US20050020635A1 - C7 carbamoyloxy substituted taxane compositions - Google Patents
C7 carbamoyloxy substituted taxane compositions Download PDFInfo
- Publication number
- US20050020635A1 US20050020635A1 US10/867,275 US86727504A US2005020635A1 US 20050020635 A1 US20050020635 A1 US 20050020635A1 US 86727504 A US86727504 A US 86727504A US 2005020635 A1 US2005020635 A1 US 2005020635A1
- Authority
- US
- United States
- Prior art keywords
- ncoo
- substituted
- coo
- furyl
- pyridyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 [2*][C@H]1C2[C@@](C)(C([7*])C[C@H]3OC[C@@]23OC(C)=O)C([9*])C([10*])C2=C(C)[C@@H](OC(=O)[C@H](O)C(C)C)[C@H]([14*])[C@]1(O)C2(C)C Chemical compound [2*][C@H]1C2[C@@](C)(C([7*])C[C@H]3OC[C@@]23OC(C)=O)C([9*])C([10*])C2=C(C)[C@@H](OC(=O)[C@H](O)C(C)C)[C@H]([14*])[C@]1(O)C2(C)C 0.000 description 7
- YORWDRUTBYUMDZ-DZDYHTTFSA-N C.C=C(C)OC.CC(=O)OCC(=O)Cl.CC(=O)O[C@H]1C(=O)N(C2=CC=C(CO)C=C2)[C@H]1C1=CC=CO1.CC(=O)O[C@H]1C(=O)N(C2=CC=C(CO)C=C2)[C@H]1C1=CC=CO1.CC(=O)O[C@H]1C(=O)N[C@H]1C1=CC=CO1.CCN(CC)CC.COC1=CC=C(/N=C/C2=CC=CO2)C=C1.COC1=CC=C(N)C=C1.O=C1N[C@@H](C2=CC=CO2)[C@H]1O.O=CC1=CC=CO1 Chemical compound C.C=C(C)OC.CC(=O)OCC(=O)Cl.CC(=O)O[C@H]1C(=O)N(C2=CC=C(CO)C=C2)[C@H]1C1=CC=CO1.CC(=O)O[C@H]1C(=O)N(C2=CC=C(CO)C=C2)[C@H]1C1=CC=CO1.CC(=O)O[C@H]1C(=O)N[C@H]1C1=CC=CO1.CCN(CC)CC.COC1=CC=C(/N=C/C2=CC=CO2)C=C1.COC1=CC=C(N)C=C1.O=C1N[C@@H](C2=CC=CO2)[C@H]1O.O=CC1=CC=CO1 YORWDRUTBYUMDZ-DZDYHTTFSA-N 0.000 description 1
- LJBDSLDFAWUOCF-AZZUUREOSA-N CC(=O)O[C@@]12CC[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](C)C4=CC=CC=C4)C[C@@](O)([C@@H](OC(=O)C4=CC=CC=C4)C12)C3(C)C Chemical compound CC(=O)O[C@@]12CC[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](C)C4=CC=CC=C4)C[C@@](O)([C@@H](OC(=O)C4=CC=CC=C4)C12)C3(C)C LJBDSLDFAWUOCF-AZZUUREOSA-N 0.000 description 1
- IGIJTYKBUCZWGB-GPQNYWIZSA-N CC(=O)O[C@@]12CO[C@@H]1C[C@H](OP(P(P)P)P(P)P)[C@@]1(C)C(=O)[C@H](OP(P(P)P)P(PP)P(P)P)C3=C(C)[C@@H](C)C[C@@](O)([C@@H](OC(=O)C4=CC=CC=C4)C12)C3(C)C Chemical compound CC(=O)O[C@@]12CO[C@@H]1C[C@H](OP(P(P)P)P(P)P)[C@@]1(C)C(=O)[C@H](OP(P(P)P)P(PP)P(P)P)C3=C(C)[C@@H](C)C[C@@](O)([C@@H](OC(=O)C4=CC=CC=C4)C12)C3(C)C IGIJTYKBUCZWGB-GPQNYWIZSA-N 0.000 description 1
- RCINICONZNJXQF-VAZQATRQSA-N CC(=O)O[C@H]1C(=O)[C@@]2(C)C([C@H](OC(=O)C3=CC=CC=C3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)C4=CC=CC=C4)C4=CC=CC=C4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O Chemical compound CC(=O)O[C@H]1C(=O)[C@@]2(C)C([C@H](OC(=O)C3=CC=CC=C3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)C4=CC=CC=C4)C4=CC=CC=C4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O RCINICONZNJXQF-VAZQATRQSA-N 0.000 description 1
- NUSZAKAULKAWJZ-FCGTXVOASA-N CN[C@@H](C)[C@@H](OPP)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)C3=CC=CC=C3)C3[C@](C)(C(=O)[C@H](OP(P(P)P)P(PP)P(P)P)C(=C1C)C2(C)C)[C@@H](O)C[C@H]1OC[C@@]31OC(C)=O Chemical compound CN[C@@H](C)[C@@H](OPP)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)C3=CC=CC=C3)C3[C@](C)(C(=O)[C@H](OP(P(P)P)P(PP)P(P)P)C(=C1C)C2(C)C)[C@@H](O)C[C@H]1OC[C@@]31OC(C)=O NUSZAKAULKAWJZ-FCGTXVOASA-N 0.000 description 1
- OUUJSMGRXAGHLC-DTWKUNHWSA-N COC(C)(C)O[C@H]1C(=O)N[C@H]1C1=CC=CO1 Chemical compound COC(C)(C)O[C@H]1C(=O)N[C@H]1C1=CC=CO1 OUUJSMGRXAGHLC-DTWKUNHWSA-N 0.000 description 1
- FFAHLMLDUMKVOX-IUYQGCFVSA-N C[C@H]1[C@@H](OPP)C(=O)N1C Chemical compound C[C@H]1[C@@H](OPP)C(=O)N1C FFAHLMLDUMKVOX-IUYQGCFVSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention is directed to novel taxanes which have exceptional utility as antitumor agents.
- Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2′R, 3′S configuration and the following structural formula: wherein Ac is acetyl.
- taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain types of cancers and toxicity to subjects when administered at various doses. Accordingly, a need remains for additional chemotherapeutic agents with improved efficacy and less toxicity.
- taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity.
- these taxanes possess a carbamoyloxy substituent at C-7, a hydroxy substituent at C-10 and a range of C-3′ substituents.
- the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a pharmaceutically acceptable carrier, and to methods of administration.
- the taxanes of the present invention correspond to structure (1): wherein
- R 2 is an ester (R 2a C(O)O—), a carbamate (R 2a R 2b NC(O)O—), a carbonate (R 2a OC(O)O—), or a thiocarbamate (R 2a SC(O)O—) wherein R 2a and R 2b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- R 2 is an ester (R 2a C(O)O—), wherein R 2a is aryl or heteroaromatic.
- 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.
- R 7 is R 7a R 7b NCOO— wherein R 7a and R 7b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
- exemplary preferred R 7 substituents include R 7a R 7b NCOO— wherein (a) R 7a and R 7b are each hydrogen, (b) one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C 1 to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or
- R 7 substituents may be those identified elsewhere herein for substituted hydrocarbyl.
- preferred R 7 substituents include R 7a R 7b NCOO— wherein one of R 7a and R 7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
- R 9 is keto in one embodiment of the present invention
- R 9 may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, ⁇ - or ⁇ -hydroxy or ⁇ - or ⁇ -acyloxy.
- R 9 when R 9 is acyloxy, it may be an ester (R 9a C(O)O—), a carbamate (R 9a R 9b NC(O)O—), a carbonate (R 9a OC(O)O—), or a thiocarbamate (R 9a SC(O)O—) wherein R 9a and R 9b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
- R 9 is an ester (R 9a C(O)O—)
- R 9a is or unsubstituted alkyl, or unsubstituted alkenyl, or unsubstituted aryl or or unsubstituted heteroaromatic. Still more preferably, R 9 is an ester (R 9a C(O)O—), wherein R 9a is substituted or unsubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or or unsubstituted pyridyl.
- 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, branched or cyclic), or hexyl (straight, branched or cyclic).
- 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) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
- Exemplary 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, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl.
- Exemplary preferred X 3 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.
- Exemplary X 5 substituents include —COX 10 , —COOX 10 or —CONHX 10 wherein X 10 is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic.
- Exemplary preferred X 5 substituents include —COX 10 , —COOX 10 or —CONHX 10 wherein X 10 is (i) substituted or unsubstituted C 1 to C 8 alkyl such as substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (straight, branched or cyclic), or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight,
- the taxanes of the present invention correspond to structure (2): wherein
- R 7 may be R 7a R 7b NCOO— wherein one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C 1 to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substituted phenyl such
- R 7 substituents include R 7a R 7b NCOO— wherein one of R 7a and R 7b is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted methyl, ethyl, or straight, branched or cyclic propyl.
