formula:

Taxol and docetaxel are also useful as chemotherapeutic agents, but when administered in varying amounts, there are limitations in terms of effectiveness, such as limited efficacy for certain types of cancer and toxicity to patients.

Thus, there remains a need for another chemotherapeutic agent with improved efficacy and reduced toxicity.

Accordingly, it is an object of the present invention to provide taxanes comparable to Taxol and docetaxel in terms of efficacy and toxicity as antitumor agents. In general, the taxanes of the present invention are carbonates at the C-10 position, hydroxy substituents at C (7), and a range of C (2), C (9), C (14), and C (13). Side chain substituents.

Thus, briefly described, the present invention relates to pharmaceutical compositions comprising the taxane compound itself, taxanes and pharmaceutically acceptable carriers, and methods of administration thereof.

Some of the other objects and features of the present invention will be apparent, and some will be pointed out herein below.

In one embodiment of the invention, the taxanes of the invention correspond to the structure of formula (1).

Where

R ₂ is acyloxy,

R ₇ is hydroxy,

R ₉ is keto, hydroxy or acyloxy,

R ₁₀ is carbonate,

R ₁₄ is hydrido or hydroxy,

X ₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo, wherein alkyl comprises at least two carbon atoms,

X ₅ is -COX ₁₀ , -COOX ₁₀ or -CONHX ₁₀ , wherein X ₁₀ is hydrocarbyl, substituted hydrocarbyl or heterocyclo,

Ac is acetyl,

R ₇ , R ₉ and R ₁₀ independently have alpha or beta stereoisomer configuration.

In one embodiment, R ₂ is an ester (R _2a C (O) O—), carbamate (R _2a R _2b NC (O) O—), carbonate (R _2a OC (O) O—) or Thiocarbamate (R _2a SC (O) O—), wherein R _2a and R _2b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, R ₂ is an ester (R _2a C (O) O—), wherein R _2a is an aryl or heteroaromatic group. In another preferred embodiment, R ₂ is an ester (R _2a C (O) O—), wherein R _2a is substituted or unsubstituted phenyl, furyl, thienyl or pyridyl. In one particularly preferred embodiment, R ₂ is benzoyloxy.

In one embodiment R ₉ is a keto, but in other embodiments R ₉ may have an alpha or beta stereoisomeric configuration (beta stereoisomer configuration is preferred) and may be, for example, -hydroxy or -acyloxy. . For example, when R ₉ is acyloxy, it is an ester (R _9a C (O) O-), carbamate (R _9a R _9b NC (O) O-), carbonate (R _9a OC (O ) O-) or thiocarbamate (R _9a SC (O) O-), wherein R _9a and R _9b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. When R ₉ is an ester (R _9a C (O) O—), R _9a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaromatic group. More preferably, R ₉ is an ester (R _9a C (O) O—) wherein R _9a is substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyri It's a deal. In one embodiment, R ₉ is (R _9a C (O) O—) wherein R _9a is methyl, ethyl, propyl (straight, branched or cyclic) butyl (straight, branched or cyclic), pentyl (Straight chain, branched or cyclic), or hexyl (straight chain, branched or cyclic). In another embodiment, R ₉ is (R _9a C (O) O—) wherein R _9a is substituted methyl, substituted ethyl, substituted propyl (straight, branched or cyclic), substituted butyl ( Straight, branched or cyclic), substituted pentyl (straight, branched or cyclic) or substituted hexyl (straight, branched or cyclic), wherein the substituent (s) are heterocyclo, alkoxy, alkenoxy , Alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether residues, but not phosphorus containing residues.

In one embodiment, R ₁₀ is R _10a OCOO-, wherein R _10a is (i) substituted or unsubstituted C ₁ to C ₈ alkyl such as methyl, ethyl, propyl, butyl, pentyl or hexyl (linear, branched or Cyclic), (ii) substituted or unsubstituted C ₂ to C ₈ alkenyl (linear, branched or cyclic) such as ethenyl, propenyl, butenyl, pentenyl or hexenyl, (iii) ethynyl, Substituted or unsubstituted C ₂ to C ₈ alkynyl (straight or branched), (iv) substituted or unsubstituted phenyl, such as propynyl, butynyl, pentynyl or hexynyl, or (v) furyl, thienyl or pyri Substituted or unsubstituted heterocyclo groups such as dill. Substituents may be hydrocarbyl or heteroatom containing substituents as shown for hydrocarbyl substituted in any other part of this specification. In a preferred embodiment, R _10a is methyl, ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl Or thienyl. In another embodiment, R _10a is substituted ethyl, substituted propyl (straight, branched or cyclic), substituted propenyl (straight or branched), substituted isobutenyl, substituted furyl or substituted thienyl Wherein the substituent (s) are heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and Although selected from the group consisting of ether moieties, it is not a phosphorus containing moiety.

Examples of X ₃ substituents include substituted or unsubstituted C ₂ to C ₈ alkyl, substituted or unsubstituted C ₂ to C ₈ alkenyl, substituted or unsubstituted C ₂ to C ₈ alkynyl, 5 or 6 membered ring atoms Substituted or unsubstituted heteroaromatic groups, and substituted or unsubstituted phenyl. Preferred examples of X ₃ substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl and pyridyl.

Examples of X ₅ substituents include -COX ₁₀ , -COOX ₁₀ or -CONHX ₁₀ , wherein X ₁₀ is a substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic group. Preferred examples of X ₅ substituents include -COX ₁₀ , -COOX ₁₀ or -CONHX ₁₀ , wherein X ₁₀ represents (i) substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl ( Substituted or unsubstituted C ₁ to C ₈ alkyl, such as straight chain, branched or cyclic), pentyl (straight, branched or cyclic) or hexyl (straight, branched or cyclic), (ii) substituted or unsubstituted Ethenyl, propenyl (straight, branched or cyclic), butenyl (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched or cyclic) Substituted or unsubstituted C ₂ to C ₈ alkenyl, such as (iii) substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched) or hexynyl (straight or branched), substituted or unsubstituted C ₂ to C ₈ alkynyl, (iv) substituted or unsubstituted phenyl, or (v), such as pu Substituted or unsubstituted heteroaromatic groups, such as thienyl or pyridyl, wherein the substituent (s) are heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy , Nitro, amino, amido, thiol, ketal, acetal, ester and ether residues, but not phosphorus containing residues.

In one embodiment, the taxanes of the invention correspond to the structure of formula (II):

Where

R ₇ is hydroxy,

R ₁₀ is carbonate,

X ₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms,

X ₅ is —COX ₁₀ , —COOX ₁₀ or —CONHX ₁₀ , wherein X ₁₀ is hydrocarbyl, substituted hydrocarbyl or heterocyclo.

For example, in a preferred embodiment where the taxane corresponds to the structure of Formula 2, R ₁₀ is R _10a OCOO—, where R _10a is substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl or hexyl, more preferred Preferably substituted or unsubstituted methyl, ethyl or propyl, even more preferably substituted or unsubstituted methyl, ethyl and most preferably unsubstituted methyl or ethyl. While R _7a is selected from the above groups, in one embodiment X ₃ is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably from substituted or unsubstituted alkenyl, phenyl or heterocyclo And even more preferably from substituted or unsubstituted phenyl or heterocyclo, most preferably heterocyclo such as furyl, thienyl or pyridyl. While R _10a and X ₃ are selected from the above groups, in one embodiment X ₅ is —COX ₁₀ (X ₁₀ is phenyl, alkyl or heterocyclo, more preferably phenyl). Or R _10a and X ₃ are selected from the above groups, while in one embodiment X ₅ is —COX ₁₀ (X ₁₀ is phenyl, alkyl or heterocyclo, more preferably phenyl), or —COOX ₁₀ (X ₁₀ is alkyl, preferably t-butyl). Thus, in a more preferred embodiment the taxane is (i) X ₅ is -COOX ₁₀ (X ₁₀ is t-butyl) or -COX ₁₀ (X ₁₀ is phenyl), and (ii) X ₃ is substituted or unsubstituted Cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl or pyridyl, even more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl and (iii) R _10a is unsubstituted methyl, ethyl or propyl, more preferably methyl or ethyl.

In a preferred embodiment the taxanes correspond to the structure of formula 1 or 2 wherein R ₁₀ is R _10a OCOO—, wherein R _10a is methyl. In this embodiment, X ₃ is preferably cycloalkyl, isobutenyl, or heterocyclo, more preferably heterocyclo, even more preferably furyl, thienyl or pyridyl; X ₅ is preferably benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, most preferably t-butoxycarbonyl . In one alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is hydroxy; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is hydroxy; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is acyloxy; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is acyloxy; R ₁₄ is hydrido. In each alternative to this embodiment, when the taxane has the structure of Formula 1, R ₇ and R ₁₀ may each have a beta stereoisomeric configuration, or each may have an alpha stereoisomeric configuration, or R ₇ may be alpha It may have a stereoisomeric configuration and R ₁₀ may have a beta stereoisomeric configuration, or R ₇ may have a beta stereoisomeric configuration and R ₁₀ may have an alpha stereoisomeric configuration.

Furthermore, in a preferred embodiment the taxanes correspond to the structure of formula 1 or 2 wherein R ₁₀ is R _10a OCOO- (where R _10a is ethyl). In this embodiment, X ₃ is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl (eg p-nitrophenyl) or heterocyclo, more preferably heterocyclo, even more preferably furyl , Thienyl or pyridyl; X ₅ is preferably benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is hydroxy; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is hydroxy; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is acyloxy; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is acyloxy; R ₁₄ is hydrido. In each alternative to this embodiment, when the taxane has the structure of Formula 1, R ₇ and R ₁₀ may each have a beta stereoisomeric configuration, or each may have an alpha stereoisomeric configuration, or R ₇ may be alpha It may have a stereoisomeric configuration and R ₁₀ may have a beta stereoisomeric configuration, or R ₇ may have a beta stereoisomeric configuration and R ₁₀ may have an alpha stereoisomeric configuration.

Furthermore, in a preferred embodiment the taxanes correspond to the structure of formula 1 or 2 wherein R ₁₀ is R _10a OCOO—, where R _10a is propyl. In this embodiment, X ₃ is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl (eg p-nitrophenyl) or heterocyclo, more preferably heterocyclo, even more preferably furyl , Thienyl or pyridyl; X ₅ is preferably benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is keto; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is hydroxy; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is hydroxy; R ₁₄ is hydrido. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is acyloxy; R ₁₄ is hydroxy. In another alternative to this embodiment, X ₃ is heterocyclo; X ₅ is benzoyl, alkoxycarbonyl or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, even more preferably t-butoxycarbonyl; R ₂ is benzoyl; R ₉ is acyloxy; R ₁₄ is hydrido. In each alternative to this embodiment, when the taxane has a structure of Formula 1, R ₇ and R ₁₀ may each have a beta stereoisomer configuration, or each may have an alpha stereoisomer configuration, or R ₇ may be alpha It may have a stereoisomeric configuration and R ₁₀ may have a beta stereoisomeric configuration, or R ₇ may have a beta stereoisomeric configuration and R ₁₀ may have an alpha stereoisomeric configuration.

Taxanes of general formula (1) are treated with β-lactams with alkoxides having a taxane tetracyclic nucleus and C-13 metallic oxide substituents to give compounds having β-amido ester substituents at C-13 (Holton, U.S. Pat. 5,466,834), which can be obtained by removing hydroxy protecting groups. The β-lactam has a structure of Formula 3, and the alkoxide has a structure of Formula 4.

Wherein P ₂ is a hydroxy protecting group and X ₃ and X ₅ are as defined above

Wherein M is a metal or ammonium, P ₇ is a hydroxy protecting group and R ₁₀ is as defined above.