- preferred R 7 substituents include R 7a R 7b NCOO— wherein one of R 7a and R 7b is hydrogen and the other is substituted or unsubstituted phenyl or heterocyclo.
- X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R 7a , R 7b , and X 3 are selected from among these, in one embodiment X 5 is selected from —COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
- X 5 is selected from —COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is —COOX 10 wherein X 10 is alkyl, preferably t-butyl.
- X 5 is —COOX 10 wherein X 10 is tert-butyl or X 5 is —COX 10 wherein X 10 is phenyl
- X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl
- R 7 is R 7a R 7b NCOO—, one of R 7a and R 7b is hydrogen and the other is substituted or unsubstituted C 1 to C8 alkyl, phenyl or heterocyclo.
- X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is keto and R 14 is hydrido.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is keto and R 14 is hydrido.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is keto and R 14 is hydroxy.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is hydroxy
- R 14 is hydroxy.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is hydroxy and R 14 is hydrido.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is acyloxy
- R 14 is hydroxy.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is acyloxy
- R 14 is hydrido.
- R 7 and R 10 may each have the beta stereochemical configuration
- R 7 and R 10 may each have the alpha stereochemical configuration
- R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
- R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
- X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is keto and R 14 is hydrido.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is keto and R 14 is hydrido.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is keto and R 14 is hydroxy.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is hydroxy
- R 14 is hydroxy.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is hydroxy and R 14 is hydrido.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is acyloxy
- R 14 is hydroxy.
- X 3 is heterocyclo
- X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl
- R 2 is benzoyl
- R 9 is acyloxy
- R 14 is hydrido.
- R 7 and R 10 may each have the beta stereochemical configuration
- R 7 and R 10 may each have the alpha stereochemical configuration
- R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
- R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
- Taxanes having the general formula 1 may be obtained by carbamoylation of a suitably protected taxane intermediate having the following formula: wherein X 3 and X 5 are as previously defined, P 2 and P 10 are hydroxy protecting groups, by reaction with an isocyanate or a carbamoyl chloride, followed by removal of the hydroxy protecting groups.
- the intermediate taxane may be obtained by treatment of ⁇ -lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a ⁇ -amido ester substituent at C-13 (as described more fully in Holton U.S. Pat. No. 5,466,834), followed by removal of P 7 .
- the ⁇ -lactam has the following structural formula (3): wherein P 2 is a hydroxy protecting group and X 3 and X 5 are as previously defined and the alkoxide has the structural formula (4): wherein M is a metal or ammonium, and P 7 and P 10 are hydroxy protecting groups.
- the alkoxide may be prepared from 10-deacetylbaccatin III by protection of the C-7 and C-10 hydroxyl groups (as described more fully in Holton et al., PCT Patent Application WO 99/09021) followed by treatment with a metallic amide.
- Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Pat. No. 5,728,725 or Springfield et al., U.S. Pat. No. 6,002,023.
- Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No. 5,352,806.
- Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.
- the ⁇ -lactam may be prepared as described in Holton, U.S. Pat. No. 5,430,160 and the resulting enatiomeric mixtures of ⁇ -lactams may be resolved by a stereoselective hydrolysis using a lipase or enzyme as described, for example, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614 or a liver homogenate as described, for example, in PCT patent application No. 00/41204.
- the ⁇ -lactam in a preferred embodiment in which the ⁇ -lactam is furyl substituted at the C(4) position, can be prepared as illustrated in the following reaction scheme: wherein Ac is acetyl, NEt 3 is triethylamine, CAN is ceric ammonium nitrate, and p-TsOH is p-toluenesulfonic acid.
- the beef liver resolution may be carried out, for example, by combining the enatiomeric ⁇ -lactam mixture with a beef liver suspension (prepared, for example, by adding 20 g of frozen beef liver to a blender and then adding a pH 8 buffer to make a total volume of 1 L).
- Compounds of formula 1 of the instant invention are useful for inhibiting tumor growth in mammals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the instant invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier.
- the carrier also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the antitumor compounds.
- the carrier is “pharmaceutically or pharmacologically acceptable” if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate.
- compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper formulation is dependent upon the route of administration chosen.
- compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route.
- Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
- parenteral e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal
- topical nasal, transdermal, intraocular
- intravesical, intrathecal enteral
- compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517, the contents of which are incorporated herein by reference).
- compositions are preferably formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally.
- Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 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 of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier.
- suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid.
- such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption.
- the antitumor compounds of the present invention are also preferably formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal routes.
- the compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a pharmaceutically acceptable carrier.
- Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art.
- Suitable carriers used in formulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.
- nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.
- Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., ⁇ -glycerol formal, ⁇ -glycerol formal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benz
- Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution).
- oils rich in triglycerides for example, safflower oil, soybean oil or mixtures thereof
- alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution).
- triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn®II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), natural or synthetic glycerol derivatives containing the docosahexaenoyl group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® (from Martek Biosciences Corp., Columbia
- compositions of the invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total composition, as is well known in the formulation art.
- Such additives include cryoprotective agents for preventing reprecipitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cety
- a pharmaceutical composition of the invention comprises at least one nonaqueous, pharmaceutically acceptable solvent and an antitumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being bound to a particular theory, it is believed that the ethanol solubility of the antitumor compound may be directly related to its efficacy.
- the antitumor compound can also be capable of being crystallized from a solution. In other words, a crystalline antitumor compound, such as compound 1393, can be dissolved in a solvent to form a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound.
- the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measured according to the protocol set forth in the working examples.
- ID50 value i.e, the drug concentration producing 50% inhibition of colony formation
- Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner.
- Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in treating cancer. It is understood that the dosage of the antitumor compounds will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of antitumor compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the antitumor compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art.
- an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route.
- the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m 2 of patient body surface area, or at least 50, 100,150, 200, 300, 400, or 500 mg of the antitumor compound per m 2 of patient body surface area, wherein the average body surface area for a human is 1.8 m 2 .
- a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m 2 of patient body surface area, more preferably from about 25 to about 400 mg/M 2 even more preferably, from about 40 to about 300 mg/m 2 , and even more preferably from about 50 to about 200 mg/m 2 .
- the compositions for parenteral administration are prepared in such a way that a single dose contains at least 20 mg of the antitumor compound per m 2 of patient body surface area, or at least 40, 50,100,150, 200, 300, 400, or 500 mg of the antitumor compound per m 2 of patient body surface area.
- a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m 2 of patient body surface area, more preferably from about 40 to about 400 mg/m 2, and even more preferably, from about 60 to about 350 mg/m 2 .
- the dosage may vary depending on the dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose ranges. The most preferred dosage will be tailored to the individual subject, as is understood and determinable by one of ordinary skill in the art without undue experimentation.
- the concentration of the antitumor compound in a liquid pharmaceutical composition is preferably between about 0.01 mg and about 10 mg per ml of the composition, more preferably between about 0.1 mg and about 7 mg per ml, even more preferably between about 0.5 mg and about 5 mg per ml, and most preferably between about 1.5 mg and about 4 mg per ml. Relatively low concentrations are generally preferred because the antitumor compound is most soluble in the solution at low concentrations.
- the concentration of the antitumor compound in a solid pharmaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %.
- solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution.
- a pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride)
- An appropriate volume of a carrier which is a solution, such as Cremophor® EL solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient.
- a pharmaceutically acceptable solution for oral administration e.g., ethanol or methylene chloride
- powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g.,ethanol or methylene chloride) to form a solution.
- the solvent can optionally be capable of evaporating when the solution is dried under vacuum.
- An additional carrier can be added to the solution prior to drying, such as Cremophor® EL solution.
- the resulting solution is dried under vacuum to form a glass.
- the glass is then mixed with a binder to form a powder.
- the powder can be mixed with fillers or other conventional tabletting agents and processed to form a tablet for oral administration to a patient.
- the powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration.
- Emulsions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution.
- An appropriate volume of a carrier which is an emulsion, such as Liposyn® II or Liposyn® III emulsion, is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient.
- emulsions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
- Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution.
- a pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride)
- An appropriate volume of a carrier which is a solution, such as Cremophor® solution is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient.
- such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
- the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable taxane concentration prior to use as is known in the art.
- hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
- substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom.
- substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
- alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
- alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
- aryl or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
- halogen or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
- heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
- the heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
- heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
- substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- heteroaromatic as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
- the heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
- Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
- acyl denotes the moiety formed by removal of the hydroxyl group from the group —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R 1 , R 1 O—, R 1 R 2 N—, or R 1 S—, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
- acyloxy denotes an acyl group as described above bonded through an oxygen linkage (—O—), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”
- alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted hydrocarbon moieties.
- hydroxyl protecting group and “hydroxy protecting group” as used herein denote a group capable of protecting a free hydroxyl group (“protected hydroxyl”) which, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule.
- protected hydroxyl a group capable of protecting a free hydroxyl group
- a variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in “Protective Groups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser.
- Exemplary 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.
- Example 1 The procedures described in Example 1 were repeated, but other suitably protected ⁇ -lactams and acylating agents were substituted for the ⁇ -lactam and acylating agent of Example 1 to prepare the series of compounds having the combination of substituents identified in the following table.
- R 7 is as previously defined, including wherein R 7 is R 7a R 7b NCOO— and (a) R 7a and R 7b are each hydrogen, (b) one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C 1 to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 3 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 3 to C 8 alkynyl such as ethynyl or straight or
- R 7 may be R 7a R 7b NCOO— wherein one of R 7a and R 7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
- R 10 is hydroxy and R 7 in each of the series (that is, each of series “A” through “K”) is as previously defined, including wherein R 7 is R 7a R 7b NCOO— and one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C 1 to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or straight or branched propy
- substituents may be those identified elsewhere herein for substituted hydrocarbyl.
- preferred R 7 substituents include R 7a R 7b NCOO— wherein one of R 7a and R 7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
- preferred R 7 substituents include R 7a R 7b NCOO— wherein one of R 7a and R 7b is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl.
- X 10 is as otherwise as defined herein.
- heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 7 and R 10 each have the beta stereochemical configuration.
- X 10 and R 2a are as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 and R 10 each have the beta stereochemical configuration.
- X 10 and R 9a are as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 , R 9 and R 10 each have the beta stereochemical configuration.
- X 10 is as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 7 , R 9 (series D only) and R 10 each have the beta stereochemical configuration.
- X 10 , R 2a and R 9a are as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 , R 9 and R 10 each have the beta stereochemical configuration.
- X 10 and R 2a are as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 , R 9 and R 10 each have the beta stereochemical configuration.
- X 10 is as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 and R 10 each have the beta stereochemical configuration.
- X 10 and R 2a are as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 and R 10 each have the beta stereochemical configuration.
- X 10 and R 2a are as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 , R 9 and R 10 each have the beta stereochemical configuration.
- X 10 , R 2a and R 9a are as otherwise as defined herein.
- heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl
- X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
- R 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
- R 7 , R 9 and R 10 each have the beta stereochemical configuration.
- any substituents of each X 3 , X 5 , R 2 , R 7 , and R 9 may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
- HCT116 Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a CO 2 incubator at 37° C. for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37° C.
- medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin
- the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound.
- HBSS Hank's Balance Salt Solution
Abstract
Taxanes having a carbamoyloxy substituent at C(7), a hydroxy substituent at C(10, and a range of C(2), C(9), C(14), and side chain substituents.
Description
- This application claims priority from U.S. provisional application Ser. No. 60/179,670, filed on Feb. 2, 2000.
- The present invention is directed to novel taxanes which have exceptional utility as antitumor agents.
- The taxane family of terpenes, of which baccatin III and taxol are members, has been the subject of considerable interest in both the biological and chemical arts. Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2′R, 3′S configuration and the following structural formula:
wherein Ac is acetyl. -
- Although taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain types of cancers and toxicity to subjects when administered at various doses. Accordingly, a need remains for additional chemotherapeutic agents with improved efficacy and less toxicity.
- Among the objects of the present invention, therefore, is the provision of taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity. In general, these taxanes possess a carbamoyloxy substituent at C-7, a hydroxy substituent at C-10 and a range of C-3′ substituents.
- Briefly, therefore, the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a pharmaceutically acceptable carrier, and to methods of administration.
- Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
-
-
- R2 is acyloxy;
- R7 is carbamoyloxy;
- R9 is keto, hydroxy, or acyloxy;
- R10 is hydroxy;
- R14 is hydrido or hydroxy;
- X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
- X5 is —COX10, —COOX10, or —CONHX10;
- X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
- Ac is acetyl; and
- R7, R9, and R10 independently have the alpha or beta stereochemical configuration.
- In one embodiment, R2 is an ester (R2aC(O)O—), a carbamate (R2aR2bNC(O)O—), a carbonate (R2aOC(O)O—), or a thiocarbamate (R2aSC(O)O—) wherein R2a and R2bare independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, R2 is an ester (R2aC(O)O—), wherein R2ais aryl or heteroaromatic. In another preferred embodiment, R2 is an ester (R2aC(O)O—), wherein R2a is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R2 is benzoyloxy.
- In one embodiment, R7 is R7aR7bNCOO— wherein R7a and R7b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. Exemplary preferred R7 substituents include R7aR7bNCOO— wherein (a) R7a and R7b are each hydrogen, (b) one of R7a and R7b is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, or (c) R7a and R7b are independently (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R7 substituents include R7aR7bNCOO— wherein one of R7a and R7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
- While R9 is keto in one embodiment of the present invention, in other embodiments R9 may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, α- or β-hydroxy or α- or β-acyloxy. For example, when R9 is acyloxy, it may be an ester (R9aC(O)O—), a carbamate (R9aR9bNC(O)O—), a carbonate (R9aOC(O)O—), or a thiocarbamate (R9aSC(O)O—) wherein R9a and R9b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R9 is an ester (R9aC(O)O—), R9a is or unsubstituted alkyl, or unsubstituted alkenyl, or unsubstituted aryl or or unsubstituted heteroaromatic. Still more preferably, R9 is an ester (R9aC(O)O—), wherein R9a is substituted or unsubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or or unsubstituted pyridyl. In one embodiment R9 is (R9aC(O)O—) wherein R9a is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl, (straight, branched or cyclic), or hexyl (straight, branched or cyclic). In another embodiment R9 is (R9aC(O)O—) wherein R9a 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) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
- Exemplary X3 substituents include substituted or unsubstituted C2 to C8 alkyl, substituted or unsubstituted C2 to C8 alkenyl, substituted or unsubstituted C2 to C8 alkynyl, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X3 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.
- Exemplary X5 substituents include —COX10, —COOX10 or —CONHX10 wherein X10 is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred X5 substituents include —COX10, —COOX10 or —CONHX10 wherein X10 is (i) substituted or unsubstituted C1 to C8 alkyl such as substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (straight, branched or cyclic), or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C2 to C8 alkenyl such as 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); (iii) substituted or unsubstituted C2 to C8 alkynyl such as substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or hexynyl (straight or branched); (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
-
-
- R7 is carbamoyloxy;
- R10 is hydroxy;
- X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;
- X5 is —COX10, —COOX10, or —CONHX10; and
- X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
- For example, in this preferred embodiment in which the taxane corresponds to structure (2), R7 may be R7aR7bNCOO— wherein one of R7a and R7b is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substituted phenyl such as nitro, alkoxy or halosubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R7 substituents include R7aR7bNCOO— wherein one of R7a and R7b is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R7 substituents include R7aR7bNCOO— wherein one of R7a and R7b is hydrogen and the other is substituted or unsubstituted phenyl or heterocyclo. While R7a and R7b are selected from among these, in one embodiment X3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R7a, R7b, and X3 are selected from among these, in one embodiment X5 is selected from —COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R7a, R7b, and X3 are selected from among these, in one embodiment X5 is selected from —COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is —COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure 2 in which (i) X5 is —COOX10 wherein X10 is tert-butyl or X5 is —COX10 wherein X10 is phenyl, (ii) X3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R7 is R7aR7bNCOO—, one of R7a and R7b is hydrogen and the other is substituted or unsubstituted C1 to C8 alkyl, phenyl or heterocyclo.
- Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R7 is R7aR7bNCOO— wherein R7a is methyl and R7b is hydrido. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
- Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R7 is R7aR7bNCOO— wherein R7a is ethyl and R7b is hydrido. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
- Taxanes having the general formula 1 may be obtained by carbamoylation of a suitably protected taxane intermediate having the following formula:
wherein X3 and X5 are as previously defined, P2 and P10 are hydroxy protecting groups, by reaction with an isocyanate or a carbamoyl chloride, followed by removal of the hydroxy protecting groups. - The intermediate taxane may be obtained by treatment of β-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a β-amido ester substituent at C-13 (as described more fully in Holton U.S. Pat. No. 5,466,834), followed by removal of P7. The β-lactam has the following structural formula (3):
wherein P2 is a hydroxy protecting group and X3 and X5 are as previously defined and the alkoxide has the structural formula (4):
wherein M is a metal or ammonium, and P7 and P10 are hydroxy protecting groups. - The alkoxide may be prepared from 10-deacetylbaccatin III by protection of the C-7 and C-10 hydroxyl groups (as described more fully in Holton et al., PCT Patent Application WO 99/09021) followed by treatment with a metallic amide.