Alkoxides protect C-7 hydroxyl groups after the selective carbonate formation of C-10 hydroxyl groups from 10-deacetylbaccatin III (see PCT Patent Application WO 99/09021 to Holton et al. Described in detail), and may be prepared by treating with a metallic amide. Acylating agents usable for the selective acylation of C (10) hydroxyl groups of taxanes include dimethyldicarbonate, diethyldicarbonate, di-t-butyldicarbonate, dibenzyldicarbonate, and the like. Acylation of the C (10) hydroxy group of the taxanes is carried out at a suitable rate for many acylating agents, but it has been found that the reaction rate can be increased if the Lewis acid is included in the reaction mixture. Preferred as Lewis acids are zinc chloride, stannous chloride, cerium trichloride, cuprous chloride, lanthanum trichloride, dysprosium trichloride and ytterbium trichloride. When the acylating agent is dicarbonate, zinc chloride or cerium trichloride is most preferred.

Derivatives of 10-deacetylbaccatin III having alternative substituents to C (2), C (9) and C (14), and methods for their preparation are known in the art. Taxane derivatives having an acyloxy substituent other than benzoyloxy in C (2) may be prepared, for example, as described in US Pat. No. 5,728,725 to Holton et al. Or US Pat. No. 6,002,023 to Kingston et al. Can be. Taxanes having acyloxy or hydroxy substituents in place of keto in C (9) may be prepared, for example, as described in US Pat. No. 6,011,056 to Holton et al. Or US Pat. No. 5,352,806 to Gunawardana et al. Can be. Taxanes with beta hydroxy substituents on C (14) can be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.

Processes for the preparation and separation of β-lactam starting materials are usually well known. For example, β-lactam can be prepared as described in Holton's US Pat. No. 5,430,160, and the enantiomeric mixture of the resulting β-lactam is a lipase, an enzyme (e.g. Patel's U.S. Pat. 5,879,929 and Patel's US Pat. No. 5,567,614), or by stereoselective hydrolysis using liver homogenates (e.g., described in PCT Patent Application 00/41204). In a preferred embodiment where β-lactam is substituted with furyl at position C (4), β-lactam can be prepared as illustrated in the following scheme:

Wherein Ac is acetyl, NEt ₃ is triethylamine, CAN is ceric ammonium nitrate, and p-TsOH is p-toluenesulfonic acid

Separation using bovine livers is accomplished by, for example, enantiomeric mixtures of β-lactams with a suspension of bovine livers (20 g of frozen bovine liver added to the blender, followed by pH 8 buffer to 1 L total volume) and By mixing.

Formula 1 compounds of the present invention are useful for inhibiting tumor proliferation in mammals, including humans, preferably in an anti-tumorally effective amount of a compound of the present invention in combination with one or more pharmaceutically or pharmaceutically acceptable carriers. It is administered in the form of a pharmaceutical composition comprising. Such carriers, also known in the art as excipients, vehicles, adjuvants, adjuvant or diluents, are any pharmaceutically inert material, impart suitable density and form to the composition and should not reduce the therapeutic efficacy of antitumor compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if no side reactions, allergic reactions or other inappropriate reactions occur when administered to a mammal or human.

Pharmaceutical compositions containing the antitumor compounds of the present invention may be formulated in any manner conventional. Proper formulation will depend upon the route of administration chosen. The composition of the present invention may be suitably formulated for any route of administration so long as the drug can be delivered to the target tissue via the route of administration. Suitable routes of administration include oral administration, parenteral administration (e.g., intravenous, intraarterial, subcutaneous, rectal, intramuscular, orbital, intravesicular, intraspinal, intraperitoneal or intrasternal), topical administration (nasal, Transdermal, intraocular administration), intrathecal administration, intradural administration, intestinal administration, lung administration, lymphatic administration, intraluminal administration, vaginal administration, urethral administration, intradermal administration, ear administration, intramammary administration, oral administration orthotopic, intratracheal, intralesional, transdermal, endoscopic, transmucosal, sublingual and enteral administration.

Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those skilled in the art and include the type of specific antitumor compound used, and its concentration, stability and intended biocompatibility; The disease, disorder or condition to be treated with this composition; The patient, his age, weight and general symptoms; And the number of factors including the route of administration. Suitable carriers can be readily determined by one skilled in the art (JG Nairn, Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985, the contents of which are incorporated herein by reference). ), pp. 1492-1517).

Compositions of the invention are preferably tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, It is formulated as a tablet, dragee, lozenge or any other oral dosage form. Techniques for the preparation of oral dosage forms useful in the present invention and their compositions are described in 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979; Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); And Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

Compositions for oral administration of the present invention comprise an antitumorally effective amount of a compound of the present invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch Other conventional materials, including sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and stearic acid. In addition, such solid dosage forms may be uncoated or coated by known techniques to delay disintegration, absorption, and the like.

In addition, the anti-tumor compositions of the invention are preferably for parenteral administration, e.g., by intravenous, intraarterial, subcutaneous, rectal, intramuscular, orbital, intravesicular, intramedullary, intraperitoneal or intrasternal routes. It is formulated for injection via. Compositions for parenteral administration of the present invention comprise an antitumorally effective amount of a compound of the present invention in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersants, emulsions, or any other dosage form that can be administered parenterally. Techniques for preparing parenteral dosage forms and compositions thereof are known in the art.

Suitable carriers for use in formulating liquid dosage forms for oral or parenteral administration include non-aqueous and pharmaceutically acceptable polar solvents (e.g. oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof). In addition, water, saline solution, dextrose solution (eg DW5), electrolyte solution, or any other liquid that is aqueous and pharmaceutically acceptable.

Suitable non-aqueous and pharmaceutically acceptable polar solvents include alcohols such as α-glycerol formal, β-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms (methanol). , Ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycols, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol or Stearyl alcohol), fatty acid esters of fatty alcohols (polyalkylene glycols such as polypropylene glycol and polyethylene glycol, sorbitan, sucrose, and cholesterol); Amides [eg, dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N- (β-hydroxyethyl) -lactamide, N, N-dimethylacetamide_amide, 2-pyrroli Dinon, 1-methyl-2-pyrrolidinone or polyvinylpyrrolidone]; Esters [eg 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetic acid esters (monoacetin, diacetin and triacetin), aliphatic or aromatic esters (ethyl caprylate or octanoate) ), Alkyl oleate, benzyl benzoate, benzyl acetate, dimethyl sulfoxide (DMSO), esters of glycerine (mono-, di- or tri-glyceryl citrate or tartarate), ethyl benzoate, ethyl acetate, ethyl Carbonates, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, glyceryl monostearate, glyceride esters (mono-, di- or tri-glycerides), fatty acid esters (isopropyl myristate), fatty acid derived PEG esters (PEG-hydroxyoleate and PEG-hydroxystearate), N-methyl pyrrolidinone, Pluronic 60, polyoxyethylene sorbitol oleic acid Lee ester (poly (ethoxylated) _30-60 sorbitol poly (oleate) _2-4, poly (oxyethylene) _15-20 monooleate, poly (oxyethylene) _15-20 mono 12-hydroxy stearate, and poly (Oxyethylene) _15-20 monoricinoleate), polyethylene sorbitan ester (polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxy Ethylene-Sorbitan Monostearate, and Polysorbate® 20, 40, 60 or 80 (ICI Americas, Wilmington, DE), polyvinylpyrrolidone, alkenyleneoxy modified fatty acid esters (polyoxyl 40 hydrogenated beaver oils and polyoxyethylated beaver oils such as Cremophor® EL solution or Cremophor® RH 40 solution), saccharide fatty acid esters (ie, monosaccharides (ribose, Ribul) Ross, ah Pentasaccharides such as vinose, xylose, lyxose and xylose, hexasaccharides such as glucose, fructose, galactose, mannose and sorbose, trisaccharides, tetrasaccharides, saccharides, and octasaccharides, disaccharides (can Crude, maltose, lactose and trehalose) or oligosaccharides, or mixtures thereof and saturated fatty acids such as C ₄ to C ₂₂ fatty acids (caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid) And condensation products of palmitoleic acid, oleic acid, elic acid, erucic acid and linoleic acid), or steroid esters); Alkyl, aryl or cyclic ethers having 2 to 30 carbon atoms [eg, diethyl ether, tetrahydrofuran, dimethyl isosorbide and diethylene glycol monoethyl ether]; Glycofurol [tetrahydrofurfuryl alcohol polyethylene glycol ether]; Ketones having 3 to 30 carbon atoms (eg, acetone, methyl ethyl ketone and methyl isobutyl ketone); Aliphatic, cycloaliphatic or aromatic hydrocarbons having 4 to 30 carbon atoms [eg, benzene, cyclohexane, dichloromethane, dioxolane, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfone , Tetramethylene sulfoxide, toluene, or dimethyl sulfoxide (DMSO)]; Mineral oils such as mineral oils, vegetable oils, animal oils, perfumed or synthetic oils [eg, aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oils; Linseed oil, floating oil, safflower oil, soybean oil, castor oil, cottonseeds, peanut oil, rapeseed oil, coconut oil, palm oil, olive oil, corn oil, corn germ oil, sesame oil, peach seed oil and Vegetable oils such as peanut oil and glycerides such as mono-, di- or tri-glycerides; Animal oils such as fish oil, seafood oil, whale oil, cod liver oil, haliber, squalene, shark liver oil, oleic oil and polyoxyethylated beaver oil; Alkyl or aryl halides having 1 to 30 carbon atoms, optionally having one or more halogen substituents; Methylene chloride; Monoethanolamine; Petroleum benzine; Trolamine; Omega-3 polyunsaturated fatty acids [eg, alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid]; Polyglycol esters of 12-hydroxycetearic acid and polyethylene glycol (Solutol® HS-15 (BASF, Ludwigshafen, Germany)); Polyoxyethylene glycol; Sodium laurate; Sodium oleate; Or sorbitan monooleate, but is not limited thereto.

Pharmaceutically acceptable other solvents for use in the present invention are well known to those skilled in the art and include The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients (American Pharmaceutical Association, Washington, DC, and The Pharmaceutical). Society of Great Britain, London, England, 1968), Modern Pharmaceutics (G. Banker et al., Eds., 3d ed.) (Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics ( Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms (H. Lieberman et al., Eds.,) (Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed. , 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19 (National Publishing, Philadelphia, PA, 2000), AJ Spiegel et al., And Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, no. 10, pp. 917-927 (1963).

Preferred solvents include triglyceride-rich oils such as safflower oil, soybean oil or mixtures thereof, and polyoxyl 40 hydrogenated beaver oil and polyoxyethylated beaver oil (e.g. Cremophor® EL solution or Cremo Solvents known to stabilize anti-tumor compounds, such as alkyleneoxy modified fatty acid esters such as Fort® RH 40 solution). Commercially available triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid® emulsion (McGaw, Irvine, California), Lipo Lyposyn® II 20% emulsion (20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phospholipids and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), liposin 2% fat emulsion (2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phospholipid and 25 mg glycerin; Abbott Laboratories, Chicago, Illinois), based on total fatty acid content Natural or synthetic glycerol derivatives containing from 25% to 100% by weight of docosahexaenoyl groups (Dhasco, Martek Biosciences Corp., Columbia, MD), DHA Maguro®; Daito Enterprises, Los Angeles, CA) Include ahkal (Soyacal, registered trademark), and trafficking probe emulsion (Travemulsion, registered trademark)). Preferred solvent for dissolving the anti-tumor compound to form solutions, emulsions and the like is ethanol.