- Derivatives of 10-deacetylbaccatin III having alternative substituents at C(2), C(9) and C(14) and processes for their preparation are known in the art. Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat. No. 6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No. 5,352,806. Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.
- Processes for the preparation and resolution of the β-lactam starting material are generally well known. For example, the β-lactam may be prepared as described in Holton, U.S. Pat. No. 5,430,160 and the resulting enatiomeric mixtures of β-lactams may be resolved by a stereoselective hydrolysis using a lipase or enzyme as described, for example, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614 or a liver homogenate as described, for example, in PCT patent application No. 00/41204. In a preferred embodiment in which the β-lactam is furyl substituted at the C(4) position, the β-lactam can be prepared as illustrated in the following reaction scheme:
wherein Ac is acetyl, NEt3 is triethylamine, CAN is ceric ammonium nitrate, and p-TsOH is p-toluenesulfonic acid. The beef liver resolution may be carried out, for example, by combining the enatiomeric β-lactam mixture with a beef liver suspension (prepared, for example, by adding 20 g of frozen beef liver to a blender and then adding a pH 8 buffer to make a total volume of 1 L). - Compounds of formula 1 of the instant invention are useful for inhibiting tumor growth in mammals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the instant invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier. The carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the antitumor compounds. The carrier is “pharmaceutically or pharmacologically acceptable” if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate.
- The pharmaceutical compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper formulation is dependent upon the route of administration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
- Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517, the contents of which are incorporated herein by reference).
- The compositions are preferably formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally. Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 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).
- The compositions of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption.
- The antitumor compounds of the present invention are also preferably formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal routes. The compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art.
- Suitable carriers used in formulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable liquid.
- Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerol formal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, or tri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated)30-60 sorbitol poly(oleate)2-4, poly(oxyethylene)15-20 monooleate, poly(oxyethylene)15-20 mono 12-hydroxystearate, and poly(oxyethylene)15-20 mono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, Del., polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C4-C22 fatty acid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil and glycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-1 5, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate.
- Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds., )(Marcel Dekker, Inc., New York, N.Y., 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), A. J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, J
OURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963). - Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution). Commercially available triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn®II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Ill.), natural or synthetic glycerol derivatives containing the docosahexaenoyl group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro® (from Daito Enterprises, Los Angeles, Calif.), Soyacal®, and Travemulsion®. Ethanol is a preferred solvent for use in dissolving the antitumor compound to form solutions, emulsions, and the like.
- Additional minor components can be included in the compositions of the invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total composition, as is well known in the formulation art. Such additives include cryoprotective agents for preventing reprecipitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g., bentonites), adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, or sorbitol, cellulose, or calcium phosphate), diluents (e.g., water, saline, electrolyte solutions), binders (e.g., starches such as maize starch, wheat starch, rice starch, or potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g., starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as 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 (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, and thiophenols).
- In a preferred embodiment, a pharmaceutical composition of the invention comprises at least one nonaqueous, pharmaceutically acceptable solvent and an antitumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being bound to a particular theory, it is believed that the ethanol solubility of the antitumor compound may be directly related to its efficacy. The antitumor compound can also be capable of being crystallized from a solution. In other words, a crystalline antitumor compound, such as compound 1393, can be dissolved in a solvent to form a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound. It is also preferred that the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measured according to the protocol set forth in the working examples.
- Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner.
- Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in treating cancer. It is understood that the dosage of the antitumor compounds will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of antitumor compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the antitumor compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route. Preferably, the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m2 of patient body surface area, or at least 50, 100,150, 200, 300, 400, or 500 mg of the antitumor compound per m2 of patient body surface area, wherein the average body surface area for a human is 1.8 m2. Preferably, a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m2 of patient body surface area, more preferably from about 25 to about 400 mg/M2 even more preferably, from about 40 to about 300 mg/m2, and even more preferably from about 50 to about 200 mg/m2. Preferably, the compositions for parenteral administration are prepared in such a way that a single dose contains at least 20 mg of the antitumor compound per m2 of patient body surface area, or at least 40, 50,100,150, 200, 300, 400, or 500 mg of the antitumor compound per m2 of patient body surface area. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m2 of patient body surface area, more preferably from about 40 to about 400 mg/m2, and even more preferably, from about 60 to about 350 mg/m2. However, the dosage may vary depending on the dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose ranges. The most preferred dosage will be tailored to the individual subject, as is understood and determinable by one of ordinary skill in the art without undue experimentation.
- The concentration of the antitumor compound in a liquid pharmaceutical composition is preferably between about 0.01 mg and about 10 mg per ml of the composition, more preferably between about 0.1 mg and about 7 mg per ml, even more preferably between about 0.5 mg and about 5 mg per ml, and most preferably between about 1.5 mg and about 4 mg per ml. Relatively low concentrations are generally preferred because the antitumor compound is most soluble in the solution at low concentrations. The concentration of the antitumor compound in a solid pharmaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %.
- In one embodiment, solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® EL solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol, which is known in the art to cause adverse physiological effects when administered at certain concentrations in oral formulations.
- In another embodiment, powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g.,ethanol or methylene chloride) to form a solution. The solvent can optionally be capable of evaporating when the solution is dried under vacuum. An additional carrier can be added to the solution prior to drying, such as Cremophor® EL solution. The resulting solution is dried under vacuum to form a glass. The glass is then mixed with a binder to form a powder. The powder can be mixed with fillers or other conventional tabletting agents and processed to form a tablet for oral administration to a patient. The powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration.
- Emulsions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is an emulsion, such as Liposyn® II or Liposyn® III emulsion, is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient. If desired, such emulsions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
- Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
- If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable taxane concentration prior to use as is known in the art.
- Definitions
- The terms “hydrocarbon” and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
- The “substituted hydrocarbyl” moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
- Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
- Unless otherwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
- The terms “aryl” or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
- The terms “halogen” or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
- The terms “heterocyclo” or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- The term “heteroaromatic” as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
- The term “acyl,” as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R1, R1O—, R1R2N—, or R1S—, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
- The term “acyloxy,” as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (—O—), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”
- Unless otherwise indicated, the alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted hydrocarbon moieties.
- Unless otherwise indicated, the carbamoyloxy moieties described herein are derivatives of carbamic acid in which one or both of the amine hydrogens is optionally replaced by a hydrocarbyl, substituted hydrocarbyl or heterocyclo moiety.
- The terms “hydroxyl protecting group” and “hydroxy protecting group” as used herein denote a group capable of protecting a free hydroxyl group (“protected hydroxyl”) which, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule. A variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in “Protective Groups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser. Exemplary 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; “Bz” means benzoyl; “Et” means ethyl; “Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl; “tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unless otherwise defined; “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, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; “protected hydroxy” means—OP wherein P is a hydroxy protecting group; “PhCO” means phenylcarbonyl; “tBuOCO” and “Boc” mean tert-butoxycarbonyl; “tAmOCO” means tert-amyloxycarbonyl; “2-FuCO” means 2-furylcarbonyl; “2-ThCO” means 2-thienylcarbonyl; “2-PyCO” means 2-pyridylcarbonyl; “3-PyCO” means 3-pyridylcarbonyl; “4-PyCO” means 4-pyridylcarbonyl; “C4H7CO” means butenylcarbonyl; “tC3H5CO” means trans-propenylcarbonyl; “EtOCO” means ethoxycarbonyl; “ibueCO” means isobutenylcarbonyl; “iBuCO” means isobutylcarbonyl; “iBuOCO” means isobutoxycarbonyl; “iPrOCO” means isopropyloxycarbonyl; “nPrOCO” means n-propyloxycarbonyl; “nPrCO” means n-propylcarbony; “ibue” means isobutenyl; “THF” means tetrahydrofuran; “DMAP” means 4-dimethylamino pyridine; “LHMDS” means Lithium HexamethylDiSilazanide.
- The following examples illustrate the invention.
- To a solution of N-debenzoyl-N-isobutenyl-3′-desphenyl-3′-(2-furyl)-2′-(2-methoxy-2-propyl)-10-triethylsilyl taxol (400 mg, 0.413 mmol) in 4 mL anhydrous pyridine was added 4-dimethylaminopyridine (10 mg, 0.08 mmol) under a nitrogen atmosphere. To this mixture was added dropwise phenyl isocyanate (112 L, 1.034 mmol). TLC (silica gel, 2:3 ethyl acetate:hexane) after 3 h showed no starting material. The reaction mixture was cooled to 0° C. (ice-water bath) and quenched by adding 50 L of water.
- To the reaction at 0° C. (ice-water bath) was added 4 mL of acetonitrile and 2 mL of 48% aqueous hyderofluoric acid and the cooling bath removed. The reaction was stirred at room temperature for 12.5 h and then diluted with 60 mL of ethyl acetate and washed with 10 mL of saturated aqueous NaHCO3 followed by 15 mL of saturated aqueous NaCl. The organic layer was dried over Na2SO4 and concentrated under reduce pressure to give 390 mg of an off-white solid which was purified byflash-chromatography (silica gel,1:1 ethyl acetate:hexane)to give 320 mg (86%) of N-debenzoyl-N-isobutenyl-3′-desphenyl-3′-(2-furyl)-7-phenylcarbamoyl taxol: mp 188-89C; 1H NMR (CDCl3) 8.11 (m, 2H), 7.60(m,1H), 7.46-7.51 (m, 2H), 7.26-7.40(m, 6H), 6.34(dd, J=3.1, 1.5 Hz, 1H), 6.25 (d, J=3.1 Hz, 1H), 6.21(dd, J=8.8,8.7 Hz, 1H), 5.67(2H), 5.47(2H), 4.98-5.01 (m, 3H), 4.76(m, 1H), 4.32 (d, J=8.0 Hz, 1H), 4.21 (d, J=8.0 Hz, 1H), 4.09(d, J=7.6 Hz, 1H), 3.99 (m, 1H), 3.30 (d, J=5.5 Hz, 1H), 2.60-2.68(m, 1H), 2.43 (s, 3H), 2.37 (m, 1H), 2.08( m, 1H), 1.98 (s, 3H), 1.91 (bs, 3H), 1.84 (bs, 3H), 1.80 (s, 3H), 1.23(s, 3H), 1.10(s, 3H); Anal. Calcd. for C48H54N2O15: C, 64.13; H, 6.05. Found: C, 63.78; H, 6.20.
- The procedures described in Example 1 were repeated, but other suitably protected β-lactams and acylating agents were substituted for the β-lactam and acylating agent of Example 1 to prepare the series of compounds having the combination of substituents identified in the following table.
Compound X5 X3 R7 5522 ibueCO— 2-furyl 3,4-diFPhNHCOO— 6404 tAmOCO— 2-furyl 3,4-diFPhNHCOO— 5415 tBuOCO— 2-furyl 3,4-diFPhNHCOO— 5800 tC3H5CO— 2-furyl 3,4-diFPhNHCOO— 5575 ibueCO— 2-furyl C3H5NHCOO— 5385 tbuOCO— 2-furyl C3H5NHCOO— 5844 tC3H5CO— 2-furyl C3H5NHCOO— 5373 tBuOCO— 2-furyl chexNHCOO— 5895 tC3H5CO— 2-furyl chexNHCOO— 5588 ibueCO— 2-furyl EtNHCOO— 5393 tBuOCO— 2-furyl EtNHCOO— 6696 tBuOCO— 2-furyl EtNHCOO— 5822 tC3H5CO— 2-furyl EtNHCOO— 5565 ibueCO— 2-furyl mnipNHCOO— 6476 tAmOCO— 2-furyl mnipNHCOO— 5400 tBuOCO— 2-furyl mnipNHCOO— 5747 tC3H5CO— 2-furyl mnipNHCOO— 5535 ibueCO— 2-furyl PhNHCOO— 6399 tAmOCO— 2-furyl PhNHCOO— 5757 tC3H5CO— 2-furyl PhNHCOO— 5665 tBuOCO— 2-furyl PrNHCOO— 5454 tBuOCO— 2-furyl tBuNHCOO— - Following the processes described in Example 1 and elsewhere herein, the following specific taxanes having structural formula 14 and the combinations of substituents identified in the following table may be prepared, wherein R7 is as previously defined, including wherein R7 is R7aR7bNCOO— and (a) R7a and R7b are each hydrogen, (b) one of R7a and R7b is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C3 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C3 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, or (c) R7a and R7b are independently (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. For example, R7 may be R7aR7bNCOO— wherein one of R7a and R7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
(14) X5 X3 R7 tBuOCO— 2-furyl R7aR7bNCOO— tBuOCO— 3-furyl R7aR7bNCOO— tBuOCO— 2-thienyl R7aR7bNCOO— tBuOCO— 3-thienyl R7aR7bNCOO— tBuOCO— 2-pyridyl R7aR7bNCOO— tBuOCO— 3-pyridyl R7aR7bNCOO— tBuOCO— 4-pyridyl R7aR7bNCOO— tBuOCO— isobutenyl R7aR7bNCOO— tBuOCO— isopropyl R7aR7bNCOO— tBuOCO— cyclopropyl R7aR7bNCOO— tBuOCO— cyclobutyl R7aR7bNCOO— tBuOCO— cyclopentyl R7aR7bNCOO— tBuOCO— phenyl R7aR7bNCOO— benzoyl 2-furyl R7aR7bNCOO— benzoyl 3-furyl R7aR7bNCOO— benzoyl 2-thienyl R7aR7bNCOO— benzoyl 3-thienyl R7aR7bNCOO— benzoyl 2-pyridyl R7aR7bNCOO— benzoyl 3-pyridyl R7aR7bNCOO— benzoyl 4-pyridyl R7aR7bNCOO— benzoyl isobutenyl R7aR7bNCOO— benzoyl isopropyl R7aR7bNCOO— benzoyl cyclopropyl R7aR7bNCOO— benzoyl cyclobutyl R7aR7bNCOO— benzoyl cyclopentyl R7aR7bNCOO— benzoyl phenyl R7aR7bNCOO— 2-FuCO— 2-furyl R7aR7bNCOO— 2-FuCO— 3-furyl R7aR7bNCOO— 2-FuCO— 2-thienyl R7aR7bNCOO— 2-FuCO— 3-thienyl R7aR7bNCOO— 2-FuCO— 2-pyridyl R7aR7bNCOO— 2-FuCO— 3-pyridyl R7aR7bNCOO— 2-FuCO— 4-pyridyl R7aR7bNCOO— 2-FuCO— isobutenyl R7aR7bNCOO— 2-FuCO— isopropyl R7aR7bNCOO— 2-FuCO— cyclopropyl R7aR7bNCOO— 2-FuCO— cyclobutyl R7aR7bNCOO— 2-FuCO— cyclopentyl R7aR7bNCOO— 2-FuCO— phenyl R7aR7bNCOO— 2-ThCO— 2-furyl R7aR7bNCOO— 2-ThCO— 3-furyl R7aR7bNCOO— 2-ThCO— 2-thienyl R7aR7bNCOO— 2-ThCO— 3-thienyl R7aR7bNCOO— 2-ThCO— 2-pyridyl R7aR7bNCOO— 2-ThCO— 3-pyridyl R7aR7bNCOO— 2-ThCO— 4-pyridyl R7aR7bNCOO— 2-ThCO— isobutenyl R7aR7bNCOO— 2-ThCO— isopropyl R7aR7bNCOO— 2-ThCO— cyclopropyl R7aR7bNCOO— 2-ThCO— cyclobutyl R7aR7bNCOO— 2-ThCO— cyclopentyl R7aR7bNCOO— 2-ThCO— phenyl R7aR7bNCOO— 2-PyCO— 2-furyl R7aR7bNCOO— 2-PyCO— 3-furyl R7aR7bNCOO— 2-PyCO— 2-thienyl R7aR7bNCOO— 2-PyCO— 3-thienyl R7aR7bNCOO— 2-PyCO— 2-pyridyl R7aR7bNCOO— 2-PyCO— 3-pyridyl R7aR7bNCOO— 2-PyCO— 4-pyridyl R7aR7bNCOO— 2-PyCO— isobutenyl R7aR7bNCOO— 2-PyCO— isopropyl R7aR7bNCOO— 2-PyCO— cyclopropyl R7aR7bNCOO— 2-PyCO— cyclobutyl R7aR7bNCOO— 2-PyCO— cyclopentyl R7aR7bNCOO— 2-PyCO— phenyl R7aR7bNCOO— 3-PyCO— 2-furyl R7aR7bNCOO— 3-PyCO— 3-furyl R7aR7bNCOO— 