For various purposes well known in the pharmaceutical industry, additional trace ingredients can be included in the compositions of the present invention. Most of these components impart the property of improving the retention of the anti-tumor compound to the administered site, the property of protecting the stability of the composition, the property of adjusting the pH, and the property of promoting the processing of the anti-tumor compound into a pharmaceutical formulation. something to do. Each of these components is preferably present in less than about 15% by weight of the total composition, more preferably in less than about 5% by weight of the total composition, and most preferably in less than about 0.5% by weight of the total composition. . Some components, such as fillers or diluents, may be present up to 90% by weight of the total composition, as is well known in the pharmaceutical formulation art. Such additives include cryoprotectants, surfactants, wetting agents or emulsifiers (eg lecithin, polysorbate-80, Tween® 80, Pluronic 60, polyoxyethylene to prevent reprecipitation of taxanes). Stearates), preservatives (eg ethyl-p-hydroxybenzoate), microbial preservatives (eg benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and parabens), pH Adjuvants or buffers (eg, acid, base, sodium acetate, sorbitan monolaurate) for the adjustment, adjuvants (eg, glycerin) for the adjustment of the osmotic pressure, thickeners (eg, aluminum monostearate, Stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax ester, polyethylene glycol), colorant, dye, flow aid, nonvolatile silicone (E.g. cyclomethicone), clay (e.g. bentonite), adhesives, bulking agents, flavoring agents, sweeteners, absorbents, fillers (e.g. sugars such as lactose, sucrose, mannitol or sorbitol, cellulose, Or calcium phosphate), diluents (e.g., water, saline and electrolyte solutions), binders (e.g., starches such as corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth rubber, methyl cellulose, Starches such as hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers and acacia), disintegrants (e.g., starch such as corn starch, wheat starch, rice starch, potato starch or carboxymethyl starch, Crosslinked polyvinyl pyrrolidone, agar, salts such as alginic acid or sodium alginate, croscarmellose sodium, or crospovidone), lubricants (e.g., silica, talc, stearic acid) Or salts thereof such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions, including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide), and Antioxidants (eg, sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenol and thiophenol).

In a preferred embodiment, the pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable non-aqueous solvent, and an anti-tumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg / ml. It includes. Without wishing to be bound by any theory, it is believed that the solubility of the antitumor compound in ethanol is directly related to its efficacy. In addition, anti-tumor compounds can be crystallized from solution. That is, crystalline anti-tumor compounds, such as compound 1393, can be dissolved in a solvent to form a solution and then recrystallized without producing any amorphous anti-tumor compounds upon evaporation of the solvent. In addition, the ID50 value of the anti-tumor compound (ie, drug concentration that inhibits colony formation by 50%) is 4, 5, 6, 7, 8 as compared to paclitaxel as measured according to the procedures described in the Examples herein. It is preferred to be at least 9 or 10 times lower.

Dosage forms by this route may be continuous or intermittent, for example, depending on the physiological condition of the patient, whether the administration is for therapeutic or prophylactic purposes, and other factors known to the expert and evaluable by the expert.

The dosage and method of administration of the pharmaceutical compositions of the invention can be readily determined by one skilled in the art of treating cancer. It is understood that the dosage of the antitumor compound will vary depending on the age, sex, health condition and weight of the patient, the type of treatment (if any) involved, the frequency of treatment, and the nature of the desired effect. For any mode of administration, the amount of actual antitumor compound delivered, as well as the schedule of administration necessary to achieve the desired beneficial effect herein, will depend, in part, on the biocompatibility of the antitumor compound, the disease to be treated, the desired dosage, and the skilled person. It will depend on such factors as other obvious factors. In the present invention, the dosage administered to an animal (particularly a human) should be sufficient to allow for the desired therapeutic response in the animal over a suitable period of time. Preferably, whether oral or otherwise administered, an effective amount of an anti-tumor compound is any amount that can result in the desired therapeutic response when administered by that route. For oral administration the compounds are preferably, the patient's body surface area the amount of a single dose of a formulation for one or more orally 1 m ² per 20 mg or more Anti containing positive compounds, or body surface area 1 m ² per 50, 100 of the patient, It is prepared in such a way that it contains at least 150, 200, 300, 400 or 500 mg of antitumor compound (human average body surface area is 1.8 m ² ). Preferably, the single dose of the composition for oral administration contains about 20 to about 600 mg of the antitumor compound per m ² of body surface area of the patient, more preferably about 25 to about 400 mg / m ² , even more preferred Preferably about 40 to about 300 mg / m ² , most preferably about 50 to about 200 mg / m ² antitumor compound. Parenteral composition for administration is preferably, body surface area of the amount of a single dose patient 1 m ² per 20 mg or more containing the anti-tumor compound, or the patient's body surface area 1 m ² per 40, 50, 100, 150, 200, It is prepared in such a way that it contains at least 300, 400 or 500 mg of antitumor compound. Preferably, the single dosage of the one or more parenteral preparations contains from about 20 to about 500 mg of antitumor compound per m ² of body surface area of the patient, more preferably from about 40 to about 400 mg / m ² , Even more preferably, from about 60 to about 350 mg / m ² of antitumor compound. However, the dosage can vary depending on the dosing schedule, which can be adjusted as needed to achieve the desired therapeutic effect. It is to be understood that the range of effective dosages provided herein is not intended to limit the present invention and is intended to represent the range of preferred dosages. The most preferred dosage will vary for each patient, as can be understood and determined by one skilled in the art without unnecessary experimentation.

The concentration of antitumor compound in the liquid pharmaceutical composition is preferably from about 0.01 mg to about 10 mg per ml of composition, more preferably from about 0.1 mg / ml to about 7 mg / ml, even more preferably about 0.5 mg / ml to about 5 mg / ml, most preferably about 1.5 mg / ml to about 4 mg / ml. Since anti-tumor compounds have high solubility at low concentrations in solution, relatively low concentrations are generally preferred. The concentration of the anti-tumor compound in the solid pharmaceutical composition for oral administration is preferably about 5% to about 50% by weight, more preferably about 8% to about 40% by weight, most preferably based on the total weight of the composition Is between about 10% and about 30% by weight.

In one embodiment, solutions for oral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent (eg, ethanol or methylene chloride) capable of dissolving the anti-tumor compound to form a solution. A suitable volume of carrier in solution, such as Cremophor® EL solution, is added to the solution under agitation to produce a pharmaceutically acceptable solution that can be administered orally to the patient. If desired, such solutions may be formulated with or without a minimum amount of ethanol known in the art to cause physiological side effects when administered at a particular concentration in an oral formulation.

In another embodiment, powders or tablets for oral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent (eg, ethanol or methylene chloride) capable of dissolving the anti-tumor compound to form a solution. . This solvent can optionally be evaporated when the solution is dried under vacuum. Prior to drying, additional carriers such as Cremophor® EL solution can be added. The resulting solution is dried under vacuum to form a glass. This glass is mixed with a binder to form a powder. This powder may be mixed with fillers or other conventional tablet aids and then processed to form tablets for oral administration to a patient. The powder may also be added to a liquid carrier as described above to form solutions, emulsions or suspensions for oral administration.

Emulsions for parenteral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent (eg, ethanol or methylene chloride) capable of dissolving the anti-tumor compound to form a solution. A suitable volume of carrier in tangent, such as liposin® II or liposin® III emulsion, is added to the solution under stirring to produce a pharmaceutically acceptable emulsion that can be parenterally administered to a patient. If desired, such emulsions may be formulated with or without minimal amounts of ethanol or Cremophor® solutions known in the art to cause physiological side effects when administered at certain concentrations in parenteral formulations.

Solutions for parenteral administration are prepared by dissolving the compound in any pharmaceutically acceptable solvent (eg, ethanol or methylene chloride) capable of dissolving the anti-tumor compound to form a solution. A suitable volume of carrier in solution, such as a Cremophor® solution, is added to the solution under agitation to produce a pharmaceutically acceptable solution for parenteral administration to the patient. If desired, such solutions may be formulated with or without minimal amounts of ethanol or Cremophor® solutions known in the art to cause physiological side effects when administered at specific concentrations in parenteral formulations. .

If desired, the emulsions or solutions described above for oral or parenteral administration may be packaged in IV bags, vials or other conventional containers in diluted or concentrated form with any pharmaceutically acceptable liquid, such as saline, Allowable taxane concentrates can be formed in their pre-use state as known in the art.

<Definition>

As used herein, the terms "hydrocarbon" and "hydrocarbyl" refer to organic compounds or radicals consisting solely of carbon and hydrogen elements. Such residues include alkyl, alkenyl, alkynyl and aryl residues. These residues also include alkyl, alkenyl, alkynyl and aryl residues substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless stated otherwise, these moieties preferably comprise 1 to 20 carbon atoms.

A "substituted hydrocarbyl" moiety as described herein is a hydrocarbyl substituted with one or more non-carbon atoms, including moieties where the carbon chain atoms are substituted with heteroatoms such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms. Bill residues. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, cyano, thiol, ketal, acetal, Esters and ethers are included.

The term "heteroatom" refers to atoms other than carbon and hydrogen.

A "heterosubstituted methyl" moiety as described herein means a methyl group wherein the carbon atom is covalently bonded with one or more heteroatoms (which are nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms) and optionally hydrogen. In other words, heteroatoms are substituted with other atoms such as heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, Ester and ether moieties may be formed.

"Heterosubstituted acetate" residues described herein mean acetate groups in which the carbon atom is covalently bonded with one or more heteroatoms (which are nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms) and optionally hydrogen. In other words, heteroatoms are substituted with other atoms such as heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, Ester and ether moieties may be formed.

Unless stated otherwise, the alkyl groups described herein are preferably lower alkyls containing from 1 to 8 carbon atoms in the main chain and up to 20 carbon atoms. Alkyl groups may be straight, branched or cyclic, including methyl, ethyl, propyl, isopropyl, butyl and hexyl and the like.

Unless stated otherwise, the alkenyl groups described herein are preferably lower alkenyl containing from 2 to 8 carbon atoms in the main chain and containing up to 20 carbon atoms. Alkenyl groups may be straight, branched or cyclic, including ethenyl, propenyl, isopropenyl, butenyl, isobutenyl and hexenyl and the like.

Unless stated otherwise, the alkynyl groups described herein are preferably lower alkynyl containing from 2 to 8 carbon atoms in the main chain and containing up to 20 carbon atoms. Alkynyl groups can be straight or branched, including ethynyl, propynyl, butynyl, isobutynyl, hexenyl and the like.

As used herein, alone or as part of another group, the term “aryl” or “ar” refers to a monocyclic aromatic group which may be optionally substituted, preferably monocyclic containing 6 to 12 carbons in the ring portion. Or a bicyclic group (eg, phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl). Phenyl and substituted phenyl are more preferred aryls.

The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine and iodine.

As used herein, alone or as part of another group, the term “heterocyclo” or “heterocyclic” refers to one or more heteroatoms in one or more rings, preferably five or six heteroatoms in each ring. It means an aromatic or non-aromatic group in the monocyclic or bicyclic form of the optionally substituted and fully saturated or unsaturated state having Preferably the heterocyclo group has one or two oxygen atoms, one or two sulfur atoms and / or one to four nitrogen atoms in the ring and is bonded to the rest of the molecule via carbon or heteroatoms. Can be. Examples of heterocyclo include heteroaromatic groups such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl and isoquinolinyl and the like. Examples of substituents include hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, sia One or more substituents selected from the group consisting of furnaces, thiols, ketals, acetals, esters and ethers.

As used herein, alone or as part of another group, the term “heteroaromatic group” is optionally substituted with one or more heteroatoms in one ring, preferably five or six heteroatoms in each ring. It means an aromatic group which can be. Preferably the heteroaromatic group has one or two oxygen atoms, one or two sulfur atoms and / or one to four nitrogen atoms in the ring, and is bonded to the rest of the molecule via carbon or heteroatoms. Can be. Examples of heteroaromatic groups include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl and isoquinolinyl, and the like. Examples of substituents include hydrocarbyl, substituted hydrocarbyl, Group consisting of keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketal, acetal, ester and ether One or more substituents selected from are included.