3-PyCO— 2-thienyl R7aR7bNCOO— 3-PyCO— 3-thienyl R7aR7bNCOO— 3-PyCO— 2-pyridyl R7aR7bNCOO— 3-PyCO— 3-pyridyl R7aR7bNCOO— 3-PyCO— 4-pyridyl R7aR7bNCOO— 3-PyCO— isobutenyl R7aR7bNCOO— 3-PyCO— isopropyl R7aR7bNCOO— 3-PyCO— cyclopropyl R7aR7bNCOO— 3-PyCO— cyclobutyl R7aR7bNCOO— 3-PyCO— cyclopentyl R7aR7bNCOO— 3-PyCO— phenyl R7aR7bNCOO— 4-PyCO— 2-furyl R7aR7bNCOO— 4-PyCO— 3-furyl R7aR7bNCOO— 4-PyCO— 2-thienyl R7aR7bNCOO— 4-PyCO— 3-thienyl R7aR7bNCOO— 4-PyCO— 2-pyridyl R7aR7bNCOO— 4-PyCO— 3-pyridyl R7aR7bNCOO— 4-PyCO— 4-pyridyl R7aR7bNCOO— 4-PyCO— isobutenyl R7aR7bNCOO— 4-PyCO— isopropyl R7aR7bNCOO— 4-PyCO— cyclopropyl R7aR7bNCOO— 4-PyCO— cyclobutyl R7aR7bNCOO— 4-PyCO— cyclopentyl R7aR7bNCOO— 4-PyCO— phenyl R7aR7bNCOO— C4H7CO— 2-furyl R7aR7bNCOO— C4H7CO— 3-furyl R7aR7bNCOO— C4H7CO— 2-thienyl R7aR7bNCOO— C4H7CO— 3-thienyl R7aR7bNCOO— C4H7CO— 2-pyridyl R7aR7bNCOO— C4H7CO— 3-pyridyl R7aR7bNCOO— C4H7CO— 4-pyridyl R7aR7bNCOO— C4H7CO— isobutenyl R7aR7bNCOO— C4H7CO— isopropyl R7aR7bNCOO— C4H7CO— cyclopropyl R7aR7bNCOO— C4H7CO— cyclobutyl R7aR7bNCOO— C4H7CO— cyclopentyl R7aR7bNCOO— C4H7CO— phenyl R7aR7bNCOO— EtOCO— 2-furyl R7aR7bNCOO— EtOCO— 3-furyl R7aR7bNCOO— EtOCO— 2-thienyl R7aR7bNCOO— EtOCO— 3-thienyl R7aR7bNCOO— EtOCO— 2-pyridyl R7aR7bNCOO— EtOCO— 3-pyridyl R7aR7bNCOO— EtOCO— 4-pyridyl R7aR7bNCOO— EtOCO— isobutenyl R7aR7bNCOO— EtOCO— isopropyl R7aR7bNCOO— EtOCO— cyclopropyl R7aR7bNCOO— EtOCO— cyclobutyl R7aR7bNCOO— EtOCO— cyclopentyl R7aR7bNCOO— EtOCO— phenyl R7aR7bNCOO— ibueCO— 2-furyl R7aR7bNCOO— ibueCO— 3-furyl R7aR7bNCOO— ibueCO— 2-thienyl R7aR7bNCOO— ibueCO— 3-thienyl R7aR7bNCOO— ibueCO— 2-pyridyl R7aR7bNCOO— ibueCO— 3-pyridyl R7aR7bNCOO— ibueCO— 4-pyridyl R7aR7bNCOO— ibueCO— isobutenyl R7aR7bNCOO— ibueCO— isopropyl R7aR7bNCOO— ibueCO— cyclopropyl R7aR7bNCOO— ibueCO— cyclobutyl R7aR7bNCOO— ibueCO— cyclopentyl R7aR7bNCOO— ibueCO— phenyl R7aR7bNCOO— iBuCO— 2-furyl R7aR7bNCOO— iBuCO— 3-furyl R7aR7bNCOO— iBuCO— 2-thienyl R7aR7bNCOO— iBuCO— 3-thienyl R7aR7bNCOO— iBuCO— 2-pyridyl R7aR7bNCOO— iBuCO— 3-pyridyl R7aR7bNCOO— iBuCO— 4-pyridyl R7aR7bNCOO— iBuCO— isobutenyl R7aR7bNCOO— iBuCO— isopropyl R7aR7bNCOO— iBuCO— cyclopropyl R7aR7bNCOO— iBuCO— cyclobutyl R7aR7bNCOO— iBuCO— cyclopentyl R7aR7bNCOO— iBuCO— phenyl R7aR7bNCOO— iBuOCO— 2-furyl R7aR7bNCOO— iBuOCO— 3-furyl R7aR7bNCOO— iBuOCO— 2-thienyl R7aR7bNCOO— iBuOCO— 3-thienyl R7aR7bNCOO— iBuOCO— 2-pyridyl R7aR7bNCOO— iBuOCO— 3-pyridyl R7aR7bNCOO— iBuOCO— 4-pyridyl R7aR7bNCOO— iBuOCO— isobutenyl R7aR7bNCOO— iBuOCO— isopropyl R7aR7bNCOO— IBuOCO— cyclopropyl R7aR7bNCOO— iBuOCO— cyclobutyl R7aR7bNCOO— iBuOCO— cyclopentyl R7aR7bNCOO— iBuOCO— phenyl R7aR7bNCOO— iPrOCO— 2-furyl R7aR7bNCOO— iPrOCO— 3-furyl R7aR7bNCOO— iPrOCO— 2-thienyl R7aR7bNCOO— iPrOCO— 3-thienyl R7aR7bNCOO— iPrOCO— 2-pyridyl R7aR7bNCOO— iPrOCO— 3-pyridyl R7aR7bNCOO— iPrOCO— 4-pyridyl R7aR7bNCOO— iPrOCO— isobutenyl R7aR7bNCOO— iPrOCO— isopropyl R7aR7bNCOO— iPrOCO— cyclopropyl R7aR7bNCOO— iPrOCO— cyclobutyl R7aR7bNCOO— iPrOCO— cyclopentyl R7aR7bNCOO— iPrOCO— phenyl R7aR7bNCOO— nPrOCO— 2-furyl R7aR7bNCOO— nPrOCO— 34u1y1 R7aR7bNCOO— nPrOCO— 2-thienyl R7aR7bNCOO— nPrOCO— 3-thienyl R7aR7bNCOO— nPrOCO— 2-pyridyl R7aR7bNCOO— nPrOCO— 3-pyridyl R7aR7bNCOO— nPrOCO— 4-pyridyl R7aR7bNCOO— nPrOCO— isobutenyl R7aR7bNCOO— nPrOCO— isopropyl R7aR7bNCOO— nPrOCO— cyclopropyl R7aR7bNCOO— nPrOCO— cyclobutyl R7aR7bNCOO— nPrOCO— cyclopentyl R7aR7bNCOO— nPrOCO— phenyl R7aR7bNCOO— nPrCO— 2-furyl R7aR7bNCOO— nPrCO— 3-furyl R7aR7bNCOO— nPrCO— 2-thienyl R7aR7bNCOO— nPrCO— 3-thienyl R7aR7bNCOO— nPrCO— 2-pyridyl R7aR7bNCOO— nPrCO— 3-pyridyl R7aR7bNCOO— nPrCO— 4-pyridyl R7aR7bNCOO— nPrCO— isobutenyl R7aR7bNCOO— nPrCO— isopropyl R7aR7bNCOO— nPrCO— cyclopropyl R7aR7bNCOO— nPrCO— cyclobutyl R7aR7bNCOO— nPrCO— cyclopentyl R7aR7bNCOO— nPrCO— phenyl R7aR7bNCOO— - Following the processes described in Example 1 and elsewhere herein, the following specifictaxanes having structural formula 15 may be prepared, wherein R10 is hydroxy and R7 in each of the series (that is, each of series “A” through “K”) is as previously defined, including wherein R7 is R7aR7bNCOO— and one of R7a and R7b is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substituted phenyl such as nitro, alkoxy or halosubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R7 substituents include R7aR7bNCOO— wherein one of R7a and R7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R7 substituents include R7aR7bNCOO— wherein one of R7a and R7b is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl.
- In the “A” series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7 and R10 each have the beta stereochemical configuration.
- In the “B” series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
- In the “C” series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
- In the “D” and “E” series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, R9 (series D only) and R10 each have the beta stereochemical configuration.
- In the “F” series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
- In the “G” series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
- In the “H” series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
- In the “I” series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
- In the “J” series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
- In the “K” series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
- Any substituents of each X3, X5, R2, R7, and R9 may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
(15) Series X5 X3 R7 R2 R9 R14 A1 —COOX10 heterocyclo R7aR7bNCOO— C6H5COO— O H A2 —COX10 heterocyclo R7aR7bNCOO— C6H5COO— O H A3 —CONHX10 heterocyclo R7aR7bNCOO— C6H5COO— O H A4 —COOX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkyl A5 —COX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkyl A6 —CONHX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkyl A7 —COOX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkenyl A8 —COX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkenyl A9 —CONHX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkenyl A10 —COOX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkynyl A11 —COX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkynyl A12 —CONHX10 optionally R7aR7bNCOO— C6H5COO— O H substituted C2 to C8 alkynyl B1 —COOX10 heterocyclo R7aR7bNCOO— R2aCOO— O H B2 —COX10 heterocyclo R7aR7bNCOO— R2aCOO— O H B3 —CONHX10 heterocyclo R7aR7bNCOO— R2aCOO— O H B4 —COOX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkyl B5 —COX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkyl B6 —CONHX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkyl B7 —COOX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkenyl B8 —COX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkenyl B9 —CONHX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkenyl B10 —COOX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkynyl B11 —COX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkynyl B12 —CONHX10 optionally R7aR7bNCOO— R2aCOO— O H substituted C2 to C8 alkynyl C1 —COOX10 heterocyclo R7aR7bNCOO— C6H5COO— R9aCOO— H C2 —COOX10 heterocyclo R7aR7bNCOO— C6H5COO— R9aCOO— H C3 —CONHX10 heterocyclo R7aR7bNCOO— C6H5COO— R9aCOO— H C4 —COOX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkyl C5 —COX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkyl C6 —CONHX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkyl C7 —COOX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkenyl C8 —COX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkenyl C9 —CONHX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkenyl C10 —COOX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkynyl C11 —COX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkynyl C12 —CONHX10 optionally R7aR7bNCOO— C6H5COO— R9aCOO— H substituted C2 to C8 alkynyl D1 —COOX10 heterocyclo R7aR7bNCOO— C6H5COO— OH H D2 —COX10 heterocyclo R7aR7bNCOO— C6H5COO— OH H D3 —CONHX10 heterocyclo R7aR7bNCOO— C6H5COO— OH H D4 —COOX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkyl D5 —COX10 optionally R7aR7bNOOO— C6H5COO— OH H substituted C2 to C8 alkyl D6 —CONHX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkyl D7 —COOX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkenyl D8 —CCX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkenyl D9 —CONHX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkenyl D10 —COOX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkynyl D11 —COX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkynyl D12 —CONHX10 optionally R7aR7bNCOO— C6H5COO— OH H substituted C2 to C8 alkynyl E1 —COOX10 heterocyclo R7aR7bNCOO— C6H5COO— O OH E2 —COX10 heterocyclo R7aR7bNCOO— C6H5COO— O OH E3 —CONHX10 heterocyclo R7BR7bNCOO— C6H5COO— O OH E4 —COX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkyl E5 —COX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkyl E6 —CONHX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkyl E7 —COOX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkenyl E8 —COX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkenyl E9 —CONHX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkenyl E10 —COOX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkynyl E11 —COX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkynyl E12 —CONHX10 optionally R7aR7bNCOO— C6H5COO— O OH substituted C2 to C8 alkynyl F1 —COOX10 heterocyclo R7aR7bNCOO— R2aCOO— R9aCOO— H F2 —COX10 heterocyclo R7aR7bNCOO— R2aCOO— R9aCOO— H F3 —CONHX10 heterocyclo R7aR7bNCOO— R2aCOO— R9aCOO— H F4 —COOX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkyl F5 —COX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkyl F6 —CONHX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkyl F7 —COOX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkenyl F8 —COX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkenyl F9 —CONHX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkenyl F10 —COOX10 optionally R7aR7bNCOO— R2aOOO— R9aCOO— H substituted C2 to C8 alkynyl F11 —COX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkynyl F12 —CONHX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— H substituted C2 to C8 alkynyl G1 —COOX10 heterocyclo R7aR7bNCOO— R2aCOO— OH H G2 —COX10 heterocyclo R7aR7bNCOO— R2aCOO— OH H G3 —CONHX10 heterocyclo R7aR7bNCOO— R2aCOO— OH H G4 —COOX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkyl G5 —COX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkyl G6 —CONHX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkenyl G7 —COOX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkenyl G8 —COX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkenyl G9 —CONHX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkenyl G10 —COOX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkynyl G11 —COX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkynyl G12 —CONHX10 optionally R7aR7bNCOO— R2aCOO— OH H substituted C2 to C8 alkynyl H1 —COOX10 heterocyclo R7aR7bNCOO— C6H5COO— OH OH H2 —COX10 heterocyclo R7aR7bNCOO— C6H5COO— OH OH H3 —CONHX10 heterocyclo R7aR7bNCOO— C6H5COO— OH OH H4 —COOX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkyl H5 —COX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkyl H6 —CONHX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkyl H7 —COOX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkenyl H8 —COX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkenyl H9 —CONHX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkenyl H10 —COOX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkynyl H11 —COX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkynyl H12 —CONHX10 optionally R7aR7bNCOO— C6H5COO— OH OH substituted C2 to C8 alkynyl I1 —COOX10 heterocyclo R7aR7bNCOO— R2aCOO— O OH I2 —COX10 heterocyclo R7aR7bNCOO— R2aCOO— O OH I3 —CONHX10 heterocyclo R7aR7bNOOO— R2aCOO— O OH I4 —COOX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkyl I5 —COX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkyl I6 —CONHX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkyl I7 —COOX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkenyl I8 —COX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkenyl I9 —CONHX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkenyl I10 —COOX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkynyl I11 —COX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkynyl I12 —CONHX10 optionally R7aR7bNCOO— R2aCOO— O OH substituted C2 to C8 alkynyl J1 —COOX10 heterocyclo R7aR7bNCOO— R2aCOO— OH OH J2 —COX10 heterocyclo R7aR7bNCOO— R2aCOO— OH OH J3 —CONHX10 heterocyclo R7aR7bNCOO— R2aCOO— OH OH J4 —COOX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkyl J5 —COX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkyl J6 —CONHX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkyl J7 —COOX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkenyl J8 —COX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkenyl J9 —CONHX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkenyl J10 —COOX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkynyl J11 —COX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkynyl J12 —CONHX10 optionally R7aR7bNCOO— R2aCOO— OH OH substituted C2 to C8 alkynyl K1 —COOX10 heterocyclo R7aR7bNCOO— R2aCOO— R9aCOO— OH K2 —COX10 heterocyclo R7aR7bNCOO— R2aCOO— R9aCOO— OH K3 —CONHX10 heterocyclo R7aR7bNCOO— R2aCOO— R9aCOO— OH K4 —COOX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkyl K5 —COX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkyl K6 —CONHX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkyl K7 —COOX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkenyl K8 —COX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkenyl K9 —CONHX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkenyl K10 —COOX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkynyl K11 —COX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkynyl K12 —CONHX10 optionally R7aR7bNCOO— R2aCOO— R9aCOO— OH substituted C2 to C8 alkynyl - Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a CO2 incubator at 37° C. for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37° C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound.
IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 5522 <1 6404 <10 5415 <1 5800 <10 5575 <1 5385 <1 5844 <10 5373 <10 5895 <1 5588 <1 5393 <1 6696 <1 5822 <10 5565 <1 6476 <10 5400 <1 5747 <10 5535 <1 6399 <10 5757 <10 5665 >50 5454 <10
Claims (8)
1-164. (Canceled)
165. A method of inhibiting tumor growth in a mammal, said method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a taxane having the formula
wherein
R7 is carbamoyloxy;
R10 is hydroxy;
X3 is heterocyclo;
X5 is —COOX10;
X10 is C1-8 alkyl;
Ac is acetyl; and
Bz is benzoyl.
166. The method of claim 165 wherein X10 is substituted or unsubstitued methyl, ethyl or straight or cyclic propyl, butyl, pentyl or hexyl.
167. The method of claim 165 wherein X10 is branched propyl, pentyl or hexyl.
168. The method of any of claims 165-167 wherein X3 is furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl.
169. The method of any of claims 165-167 wherein X3 is oxazolyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, thiazolyl or isoxazolyl.