As used herein, alone or as part of another group, the term "acyl" refers to RC (O)-, wherein R is R ¹ , R ¹ O-, R ¹ R ² N- or R ¹ S, and R ¹ Is hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclo, R ² is hydrogen, hydrocarbyl or substituted hydrocarbyl), formed by removing the hydroxyl group from the -COOH group of the organic carboxylic acid Means a residue.

As used herein, alone or as part of another group, the term “acyloxy” refers to an oxygen bond (—O—, such as RC (O) O—, where R is as defined with respect to the term “acyl”. Refers to an acyl group bound as described above).

Unless stated otherwise, alkoxycarbonyloxy residues described herein include lower hydrocarbons, substituted hydrocarbons or substituted hydrocarbon residues.

Unless stated otherwise, carbamoyloxy moieties described herein are carbamic acid derivatives in which one or two amine hydrogens may be optionally substituted by hydrocarbyl, substituted hydrocarbyl or heterocyclo moiety.

As used herein, the terms “hydroxyl protecting group” and “hydroxy protecting group” can protect (“protected hydroxyl”) free hydroxyl groups and do not interfere with the rest of the molecule after the reaction to which the protection is applied. Means a group that can be removed without For various protective groups on hydroxyl groups and their synthesis, see Protective Groups in Organic Synthesis, T.W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser. Examples of hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (beta-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t- Butyl (diphenyl) silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.

As used herein, "Ac" means acetyl and "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "iPr" means isopropyl; "tBu" and "t-Bu" refer to tertiary butyl; "R" means lower alkyl unless stated otherwise, and "Py" means pyridine or pyridyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "LAH" means lithium aluminum hydride; "10-DAB" means 10-desacetylbaccatin III; "Amine protecting group" includes, but is not limited to, carbamate, such as 2,2,2-trichloroethylcarbamate or t-butylcarbamate; "Protected hydroxy" means -OP (P is a hydroxy protecting group); "tBuOCO" and "Boc" mean t-butoxycarbonyl; "tAmOCO" means t-amyloxycarbonyl; "PhCO" refers to phenylcarbonyl; "2-FuCO" means 2-furylcarbonyl and "2-ThCO" means 2-thienylcarbonyl; "2-PyCO" refers to 2-pyridylcarbonyl; "3-PyCO" refers to 3-pyridylcarbonyl; "4-PyCO" refers to 4-pyridylcarbonyl; "C ₄ H ₇ CO" refers to butenylcarbonyl; "tC ₃ H ₅ CO" refers to trans-propenylcarbonyl; "EtOCO" means ethoxycarbonyl; "iBueCO" means isobutenylcarbonyl; "ibuCO" refers to isobutylcarbonyl; "iBuOCO" refers to isobutoxycarbonyl; "iPrOCO" refers to isopropyloxycarbonyl; "nPrOCO" refers to n-propyloxycarbonyl; "nPrCO" refers to n-propylcarbonyl; "ibue" means isobutenyl; "THF" means tetrahydrofuran; "DMAP" means 4-dimethylamino pyridine; "LHMDS" means lithium hexamethyldisilazanide.

The following examples illustrate the invention.

Example 1

10-ethoxycarbonyl10-deacetyl baccatin III . 0.64 mL (4.32 mmol) of diethyl pyrocarbonate was added to a mixture of 0.941 g (1.73 mmol) of 10-deacetyl baccatin III and 0.043 g (0.17 mmol) of CeCl ₃ in 40 mL of THF at 25 ° C. . After 3 hours, the reaction mixture was diluted with 200 mL of EtOAc, and then washed three times with 50 mL of a saturated NaHCO ₃ aqueous solution and brine. The organic extract was dried over Na ₂ S0 ₄ and concentrated in vacuo. The crude solid was purified by flash column chromatography on silica gel using 40% EtOAc / hexane as eluent, resulting in 0.960 g (90%) of 10-ethoxycarbonyl-10-deacetyl baccatin III. ) Was obtained in a solid state.

7-dimethylphenylsilyl-1-ethoxycarbonyl-10-deacetyl baccatin III. To a solution of 1.02 g (1.65 mmol) of 10-ethoxycarbonyl-10-deacetyl baccatin III in 30 mL of THF at -10 ° C. under nitrogen atmosphere, 0.668 mL (4.00 mmol) of chlorodimethylphenylsilane and 2.48 mL of pyridine (30.64 mmol) was added dropwise. After 90 minutes the mixture was diluted with 200 ml of a one to one mixture of ethyl acetate and hexanes. The mixture was washed with 30 ml of saturated aqueous sodium bicarbonate solution and the organic layer was isolated. The aqueous layer was extracted with 50 ml of a one-to-one mixture of ethyl acetate and hexanes, and the combined organic extracts were washed with brine, dried over NaSO ₄ and concentrated in vacuo. The crude solid was purified by flash column chromatography on silica gel using 30% EtOAc / hexane as eluent, resulting in 1.16 g of 7-dimethylphenylsilyl-10-ethoxycarbonyl-10-deacetyl baccatin III. 94%) was obtained as a solid.

¹ HNMR (400 MHz, CDCl ₃ ): δ 8.09 (dm, J = 7.64 Hz, 2H, benzoate, o), 7.59 (tt, J = 7.54, 1.43 Hz, 1H, benzoate, p), 7.57 (m, 2H, phenyl, o), 7.46 (t, J = 7.54 Hz, 2H, benzoate, m), 7.37-7.33 (m, 3H, phenyl, m, p), 6.21 (s, 1 H, H10), 5.63 (d, J = 7.05 Hz, 1 H, H2), 4.87-4.80 (m, 2H, H5 and H13), 4.44 (dd, J = 6.84, 10.37 Hz, 1 H, H7) , 4.27 (d, J = 8.27 Hz, 1H, H20α), 4.16 (qm, J = 7.00 Hz, 2H, CH ₃ -CH _2- ), 4.13 (d, J = 8.27 Hz, 1H, H20β) , 3.83 (d, J = 7.05 Hz, 1 H, H3), 2.34 (ddd, J = 6.84, 9.63, 14.66 Hz, 1 H, H6α), 2.26 (d, J = 7.65 Hz, 2 H, 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, 14.66 Hz, 1 H, H6β), 1.73 (s, 1H, Me19), 1.59 (s, 1H, C1OH), 1.32 (t, J = 7.00 Hz, 3H, CH ₃ -CH _2- ), 1.19 (s, 3 H, Me17), 1.07 (s, 3H, Me16), 0.45 (s, 3H, PhMe ₂ Si-), 0.35 (s, 3H, PhMe ₂ Si-).

7-dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3 '-(2-thienyl) -10-ethoxycarbonyl-10-deacetyl-taxotel. 0.681 mL (0.681 m) of a solution of LHMDS 1M in THF in 0.409 g (0.544 mmol) of 7-dimethylphenylsilyl-10-ethoxycarbonyl-10-deacetyl baccatin III in 5.5 mL of THF at -45 ° C under nitrogen atmosphere. Mol) was added. After 1 hour a solution of 0.317 g (0.818 mmol) of cis-N-benzoyl-3-triethylsilyloxy-4- (2-thienyl) azetidin-2-one in 3 mL THF was slowly added. The mixture was warmed to 0 ° C., after 3 h 10 ml of saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with 50 ml of ethyl acetate. The combined 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 using 40% EtOAc / hexane as eluent, resulting in 7-dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3 '. 0.574 g (93%) of-(2-thienyl) -10-ethoxycarbonyl-10-deacetyl-taxotel was obtained in the solid state.

3'-desphenyl-3 '-(2-thienyl) -10-ethoxycarbonyl-10-deacetyl taxotel. 7-dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3 '-(2-thienyl) -10-ethoxycarbonyl in 2 ml of pyridine and 2 ml of CH ₃ CN at 0 ° C. To a solution of 0.527 g (0.464 mmol) of -10-deacetyl taxotel was added 0.5 ml of an aqueous 30% HF solution. After 3 hours, 20 ml of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 70% EtOAc / hexane as eluent, resulting in 3'-desphenyl-3 '-(2-thienyl) -10-ethoxycarbonyl- 0.411 g (100%) of 10-deacetyl taxotel was obtained as a solid.

3'-desphenyl-3 '-(2-thienyl) -10-ethoxycarbonyl-10-deacetyl

Taxotel ^One H NMR data

(500 NHz CDCl ₃ )

Example 2

Although the procedure described in Example 1 was repeated, the β-lactam of Example 1 was substituted with another suitable protected β-lactam to prepare a series of compounds having a combination of substituents as defined in Formula 13 below and in the table below.

Example 3

According to the method described in Example 1 and elsewhere herein, R ₁₀ comprises R _10a OCOO— as defined above and R _10a is (i) methyl, ethyl, or a straight, branched or cyclic profile, Substituted or unsubstituted C ₁ to C ₈ alkyl such as butyl, pentyl or hexyl, (ii) propenyl or substituted or unsubstituted C ₃ to C such as straight, branched or cyclic butenyl, pentenyl or hexenyl ₈ alkenyl, (iii) propynyl, or substituted or unsubstituted C ₃ to C ₈ alkynyl, such as straight or branched butynyl, pentynyl or hexynyl, (iv) substituted or unsubstituted phenyl, or (v) Specific taxanes having the structure of formula (14) below may be prepared with a substituted or unsubstituted heteroaromatic group such as pyridyl. These substituents may be those defined herein for substituted hydrocarbyl. For example, R ₁₀ may be R _10a OCOO—, wherein R _10a is methyl, ethyl or straight, branched or cyclic propyl.

Example 4

Example 1 and was prepared according to the procedure described in other parts of the present application, in each series (that is, the series "A" through "K") R ₇ is hydroxy, R ₁₀ is R ₁₀ is R _10a OCOO as defined above R _10a is (i) substituted or unsubstituted (preferably unsubstituted) C ₂ to C ₈ alkyl (straight, branched or cyclic) such as ethyl, propyl, butyl, pentyl or hexyl, (ii ) Substituted or unsubstituted (preferably unsubstituted) C ₂ to C ₈ alkenyl (straight, branched or cyclic) such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; Substituted or unsubstituted (preferably unsubstituted) C ₂ to C ₈ alkynyl (linear or branched), such as tinyl, propynyl, butynyl, pentynyl or hexynyl, (iv) substituted or unsubstituted (preferably Preferably unsubstituted) phenyl or (v) substituted or unsubstituted (preferably unsubstituted) heteroaromatic groups such as furyl, thienyl or pyridyl To which, referred to below having the structure of Formula 15 can be prepared for specific taxanes.

In the "A" family compounds, X ₁₀ is as defined herein. Preferably, heterocyclo is substituted or unsubstituted furyl, thienyl or pyridyl, X ₁₀ is substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. t-butyl), Each of R ₇ and R ₁₀ has a beta stereoisomer configuration.

In the "B" family of compounds, X ₁₀ and R _2a are as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl, X ₁₀ is preferably substituted or unsubstituted furyl, thienyl or pyridyl, and X ₁₀ is preferably substituted or Unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg t-butyl), R _2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl, R ₇ and R ₁₀ each have a beta stereoisomer configuration.

In the “C” family of compounds, X ₁₀ and R _9a are as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), R _9a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R ₇ , R ₉ and R ₁₀ has a beta stereoisomer configuration.

In the "D" and "E" family compounds, X ₁₀ is as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), and R ₇ , R ₉ (series D only) and R ₁₀ each have a beta stereoisomeric configuration.

In the “F” family of compounds, X ₁₀ , R _2a and R _9a are as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), R _2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R ₇ , R ₉ and R ₁₀ has a beta stereoisomer configuration.

In the "G" family compounds, X ₁₀ and R _2a are as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), R _2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R ₇ , R ₉ and R ₁₀ has a beta stereoisomer configuration.

In the "H" family compounds, X ₁₀ is as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), R _2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R ₇ and R ₁₀ has a beta stereoisomer configuration.

In the "I" series compounds, X ₁₀ and R _2a are as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), R _2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R ₇ and R ₁₀ has a beta stereoisomeric configuration.

In the "J" family of compounds, X ₁₀ and R _2a are as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), R _2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl, and each of R ₇ , R ₉ and R ₁₀ has a beta stereoisomer configuration.

In the "K" family compounds, X ₃ , X ₅ , R ₂ , R ₉ and R ₁₀ are as defined herein. Preferably, heterocyclo is preferably substituted or unsubstituted furyl, thienyl or pyridyl and X ₁₀ is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (eg, t-butyl), R _2a is preferably substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl, and each of R ₇ , R ₉ and R ₁₀ has a beta stereoisomer configuration.

Any substituent of each of X ₃ , X ₅ , R ₂ , R ₉ and R ₁₀ is hydrocarbyl or heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy And any heteroatom containing substituent selected from the group consisting of nitro, amino, amido, thiol, ketal, acetal, ester and ether residues, but not phosphorus containing residues.

Example 5

Cytotoxicity As Determined by In Vitro Cell Colony Formation Assay

Four hundred HCT116 cells were plated in a 60 mm Petri dish containing 2.7 ml of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units / ml penicillin and 100 g / ml streptomycin). . Cells were incubated in a CO ₂ incubator at 37 ° C. for 5 hours to allow for attachment to the Petri dish bottom. The compounds identified in Example 2 were freshly prepared in the medium at 10 times the final concentration, and then 0.3 ml of this stock solution was added to the 2.7 ml medium of the dish. Cells were then incubated at 37 ° C. for 72 hours with drug. At the end of the incubation, the drug containing medium was drained, the dish was washed with 4 ml Hanks Balance Salt Solution (HBSS), 5 ml fresh medium was added, and the dish was transferred back to the incubator for colony formation. . After 7 days of incubation, cell colonies were counted using a colony counter. Cell viability was calculated and ID50 (drug concentration inhibiting 50% colony formation) values were determined for each experimental compound.

Example 6

Preparation of Solutions for Oral Administration

Solution 1: Antitumor Compound 1771 was dissolved in ethanol to form a solution containing 145 mg of compound per ml of solution. An equal volume of Cremophor® EL solution was added to this solution with stirring to form a solution containing 72.5 mg of compound 1771 per ml. This solution was diluted with 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to the patient.

Solution 2: Antitumor Compound 1781 was dissolved in ethanol to form a solution containing 98 mg of compound per ml of solution. An equal volume of Cremophor® EL solution was added to this solution with stirring to form a solution containing 49 mg of compound 1781 per ml. This solution was diluted with 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to the patient.

Example 7

Preparation of Oral Suspension

An oral composition of the anti-tumor compound of the present invention was prepared by suspending 25 mg of the fine powder of the compound in 1 ml of carrier containing 1% carboxymethylcellulose (CMC) in deionized water.

Example 8

Preparation of Tablets for Oral Administration

100 mg of the anti-tumor compound of the present invention was dissolved in 2 ml of methylene chloride, and 100 mg of Cremophor® EL solution was added. Methylene chloride was evaporated under vacuum to form a glass. 600 mg of microcrystalline cellulose was added to the glass, mixed and processed to form a powder capable of forming a tablet.

Example 9

Preparation of Emulsions for Parenteral Administration

Emulsion 1: The antitumor compound of the invention was dissolved in 100% ethanol to form a solution containing 40 mg of compound per ml of solution. The solution was then diluted with 19 parts by weight of liposin® II (20%) with stirring to form an emulsion for parenteral administration containing 2 mg of compound per ml.

Emulsion 2: The antitumor compound of the present invention was dissolved in 100% ethanol to form a solution containing 40 mg of compound per ml of solution. The solution was then diluted with 19 parts by weight of liposin® III (2%) with stirring to form an emulsion for parenteral administration containing 2 mg of compound per ml.

Emulsion 3: The antitumor compound of the present invention was dissolved in 100% ethanol to form a solution containing 40 mg of compound per ml of solution. The solution was then diluted with 9 parts by weight of liposin® III (2%) with stirring to form an emulsion for parenteral administration containing 4 mg of compound per ml.

Example 10

Preparation of solution for parenteral administration containing a compound

Solution 1: The antitumor compound of the present invention was dissolved in 100% ethanol to form a solution containing 140 mg of compound per ml. The solution was then diluted with the same volume of Cremophor® EL solution with stirring, followed by dilution with 9 parts by weight of saline to form a solution for parenteral administration containing 7 mg of compound per ml of solution.

Solution 2: The antitumor compound of the invention was dissolved in 100% ethanol to form a solution containing 140 mg of compound per ml of solution. The solution was then diluted with the same volume of Cremophor® EL solution with stirring, followed by dilution with 4 parts by weight of saline to form a solution for parenteral administration containing 11.7 mg of compound per ml of solution.

Solution 3: The antitumor compound of the invention was dissolved in 100% ethanol to form a solution containing 140 mg of compound per ml of solution. The solution was then diluted with the same volume of Cremophor® EL solution with stirring, followed by dilution with 2.33 parts by weight of saline to form a solution for parenteral administration containing 16.2 mg of compound per ml of solution.

Example 11

In Vivo Evaluation of Antitumor Compounds for Human Lung Tumor Xenografts

Antitumor compound 1775 was prepared with a vehicle of 10% ethanol, 10% cremophor and 80% saline. Formulated for dosing regimen. The compound was prepared in the same manner as described in Solution 2 of Example 10. Taxol (Paclitaxel, Bristol Myers Squib) used as a control compound was obtained as a commercially available drug.

The two lung tumor xenografts used in the study were SK-MES tumors, which are highly sensitive to Taxol, and NCI-H1299 (H1299) tumors, which are more resistant to Taxol compared to SK-MES neoplasms.

NCr-nude female mice with SK-MES or H1299 neoplasia (subcutaneously implanted with 1 mm of human lung tumor fragment on the flank) were treated on day 1 so that the average tumor size of 6 groups was 241 to 244 mg. Three pairs of horses were deleted. Treatment groups consist of vehicle treatment (group 1), taxol treatment (group 2), and anti-tumor compound 1755 (group 3).

The antitumor compound 1755 treatment was given by intravenous injection of the maximum tolerated dose (MTD) appropriate for each compound by giving half the dose at 1 hour intervals on a qd × 1 schedule. The MTD for antitumor compound 1755 has been described by i.v. Calculations were taken from initial single dose data for mice administered. Taxol itself gives two 18 mg / kg doses, one hour apart, divided 36 mg / kg into i.v. Administered. Vehicle control animals were injected intravenously twice a half of the total volume at 1 hour intervals. The study was terminated on day 60.

The results are summarized in Table 1, which includes mean survival days (MDS), virulence lethal counts, viable counts, complete or partial response counts, and stable disease counts. The average survival day is the number of days before the neoplasm reaches 1.5 g in size and euthanizes the animal. Complete response is obtained when the tumor is not touched at the end of the study. Partial response is obtained when the tumor shrinks to a size smaller than the size of day 1 of the study. "Stable disease" occurs when treatment limits the growth of neoplasms to small sizes that do not reach 1.5 g in size by the end of the study.

A tumor scoring system was devised to quantitatively rank the efficacy (therapeutic potential) between antitumor agents against different human solid tumor xenografts. Each mouse in the study gave a score of 1 to 10 at the end of the study. The score can be summarized as follows:

Score Explanation <1 Serious toxicity 2-3 The tumors reached a cut-off size, but significant tumor growth delays were evident. 4-6 Tumor growth was significantly suppressed (stable disease). 7-9 Partial Tumor Contraction (Partial Response) 10 Full response (perfect score)

Individual scores for each mouse were averaged with the mean score of each treatment group. This tumor scoring system quantifies treatment results and thus provides a better comparison of different antitumor compounds (complete response versus partial response).

group MDS (n) Toxic Death survival Full response Partial reaction Stable disease Average score One 12.2 ± 1.3 (6) 0 0 0 0 0 1 ± 0 2 16 ± 2.0 (6) 0 0 0 0 0 1.3 ± 0.3 3 - 0 6 5 0 One 9.2 ± 0.8

MDS values at day 12.2 were calculated for vehicle treated Control 1. Only Taxol (36 mg / kg; group 2) showed moderate 30% survival prolongation (MDS at 16.0 days) compared to vehicle control without reported tumor degeneration. In contrast, antitumor compound 1755 was highly active. Anti-tumor compound 1755 (49 mg / kg; group 3) showed 5 complete responses with significant survival extension recorded in the remaining treated animals compared to vehicle or taxol control.

In the H1299 experiment, mice were paired into three groups of six animals each on day 1 so that the average tumor size of the six groups was 229-233 mg. The treatment protocol for the H1299 experiment was identical to the SK-MES experiment protocol. MDS values of 24.5 days were calculated for vehicle treated Control 1. Taxol (36 mg / kg; group 2) was not valid in the H1299 model and showed only 10% prolongation of survival (27.0 days MDS) in 5 compared to vehicle treated animals (statistically not significant). One partial reaction was observed by Taxol treatment.

group MSD (n) Toxic Death survival Full response Partial reaction Stable disease Average score One 24.5 ± 3.3 (6) 0 0 0 0 0 1.2 ± 0.2 2 27.0 ± 4.6 (5) 0 One 0 One 0 2.7 ± 1.3 3 - 2 4 3 0 One 5.8 ± 2

Antitumor compound 1755 (49 mg / kg; group 4) was highly effective against Taxol-resistant H1299 neoplasia, allowing three animals to respond fully in the H1299 experiment. Other mice treated with this compound significantly increased survival time compared to vehicle treated or taxol treated animals.

In the H1299 experiment, two mice died of toxicity in the group treated with antitumor compound 1755. Since the dose and schedule for 3 compounds were the same as in the SK-MES experiment, the side effects experienced by nude mice do not appear to be due to systemic drug toxicity. One explanation based on the extreme response of H1299 tumors to antitumor compound 1755, including tumor necrosis and bleeding, is that the compound destroys tumor structure and stroma to secrete toxic substances from neoplasms to host mice.

Antitumor compound 1755 was effective when given in single dose for upstaged human lung tumor xenografts.

Example 12

In Vivo Evaluation of Antitumor Compounds for DU 145 Human Prostate Tumor Xenograft

Anti-tumor compounds were prepared with a vehicle of 5% ethanol, 5% cremophor and 90% saline as described in Solution 1 of Example 10. Taxol (Paclitaxel, Bristol Myers Squibb) was obtained as a commercially available drug. The dose volume was 0.3 ml per 20 g of mouse.

NCr-nude male mice were subcutaneously implanted at the end of 1 mm DU145 human prostate tumor fragment and classified into 5 treatment groups. The group average size range of DU145 was 223-228 mg. Dosing began on day 1. The anti-tumor compound was determined in i.v. Administration (single dose of compound). Taxol was administered in two divided doses (1 hour interval) at 12 mg / kg per divided dose on a qd × 1 schedule. (Total dose = 24 mg / kg). Taxol is also available on i.p. on a qd × 5 schedule with a daily dose of 18 mg / kg. Administered. Vehicles were administered i.v to the first group of control mice on a qd × 1 schedule. The study was terminated on day 91. The treatment group is shown in Table 3.

group compound mg / kg Route schedule One Vehicle - i.v. qd × 1 2 Taxol 24 i.v. qd × 1 3 Taxol 18 i.p. qd × 5 4 1781 72.6 i.v. qd × 1

The results are summarized in Table 4, which includes mean survival days (MDS), virulence lethal counts, viable counts, complete or partial response counts, and stable disease counts. The mean survival date is the number of days before neoplasia reaches 1.5 g in size and the animal is euthanized. Complete response is obtained when the tumor shrinks to a size smaller than the size of day 1 of the study. "Stable disease" occurs when treatment limits the growth of neoplasms to small sizes that do not reach 1.5 g in size by the end of the study.

group MDS (n) Toxic Death survival Full response Partial reaction Stable disease Average score One 34.3 ± 9.4 (3) One One One 0 0 2.8 ± 1.8 2 37.4 ± 8.9 (3) One One 0 0 One 2 ± 1 3 --- 5 0 0 0 0 0 ± 0 4 --- 5 0 0 0 0 0 ± 0

DU145 tumors grew gradually in 3 of 5 vehicle treated mice (group 1); MDS values of 34.3 days were calculated for these animals. One mouse in group 1 died of unknown cause on day 40, and the tumors of other mice in group 1 were no longer touched on day 71 from the initial size of paired 220 mg. Slowly regressed until This latter case is probably a poorly transplanted example.

Prostate tumors grew gradually in 3 of 5 animals administered Taxol 24 mg / kg (i.v .; qd × 1), reaching an end point of 1.5 g and having a MDS of 37.4 days (group 2). This 9% increase in survival compared to the first control is not statistically different (p = 0.82; unpaired t-test). One animal in group 2 died on day 32, probably due to side effects associated with the drug. The fifth mouse in group 2 did not show net tumor growth in a 91 day study; Tumors were the same size (196 mg) on days 6 and 91. A dose of 18 mg / kg on the qd × 5 schedule was obtained in i. Taxol administered (group 3) was highly toxic. All five mice died of drug-related side effects, including substantial weight loss (usually 20% or more).

Antitumor compound 1781 resulted in 100% mortality at the dose. The compound resulted in a weight loss of at least 20% of the treated mice before death.

Example 13

A2780 In Vivo Evaluation of Antitumor Compounds for Human Ovarian Tumor Xenograft

Anti-tumor compounds were prepared with a vehicle of 5% ethanol, 5% cremophor and 90% saline as described in Solution 1 of Example 10. Taxol (Paclitaxel, Bristol Myers Squib) and taxotere (Docetaxel: Rhone-Poulenc Rorer) were obtained as commercially available drugs. Dosing volume was 0.3 ml per 20 g of mouse.

NCr-nude female mice (subcutaneously implanted with 1 A A2780 human ovarian tumor fragment on the flank) were divided into 5 treatment groups, but 6 taxotel treated groups. The group mean size range of A2780 was 237-243 mg. Dosing began on day 1. The anti-tumor compound was determined in i.v. Administration (single dose of compound). Taxol was administered in two divided doses (1 hour interval) at 12 mg / kg per divided dose on a qd × 1 schedule (total dose = 24 mg / kg). The qd × 5 schedule also includes i.p. taxol at a daily dose of 15 mg / kg. Administered. Taxotel was i.v dosed at 70 mg / kg on a qd × 1 schedule. Vehicles were administered i.v to the first group of control mice on a qd × 1 schedule. Treatment groups were detailed in Table 5. The study was terminated on day 60.

group compound mg / kg Route schedule One Vehicle - i.v. qd × 1 2 Taxol 24 i.v. qd × 1 3 Taxol 15 i.p. qd × 5 4 1781 60.6 i.v. qd × 1 5 Taxotel 70 i.v. qd × 1

The results are summarized in Table 6, which includes mean days of survival (MDS), virulence lethal counts, viable counts, complete or partial response counts, and stable disease counts. The average survival day is the number of days before the neoplasm reaches 2.0 g in size and euthanizes the animal. Complete response is obtained when the tumor shrinks to a size smaller than the size of day 1 of the study. "Stable disease" occurs when treatment limits neoplastic growth to a small size not reaching 2.0 g by the end of the study.

group MDS (n) Toxic Death survival Full response Partial reaction Stable disease Average score One 11.7 ± 2.5 (5) 0 0 0 0 0 1.2 ± 0.2 2 21.9 ± 5.5 (5) 0 One 0 0 0 1.8 ± 0.4 3 26.5 (1) 4 0 0 0 0 0.6 ± 0.6 4 38.5 ± 8.3 (2) 0 3 0 2 One 6 ± 1.3 5 27.4 ± 3.5 (5) 0 0 0 0 0 2.5 ± 0.3

Ovarian tumors grew gradually in all five mice in the first group administered vehicle and the MDS reaching 2.0 g cut-off was 11.7 days. Thus, this ovarian tumor xenograft is a fast growing neoplasm that kills the host in a relatively short time.

Taxol (group 2) administered on a qd × 1 schedule showed moderate efficacy in this experiment. MDS values of 21.9 days calculated for group 2 mice indicate an 87% increase in survival compared to the first control animal, which is not significant (p = 0.13; unpaired t-test). One animal in the second group was recorded as a stable disease on day 61. A 15 mg / kg dose was administered on the qd × 5 schedule. The administered Taxol (Group 1) was very toxic, causing drug-related side effects in 4 animals.

Taxoteel (70 mg / kg; i.v .; qd × 1) was more effective than Taxol in this experiment. The 27.4 day MDS of all 5 mice in the fifth group was calculated to have a survival extension of 134% compared to the first control, which was statistically significant with p = 0.007 (unpaired t-test).

Compound 1781 exhibited partial response in 2 of 5 mice. The group treated with antitumor compound 1781 experienced a maximum mean group weight loss in the range of 3% to 19% by day 11, and the animal body weight was then restored. Thus, the side effects reported for antitumor compound 1781 are within the acceptable range of NCI, indicating that animals in the A2780 experiment received the appropriate MTD dose.

Example 14

In Vivo Evaluation of Antitumor Compounds for A375 Human Melanoma Xenograft

Anti-tumor compounds were prepared with a vehicle of 5% ethanol, 5% cremophor and 90% saline as described in Solution 1 of Example 10. Taxol (Paclitaxel, Bristol Myers Squib) and Taxoteel (Docetaxel: Long Furan Laura) were obtained as commercially available drugs. Dosing volume was 0.3 ml per 20 g of mouse.

Six NCr-nude female mice (subcutaneously implanted with 1 x A375 human melanoma on the side) were divided into 6 treatment groups, but 7 taxotel treated groups. The group mean size of A375 tumors ranged from 206 to 212 mg. Dosing began on day 1. The anti-tumor compound was determined in i.v. Administration (single dose of compound). Taxol was administered in two divided doses (1 hour interval) at 12 mg / kg per divided dose on a qd × 1 schedule. (Total dose = 24 mg / kg). On the qd × 5 schedule Taxol is also available at i.p. Administered. Taxotel was i.v at a dose of 70 mg / kg on a qd × 1 schedule. Vehicles were administered i.v to the first group of control mice on a qd × 1 schedule. Treatment groups were detailed in Table 7. The study was terminated on day 60.

group compound Mg / kg Route schedule One Vehicle - i.v. qd × 1 2 Taxol 24 i.v. qd × 1 3 Taxol 18 i.p. qd × 5 4 1781 72.6 i.p. qd × 1 5 Taxotel 70 i.v. qd × 1

The results are summarized in Table 8, which includes mean survival days (MDS), virulence lethal counts, viable counts, complete or partial response counts and stable counts. The average survival day is the number of days before the neoplasm reaches 2.0 g in size and euthanizes the animal. Complete response is obtained when the tumor shrinks to a size smaller than the size of day 1 of the study. "Stable disease" occurs when treatment limits neoplastic growth to a small size not reaching 2.0 g by the end of the study.

group MDS (n) Toxic Death survival Full response Partial reaction Stable disease Average score One 14.4 ± 0.9 (6) 0 0 0 0 0 1 ± 0 2 18.1 ± 0.6 (4) 2 0 0 0 0 0.8 ± 0.3 3 - 6 0 0 0 0 0 ± 0 4 45.6 (1) 5 0 0 0 0 0.5 ± 0.5 5 21.5 ± 0.5 (7) 0 0 0 0 0 2 ± 0

A375 melanoma implants grew rapidly and gradually in all six mice treated with vehicle (group 1). These neoplasms had an MDS value of 14.4 days and reached 2.0 g cut-off.

Animals (group 2) who received Taxol (24 mg / kg; i.v.) on a qd × 1 schedule received moderate treatment benefit from chemotherapy drugs. MDS values at 18.1 days showed a 26% prolongation of survival compared to the first control. This increase in survival is statistically significant (p = 0.016; unpaired t-test). Taxol administered on a qd × 5 schedule (18 mg / kg; i.p.) showed high toxicity to mice. All six animals administered at 18 mg / kg died due to toxicity.

Giving Taxoteel i.v. at a dose of 70 mg / kg showed a MDS of 21.5 days (qd × 1; group 5). This 49% survival prolongation was significant compared to the first control with p <0.0001 (unpaired t-test).

Antitumor compound 1781 caused 5 toxic lethality in each of the six mice receiving this compound. In general, 20-30% average group weight loss was reported in animals treated with this compound.

Example 15

In Vivo Evaluation of Antitumor Compounds for Panc-1 Human Pancreatic Tumor Xenograft

Anti-tumor compounds were prepared with a vehicle of ethanol 5%, cremophor 5% and saline 90% as described for solution 1 of Example 10. Taxol (Paclitaxel: Bristol Myers Squibb) was obtained as a commercial drug. The dose volume was 0.3 ml per 20 g of mouse.

Six NCr-nude female mice (subcutaneously implanted with a 1 mm ³ Panc-1 pancreatic tumor fragment at the side) were divided into treatment groups. The mean tumor size of the Panc-1 pancreatic tumor group was 192-213 mg. Dosing began on day 1. Anti-tumor compounds were administered intravenously at an estimated maximum tolerated dose (MTD) appropriate for each drug on the qd x 1 schedule (single dose of compound). iv Taxol was administered in qd x 1 schedules in two divided doses of 12 mg / kg per divided dose (hourly total dose of 24 mg / kg) at 1 hour intervals. Taxol was also administered intraperitoneally on a qd x 5 schedule at a dose of 15 mg / kg. On a qd x 1 schedule, vehicle was administered intravenously to the first group of control mice. The treatment group was detailed in Table 9. The study was terminated on day 63.

group compound mg / kg Route schedule One Vehicle --- i.v. qd x 1 2 Taxol 24 i.v. qd x 1 3 Taxol 15 i.p. qd x 5 4 1781 60 i.v. qd x 1

The results are summarized in Table 10, which includes mean survival days (MDS), virulence lethal counts, viable counts, complete or partial response counts, and stable disease counts. The average survival day is the number of days before the neoplasm reaches 1.5 g in size and euthanizes the animal. The complete response is obtained when the tumor is smaller in size than the size of day 1 of the study. "Stable disease" occurs when treatment limits the growth of neoplasms to small sizes that do not reach 1.5 g in size by the end of the study.

group MDS (n) Toxic Death survival Full response Partial reaction Stable disease Average score One 23.0 ± 3.1 (5) 0 One 0 0 One 2 ± 0.8 2 34.7 ± 3.4 (4) One One 0 0 One 2.2 ± 0.8 3 --- 4 One 0 One 0 1.2 ± 1.2 4 59.3 ± 2.9 (2) 0 4 0 4 0 6.7 ± 1.2

In Panc-1 neoplasia of mice (group 1) receiving vehicle, the calculated MDS reaching the 1.5 g cut-off point was 23.0 days. One tumor in the vehicle control did not grow, possibly due to poor transplantation of the tumor.

One stable disease was obtained in Taxol (group 2) administered intravenously at a dose of 24 mg / kg (qd x1), and 34.7 days of MDS were obtained in 4 other mice (p = 0.038, first control group). Quite different, unpaired t-test). One mouse was lethal because of the toxicity from administration of this dose of Taxol. Four of six mice belonging to Group 3 were killed due to the toxicity of Taxol administered intraperitoneally at a dose of 15 mg / kg (qd x 5).

Antitumor compound 1781 showed an overall response rate of 66.7%. Antitumor compound 1781 was quite acceptable and did not result in toxic lethality and minimal mean group weight loss. Therefore, this compound was administered at a suitable MTD dose.

Example 16

In Vivo Evaluation of Antitumor Compounds for VM46 Human Colon Tumor Xenografts

Antitumor compounds were prepared with a vehicle of 5% ethanol, 5% cremophor and 90% saline as described for solution 1 of Example 10. Taxol (Paclitaxel: Bristol-Meyer Squib) and Taxoteel (Docetaxel, Long-Poulenc Rorer) were obtained as commercially available drugs. The dose volume was 0.3 mL per 20 g of mouse.

Six NCr-nude female mice (subcutaneously implanted with 1 mm ³ of VM46 colon tumor fragment) were divided into treatment groups. The mean tumor size of the VM46 colon tumor group was 181-188 mg. Dosing began on day 1. Anti-tumor compounds were administered intravenously at an estimated maximum tolerated dose (MTD) appropriate for each drug on the qd x 1 schedule (single dose of compound). iv Taxol was administered intravenously in two divided doses of 12 mg / kg once per dose on a qd x 1 schedule (total dose 24 mg / kg). Taxol was also administered intraperitoneally in an amount of 15 mg / kg on a qd x 5 schedule. Taxotel was administered intravenously at a dose of 70 mg / kg on a qd × 1 schedule. Vehicles were administered intravenously to the first control mice on a qd x 1 schedule. Treatment groups were detailed in Table 11. The study was terminated on day 64.

group compound mg / kg Route schedule One Vehicle --- i.v. qd x 1 2 Taxol 24 i.v. qd x 1 3 Taxol 15 i.p. qd x 5 4 1781 60 i.v. qd x 1 5 Taxotel 70 i.v. qd x 1

The results are summarized in Table 12, which includes mean survival days (MDS), toxic lethal numbers, viable numbers, complete or partial response numbers, and numbers with stable disease. The average survival day is the number of days before the neoplasm reaches 1.5 g in size and euthanizes the animal. Complete response is obtained when the tumor shrinks to a size smaller than the size of day 1 of the study. "Stable disease" occurs when treatment limits neoplastic growth to a small size not reaching 1.5 g size until the end of the study.

group MDS (n) Toxic Death Full response Partial reaction Stable disease Average score One 31.0 ± 4.4 (6) 0 0 0 0 1.2 ± 0.2 2 43.3 ± 3.7 (4) 0 0 One One 3.8 ± 1.4 3 36.1 ± 12.2 (2) 3 0 One 0 1.8 ± 1.3 4 42.2 ± 7.1 (5) 0 0 One 0 3 ± 1.2 5 45.3 ± 3.6 (6) 0 0 0 0 2 ± 0

Colon cancer grew gradually in six mice (Group 1) receiving vehicle and the calculated MDS value reaching the 1.5 g end point was 31.0 days.

One partial response, one stable disease, was obtained in Taxol (Group 2) administered intravenously at a dose of 24 mg / kg (qd x1), and 43.3 days of MDS were obtained in the remaining four mice in the group. (P = 0.086, not significantly different from control, unpaired t-test). Taxol administered intraperitoneally at a dose of 15 mg / kg (qd x 5) was highly toxic, resulting in the death of three of six mice treated. Taxotel was very active in this test and showed an MDS value of 45.3 days (significant with p 0.05 compared to the first control; unpaired t-test).

Antitumor compound 1781 achieved a response rate of 16.7%. In this antitumor compound, 11-20 days longer survival extension was obtained than the 31.0 day MDS calculated for the control. Anti-tumor compound 1781 is very acceptable and does not cause toxic mortality and the maximum mean group weight loss was in the range of 3-14% on day 8.

Example 17

In Vivo Evaluation of Oral Administration of Antitumor Compounds to SKMES Human Lung Tumor Xenografts

Antitumor compound 1755 was prepared with a vehicle of 5% ethanol, 5% cremophor and 90% saline as described for solution 1 of Example 6. The compound was administered in a single bolus by oral administration in a study investigating the efficacy of this compound on SKMES human lung tumor xenografts.

NU / NU female mice (subcutaneously implanted with SKMES lung tumor fragments of 1 mm ³ in each side) were divided into 6 treatment groups. SKMES size ranges and group mean SKMES size ranges were 126-448 mg and 238-241 mg, respectively. Treatment groups consisted of untreated (Group 1), vehicle only (Group 2), Taxol treatment (40 mg / kg, Group 3) and anti-tumor compound 1755 treatment (49 mg / kg, Group 4). lost. Treatment was administered in a single oral bolus on day 1 and the study was terminated on day 60.

The results are summarized in Table 13, which includes mean survival days (MDS), toxic lethal numbers, viable numbers, complete or partial response numbers, and numbers with stable disease. The average survival day is the number of days before the SKMES neoplasm reaches 2.0 g in size and euthanizes the animal. Complete response is obtained when the tumor is not touched at the end of the study. Partial response is obtained when the tumor shrinks to a size smaller than the size of day 1 of the study. "Stable disease" occurs when treatment limits neoplastic growth to a small size not reaching 2.0 g by the end of the study.

group MDS (n) Toxic Death survival Full response Partial reaction Stable disease % Of total response One 14.5 ± 1.7 (5) 0 One 0 0 One 0 2 13.7 ± 1.4 (6) 0 0 0 0 0 0 3 13.2 ± 1.4 (6) 0 0 0 0 0 0 4 --- 0 6 4 2 0 100

Antitumor compound 1755 was highly active with a single oral dose. The overall response rate was 100%, showing 4 complete responses and 2 partial responses. Overall response rate is defined as the ratio of evaluable animals (excluding animals that die due to procedure or toxicity) to the group that undergoes a full or partial response at the end of the study.

Example 18

In Vivo Evaluation of Oral Administration of Antitumor Compounds to MX-1 Human Breast Cancer Xenografts

Antitumor compounds were administered orally in this study to investigate whether the antitumor compounds were effective against MX-1 human breast cancer xenografts. Antitumor compounds were prepared with 5% ethanol, 5% cremophor and 90% saline. Antitumor compound 1771 was formulated as described in solution 1 of Example 6. Anti-tumor compound 1781 was formulated as described in solution 2 of Example 6.

Nu / Nu female mice (11-12 weeks old; implanted 1 mm ³ MX-1 human breast cancer fragments on the side) were divided into one control group of 10 animals and 6 treatment groups of 6 animals each (group mean MX-1 tumor size range was 47-49 mg). Treatment groups are shown in Table 14 below. All treatments were administered in a single oral bolus on day 1 and the test was terminated on day 63.

The results are summarized in Table 14 and included mean survival days (MDS), virulence lethal counts, viable counts, number of complete or partial responses, and numbers with stable disease. Mean survival is the number of days before MX-1 neoplasia reaches 1.5 g in size and euthanizes the animal. Complete response is obtained when the tumor shrinks to a size smaller than the size of day 1 of the test. "Stable disease" occurs when treatment limits the growth of neoplasms to a small size not reaching 1.5 g at the end of the test.

group compound Dose (mg / kg) Mean survival (n) Weight loss (days) Toxic Death Complete response Partial reaction Stable disease One Vehicle n / a 21.5 ± 0.7 (8) n / a 0 0 0 2 2 1771 107 60.8 ± 1.0 (2) -8.1% (5) 0 4 0 0 3 1781 73 33.3 ± 2.9 (5) -9.4% (5) 0 0 0 One

The antitumor compounds evaluated are effective in the MX-1 human breast cancer xenograft model at very acceptable dosages. Anti-tumor compound 1771 showed four complete tumor degeneration among the six mice treated, the other two of these groups experienced a significant increase in survival compared to the control before reaching the study endpoint. The characteristic of the response exhibited by antitumor compound 1781 is a significant prolonged survival as compared to vehicle control mice.

In addition to survival and tumor regression responses, the effects of treatment on blood cell populations were evaluated. The major effect of antitumor compounds on the blood cell population is a significant decrease in the number of neutrophil cells. In addition, monocyte depletion was very consistent with neutrophil reduction for each antitumor compound. Antitumor compounds generally did not affect white blood cell counts, lymphocytes and platelets. There was a correlation between antitumor activity and reduced neutrophil count. In general, toxicity (determined by neutrophil reduction) and weight loss correlate with efficacy. Importantly, the toxicity observed with highly effective antitumor compounds was manageable and reversible. Neutrophil counts and body weight recovered from the lowest levels only a few days later. Weight loss, neutrophil and monocyte measurements at day 4, along with tumor weight loss at day 18, are summarized in Table 15 below.

group compound Dose (mg / kg) Weight (mg) decrease % Neutrophils (K / μl) decrease % Monocytes (K / μl) decrease % One Vehicle n / a 868.5 - 0.9115 0.096 - 2 1771 107 0.1 100.0% 0.044 95.2% 0.045 53.1% 3 1781 73 275.3 68.3% 0.117 87.2% 0.101 -

The present invention provides taxane compounds having C (10) carbonate substituents, C (7) hydroxy substituents and a range of C (2), C (9), C (14) and side chain substituents having good antitumor activity. To provide.

Claims (141)

Taxanes having the formula Where R ₂ is acyloxy, R ₇ is hydroxy, R ₉ is keto, hydroxy, or acyloxy, R ₁₀ is carbonate, R ₁₄ is hydrido or hydroxy, X ₃ is substituted or unsubstituted alkyl, wherein alkyl contains two or more carbon atoms, alkenyl, alkynyl, or heterocyclo, X ₅ is -COX ₁₀ , -COOX ₁₀ , or -CONHX ₁₀ , wherein X ₁₀ is hydrocarbyl, substituted hydrocarbyl or heterocyclo, Ac is acetyl. The taxane of claim 1, wherein R ₁₀ is R _10a OCOO—, wherein R _10a is substituted or unsubstituted C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 2, wherein X ₃ is furyl, thienyl, pyridyl, C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 2, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 2, wherein R ₁₄ is hydrido. The taxane of claim 5, wherein X ₃ is furyl, thienyl, pyridyl, C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 5, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 2, wherein R ₂ is benzoyloxy. The taxane of claim 8, wherein X ₃ is furyl, thienyl, pyridyl, C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 8, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 2, wherein R ₁₄ is hydrido and R ₉ is keto. The compound of claim 11, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 11, wherein X ₅ is —COX ₁₀ where X ₁₀ is phenyl or —COOX ₁₀ where X ₁₀ is t-butyl. The taxane of claim 2, wherein R ₂ is benzoyloxy and R ₉ is keto. 15. The compound of claim 14 wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 14, wherein X ₅ is —COX ₁₀ (where X ₁₀ is phenyl) or —COOX ₁₀ (where X ₁₀ is t-butyl). The taxane of claim 2, wherein R ₁₄ is hydrido and R ₂ is benzoyloxy. 18. The compound of claim 17, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 17, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 2, wherein R ₁₄ is hydrido, R ₉ is keto, and R ₂ is benzoyloxy. The compound of claim 20, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 20, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 1, wherein R ₁₀ is R _10a OCOO—, wherein R _10a is C ₁ -C ₈ alkyl. The compound of claim 23, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 23, wherein X ₅ is —COX ₁₀ wherein X ₁₀ is phenyl or —COOX ₁₀ where X ₁₀ is t-butyl. The taxane of claim 23, wherein R ₁₄ is hydrido. 27. The compound of claim 26, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 26, wherein X ₅ is —COX ₁₀ where X ₁₀ is phenyl or —COOX ₁₀ where X ₁₀ is t-butyl. The taxane of claim 23, wherein R ₂ is benzoyloxy. The compound of claim 29, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 30. The taxane of claim 29, wherein X ₅ is -COX ₁₀ where X ₁₀ is phenyl or -COOX ₁₀ where X ₁₀ is t-butyl. The taxane of claim 23, wherein R ₁₄ is hydrido, R ₉ is keto, and R ₂ is benzoyloxy. 33. The compound of claim 32, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 33. The taxane of claim 32, wherein X ₅ is -COX ₁₀ where X ₁₀ is phenyl or -COOX ₁₀ where X ₁₀ is t-butyl. The taxane of claim 1, wherein R ₁₀ is R _10a OCOO—, wherein R _10a is methyl or ethyl. 36. The compound of claim 35, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 35, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). 36. The taxane of claim 35, wherein R ₁₄ is hydrido. The compound of claim 38, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 38, wherein X ₅ is —COX ₁₀ , wherein X ₁₀ is phenyl, or —COOX ₁₀ , wherein X ₁₀ is t-butyl. The taxane of claim 35, wherein R ₂ is benzoyloxy. The compound of claim 41, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 41, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 35, wherein R ₁₄ is hydrido and R ₉ is keto. 45. The compound of claim 44, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 44, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 35, wherein R ₂ is benzoyloxy and R ₉ is keto. 48. The compound of claim 47, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 47, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). 36. The taxane of claim 35, wherein R ₁₄ is hydrido and R ₂ is benzoyloxy. 51. The compound of claim 50, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 51. The taxane of claim 50, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 35, wherein R ₁₄ is hydrido, R ₉ is keto, and R ₂ is benzoyloxy. The compound of claim 53, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The taxane of claim 53, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 53, wherein X ₅ is —COOX ₁₀ , wherein X ₁₀ is t-butyl. The compound of claim 56, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. Taxanes having the formula Where R ₂ is benzoyloxy, R ₇ is hydroxy, R ₁₀ is R _10a OCOO-, wherein R _10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo, X ₃ is substituted or unsubstituted alkyl, wherein alkyl contains at least 2 carbon atoms, alkenyl, alkynyl or heterocyclo, X ₅ is -COX ₁₀ , -COOX ₁₀ , or -CONHX ₁₀ , wherein X ₁₀ is hydrocarbyl, substituted hydrocarbyl or heterocyclo, Ac is acetyl. 59. The compound of claim 58, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 60. The taxane of claim 59, wherein X ₅ is -COX ₁₀ where X ₁₀ is phenyl or -COOX ₁₀ where X ₁₀ is t-butyl. The taxane of claim 58, wherein X ₃ is furyl or thienyl. The compound of claim 61, wherein X ₅ is —COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). The taxane of claim 61, wherein X ₅ is —COX ₁₀ (wherein X ₁₀ is phenyl) or —COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 58, wherein R _10a is methyl or ethyl. 65. The compound of claim 64, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 66. The compound of claim 65, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). 67. The taxane of claim 65, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 64, wherein X ₃ is furyl or thienyl. 69. The compound of claim 68, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ Alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). The taxane of claim 68, wherein X ₅ is —COX ₁₀ (where X ₁₀ is phenyl) or —COOX ₁₀ (where X ₁₀ is t-butyl). 65. The taxane of claim 64, wherein X ₃ is cycloalkyl. The compound of claim 71, wherein X ₅ is —COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). The taxane of claim 71, wherein X ₅ is —COX ₁₀ where X ₁₀ is phenyl or —COOX ₁₀ where X ₁₀ is t-butyl. 65. The taxane of claim 64, wherein X ₃ is isobutenyl. 75. The compound of claim 74, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). The taxane of claim 74, wherein X ₅ is —COX ₁₀ , wherein X ₁₀ is phenyl, or —COOX ₁₀ , wherein X ₁₀ is t-butyl. 59. The compound of claim 58, wherein X ₃ is furyl or thienyl, R _10a is ethyl, X ₅ is -COX ₁₀ (where X ₁₀ is phenyl) or -COOX ₁₀ (where X ₁₀ is t-butyl) Taxane. The taxane of claim 58, wherein X ₃ is 2-furyl or 2-thienyl, R _10a is ethyl, and X ₅ is —COOX ₁₀ , wherein X ₁₀ is t-butyl. The taxane of claim 58, wherein X ₃ is isobutenyl and X ₅ is —COOX ₁₀ wherein X ₁₀ is t-butyl. The taxane of claim 58, wherein X ₃ is cycloalkyl, R _10a is methyl or ethyl and X ₅ is —COOX ₁₀ , wherein X ₁₀ is t-butyl. Taxanes having the formula Where R ₂ is benzoyloxy, R ₇ is hydroxy, R ₁₀ is R _10a OCOO-, wherein R _10a is alkyl, alkenyl, alkynyl, phenyl or heterocyclo, wherein said alkyl comprises two or more carbon atoms; X ₃ is cycloalkyl, alkenyl, alkynyl, phenyl or heterocyclo, X ₅ is -COX ₁₀ , -COOX ₁₀ or -CONHX ₁₀ , wherein X ₁₀ is hydrocarbyl, substituted hydrocarbyl or heterocyclo, Ac is acetyl. 82. The compound of claim 81, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. The compound of claim 82, wherein X ₅ is —COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). 84. The taxane of claim 82, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). 82. The taxane of claim 81, wherein X ₃ is furyl or thienyl. 86. The compound of claim 85, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). 86. The taxane of claim 85, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). 82. The taxane of claim 81, wherein X ₃ is phenyl. 89. The compound of claim 88, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). 89. The taxane of claim 88, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). 82. The taxane of claim 81, wherein X ₃ is isobutenyl. 92. The compound of claim 91, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). 93. The taxane of claim 91, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). 82. The taxane of claim 81, wherein R _10a is ethyl. 95. The compound of claim 94, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C ₂ -C ₈ alkyl, C Taxanes which are ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 95. The compound of claim 94, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). 95. The taxane of claim 94, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). 95. The taxane of claim 94, wherein X ₃ is furyl or thienyl. 99. The compound of claim 98, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl). 99. The taxane of claim 98, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). The taxane of claim 98, wherein X ₅ is —COOX ₁₀ wherein X ₁₀ is t-butyl. A pharmaceutical composition comprising the taxane of claim 1 and at least one pharmaceutically acceptable and inert or physiologically active diluent or adjuvant. 103. The compound of claim 102, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl of a pharmaceutical composition. 107. The compound of claim 103, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 103. The pharmaceutical composition of claim 103, wherein X ₅ is -COX ₁₀ , wherein X ₁₀ is phenyl, or -COOX ₁₀ , wherein X ₁₀ is t-butyl. 103. The pharmaceutical composition of claim 102, wherein R _10a is methyl, ethyl or propyl. 107. The compound of claim 106, wherein X ₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl of a pharmaceutical composition. 107. The compound of claim 107, wherein X ₅ is -COX ₁₀ wherein X ₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyri Diyl, 4-pyridyl, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl) or -COOX ₁₀ wherein X ₁₀ is substituted or unsubstituted C ₁ -C ₈ alkyl , C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 107. The pharmaceutical composition of claim 107, wherein X ₅ is -COX ₁₀ (where X ₁₀ is phenyl) or -COOX ₁₀ (where X ₁₀ is t-butyl). 103. The compound of claim 103, wherein X ₃ is furyl or thienyl, R _10a is methyl or ethyl, and X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ where X ₁₀ is t- Butyl). 103. The compound of claim 103, wherein X ₃ is substituted or unsubstituted furyl, R _10a is methyl or ethyl, X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ wherein X ₁₀ is t -Butyl). 103. The compound of claim 103, wherein X ₃ is substituted or unsubstituted thienyl, R _10a is methyl or ethyl, X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ wherein X ₁₀ is t-butyl). 103. The compound of claim 103, wherein X ₃ is isobutenyl, R _10a is methyl or ethyl, X ₅ is -COX ₁₀ (where X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl) Pharmaceutical composition. 103. The pharmaceutical of claim 103, wherein X ₃ is alkyl, R _10a is methyl and X ₅ is -COX ₁₀ (where X ₁₀ is phenyl) or -COOX ₁₀ (where X ₁₀ is t-butyl). Composition. 103. The pharmaceutical composition of claim 103, wherein X ₃ is 2-furyl or 2-thienyl, R _10a is methyl and X ₅ is -COOX ₁₀ wherein X ₁₀ is t-butyl. 107. The pharmaceutical composition of claim 103, wherein X ₃ is 2-furyl, R _10a is ethyl and X ₅ is -COOX ₁₀ wherein X ₁₀ is t-butyl. 103. The pharmaceutical composition of claim 103, wherein X ₃ is 2-thienyl, R _10a is ethyl, and X ₅ is -COOX ₁₀ , wherein X ₁₀ is t-butyl. 105. The pharmaceutical composition of claim 103, wherein X ₃ is isobutenyl and X ₅ is -COOX ₁₀ wherein X ₁₀ is t-butyl. 107. The pharmaceutical composition of claim 103, wherein X ₃ is cycloalkyl, R _10a is methyl, and X ₅ is -COOX ₁₀ wherein X ₁₀ is t-butyl. A pharmaceutical composition comprising the taxane of claim 58 and one or more pharmaceutically acceptable and inert or physiologically active diluents or adjuvants. 62. A pharmaceutical composition comprising the taxane of claim 61 and at least one pharmaceutically acceptable and inert or physiologically active diluent or adjuvant. A composition for oral administration comprising the taxane of claim 1 and one or more pharmaceutically acceptable carriers. 123. The composition of claim 122, wherein R ₁₀ is R _10a OCOO-, wherein R _10a is substituted or unsubstituted C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 124. The compound of claim 123, wherein X ₃ is phenyl, isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C _1- C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 126. The composition of claim 124, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). 126. The composition of claim 125, wherein R _10a is methyl, ethyl or propyl. 127. The compound of claim 126, wherein X ₃ is isobutenyl, R _10a is methyl or ethyl, and X ₅ is -COX ₁₀ (where X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl) Composition. 127. The composition of claim 127, wherein X ₃ is 2-furyl or 2-thienyl, R _10a is ethyl, and X ₅ is -COOX ₁₀ , wherein X ₁₀ is t-butyl. 127. The composition of claim 127, wherein X ₃ is isobutenyl, X ₅ is -COOX ₁₀ (wherein X ₁₀ is t-butyl) and R _10a is ethyl. 123. The composition of claim 122, wherein X ₃ is phenyl, R _10a is ethyl, and X ₅ is -COOX ₁₀ , wherein X ₁₀ is t-butyl. 93. A pharmaceutical composition comprising the taxane of claim 92 and one or more pharmaceutically acceptable carriers. 123. A method of inhibiting tumor growth in a mammal comprising orally administering a composition comprising the taxane of claim 122 and at least one pharmaceutically acceptable carrier. 134. The method of claim 132, wherein R ₁₀ is R _10a OCOO-, wherein R _10a is substituted or unsubstituted C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 133. The compound of claim 133, wherein X ₃ is phenyl, isobutenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C _2- C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl. 135. The method of claim 134, wherein X ₅ is -COX ₁₀ (wherein X ₁₀ is phenyl) or -COOX ₁₀ (wherein X ₁₀ is t-butyl). 137. The method of claim 135, wherein R _10a is methyl, ethyl or propyl. 137. The compound of claim 136, wherein X ₃ is isobutenyl, R _10a is methyl or ethyl, and X ₅ is -COX ₁₀ (where X ₁₀ is phenyl) or -COOX ₁₀ (where X ₁₀ is t-butyl) Method. 137. The method of claim 137, wherein X ₃ is isobutenyl, R _10a is ethyl and X ₅ is -COOX ₁₀ , wherein X ₁₀ is t-butyl. 134. The method of claim 132, wherein X ₃ is 2-furyl or 2-thienyl, R _10a is ethyl and X ₅ is -COOX ₁₀ , wherein X ₁₀ is t-butyl. 134. The method of claim 132, wherein X ₃ is phenyl, R _10a is ethyl and X ₅ is —COOX ₁₀ , wherein X ₁₀ is t-butyl. 93. A method of inhibiting tumor growth in a mammal comprising orally administering a composition comprising a taxane of claim 92 and at least one pharmaceutically acceptable carrier.