170. The method of claim 168 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/867,275 US20050020635A1 (en) | 2000-02-02 | 2004-06-14 | C7 carbamoyloxy substituted taxane compositions |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17967000P | 2000-02-02 | 2000-02-02 | |
US09/776,494 US6359154B2 (en) | 2000-02-02 | 2001-02-02 | C7 carbamoyloxy substituted taxanes |
US10/071,924 US6750245B2 (en) | 2000-02-02 | 2002-02-06 | C7 carbamate substituted taxanes |
US10/867,275 US20050020635A1 (en) | 2000-02-02 | 2004-06-14 | C7 carbamoyloxy substituted taxane compositions |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/071,924 Continuation US6750245B2 (en) | 2000-02-02 | 2002-02-06 | C7 carbamate substituted taxanes |
Publications (1)
Publication Number | Publication Date |
---|---|
US20050020635A1 true US20050020635A1 (en) | 2005-01-27 |
Family
ID=22657498
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/776,494 Expired - Fee Related US6359154B2 (en) | 2000-02-02 | 2001-02-02 | C7 carbamoyloxy substituted taxanes |
US10/071,924 Expired - Fee Related US6750245B2 (en) | 2000-02-02 | 2002-02-06 | C7 carbamate substituted taxanes |
US10/867,275 Abandoned US20050020635A1 (en) | 2000-02-02 | 2004-06-14 | C7 carbamoyloxy substituted taxane compositions |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/776,494 Expired - Fee Related US6359154B2 (en) | 2000-02-02 | 2001-02-02 | C7 carbamoyloxy substituted taxanes |
US10/071,924 Expired - Fee Related US6750245B2 (en) | 2000-02-02 | 2002-02-06 | C7 carbamate substituted taxanes |
Country Status (23)
Country | Link |
---|---|
US (3) | US6359154B2 (en) |
EP (1) | EP1165549B1 (en) |
JP (1) | JP2003522168A (en) |
KR (1) | KR20020002417A (en) |
CN (1) | CN1362956A (en) |
AT (1) | ATE392422T1 (en) |
AU (1) | AU778991B2 (en) |
BR (1) | BR0104355A (en) |
CA (1) | CA2368510A1 (en) |
CZ (1) | CZ20013521A3 (en) |
DE (1) | DE60133600T2 (en) |
DK (1) | DK1165549T3 (en) |
ES (1) | ES2305056T3 (en) |
HK (1) | HK1047937A1 (en) |
HU (1) | HUP0200752A3 (en) |
IL (1) | IL145643A0 (en) |
MX (1) | MXPA01009923A (en) |
NO (1) | NO20014757L (en) |
NZ (1) | NZ514410A (en) |
PL (1) | PL350024A1 (en) |
PT (1) | PT1165549E (en) |
WO (1) | WO2001057028A1 (en) |
ZA (1) | ZA200108056B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6638973B2 (en) * | 2000-02-02 | 2003-10-28 | Fsu Research Foundation, Inc. | Taxane formulations |
PL350024A1 (en) * | 2000-02-02 | 2002-10-21 | Univ Florida State Res Found | C7 carbamoyloxy substituted taxanes as antitumor agents |
US7390898B2 (en) | 2002-08-02 | 2008-06-24 | Immunogen Inc. | Cytotoxic agents containing novel potent taxanes and their therapeutic use |
JP2005539009A (en) | 2002-08-02 | 2005-12-22 | イミュノジェン・インコーポレーテッド | Cytotoxic substances including new potent taxanes and their therapeutic use |
CN113952464A (en) * | 2018-03-06 | 2022-01-21 | 江苏吉贝尔药业股份有限公司 | Hydrophobic anti-tumor medicine containing ketocarbonyl and application thereof |
Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
US5227400A (en) * | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
US5243045A (en) * | 1991-09-23 | 1993-09-07 | Florida State University | Certain alkoxy substituted taxanes and pharmaceutical compositions containing them |
US5283253A (en) * | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
US5350866A (en) * | 1991-09-23 | 1994-09-27 | Bristol-Myers Squibb Company | 10-desacetoxytaxol derivatives |
US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US5567614A (en) * | 1992-01-15 | 1996-10-22 | E.R. Squibb & Sons, Inc. | Enzymatic processes for resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes |
US5714513A (en) * | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
US5721268A (en) * | 1991-09-23 | 1998-02-24 | Florida State University | C7 taxane derivatives and pharmaceutical compositions containing them |
US5780653A (en) * | 1995-06-07 | 1998-07-14 | Vivorx Pharmaceuticals, Inc. | Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers |
US5811452A (en) * | 1997-01-08 | 1998-09-22 | The Research Foundation Of State University Of New York | Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof |
US5879929A (en) * | 1993-07-14 | 1999-03-09 | Bristol-Myers Squibb Company | Enzymatic processes for the resolution of enantiomeric mixtures of lactams useful as intermediates in the preparation of taxanes |
US5912264A (en) * | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2679230B1 (en) * | 1991-07-16 | 1993-11-19 | Rhone Poulenc Rorer Sa | NOVEL DERIVATIVES OF TAXOL ANALOGS, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM. |
US5272171A (en) | 1992-02-13 | 1993-12-21 | Bristol-Myers Squibb Company | Phosphonooxy and carbonate derivatives of taxol |
US5614549A (en) * | 1992-08-21 | 1997-03-25 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
CA2109861C (en) | 1992-12-04 | 1999-03-16 | Shu-Hui Chen | 6,7-modified paclitaxels |
DE69433297T2 (en) * | 1993-02-05 | 2004-10-21 | Bryn Mawr College Bryn Mawr | SYNTHESIS OF TAXOL, ITS ANALOGS AND INTERMEDIATES WITH VARIABLE A-RING SIDE CHAINS |
IL109926A (en) | 1993-06-15 | 2000-02-29 | Bristol Myers Squibb Co | Methods for the preparation of taxanes and microorganisms and enzymes utilized therein |
US6100411A (en) | 1994-10-28 | 2000-08-08 | The Research Foundation Of State University Of New York | Taxoid anti-tumor agents and pharmaceutical compositions thereof |
WO1996013495A1 (en) | 1994-10-28 | 1996-05-09 | The Research Foundation Of State University Of New York | Taxoid derivatives, their preparation and their use as antitumor agents |
CA2231837A1 (en) | 1995-09-13 | 1997-03-20 | Florida State University | Radiosensitizing taxanes and their pharmaceutical preparations |
CA2253513A1 (en) | 1996-05-06 | 1997-11-13 | Florida State University | 1-deoxy baccatin iii, 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof |
US7288665B1 (en) | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
PL350024A1 (en) * | 2000-02-02 | 2002-10-21 | Univ Florida State Res Found | C7 carbamoyloxy substituted taxanes as antitumor agents |
-
2001
- 2001-02-02 PL PL01350024A patent/PL350024A1/en not_active Application Discontinuation
- 2001-02-02 NZ NZ514410A patent/NZ514410A/en unknown
- 2001-02-02 KR KR1020017012622A patent/KR20020002417A/en active IP Right Grant
- 2001-02-02 AU AU33302/01A patent/AU778991B2/en not_active Ceased
- 2001-02-02 WO PCT/US2001/003592 patent/WO2001057028A1/en active Application Filing
- 2001-02-02 CN CN01800316A patent/CN1362956A/en active Pending
- 2001-02-02 DK DK01905421T patent/DK1165549T3/en active
- 2001-02-02 ES ES01905421T patent/ES2305056T3/en not_active Expired - Lifetime
- 2001-02-02 MX MXPA01009923A patent/MXPA01009923A/en active IP Right Grant
- 2001-02-02 AT AT01905421T patent/ATE392422T1/en not_active IP Right Cessation
- 2001-02-02 CA CA002368510A patent/CA2368510A1/en not_active Withdrawn
- 2001-02-02 HU HU0200752A patent/HUP0200752A3/en unknown
- 2001-02-02 CZ CZ20013521A patent/CZ20013521A3/en unknown
- 2001-02-02 DE DE60133600T patent/DE60133600T2/en not_active Expired - Fee Related
- 2001-02-02 US US09/776,494 patent/US6359154B2/en not_active Expired - Fee Related
- 2001-02-02 EP EP01905421A patent/EP1165549B1/en not_active Expired - Lifetime
- 2001-02-02 IL IL14564301A patent/IL145643A0/en unknown
- 2001-02-02 BR BR0104355-2A patent/BR0104355A/en not_active IP Right Cessation
- 2001-02-02 PT PT01905421T patent/PT1165549E/en unknown
- 2001-02-02 JP JP2001557860A patent/JP2003522168A/en not_active Withdrawn
- 2001-10-01 ZA ZA200108056A patent/ZA200108056B/en unknown
- 2001-10-01 NO NO20014757A patent/NO20014757L/en not_active Application Discontinuation
-
2002
- 2002-02-06 US US10/071,924 patent/US6750245B2/en not_active Expired - Fee Related
-
2003
- 2003-01-07 HK HK03100171.8A patent/HK1047937A1/en unknown
-
2004
- 2004-06-14 US US10/867,275 patent/US20050020635A1/en not_active Abandoned
Patent Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US5243045A (en) * | 1991-09-23 | 1993-09-07 | Florida State University | Certain alkoxy substituted taxanes and pharmaceutical compositions containing them |
US5283253A (en) * | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
US5350866A (en) * | 1991-09-23 | 1994-09-27 | Bristol-Myers Squibb Company | 10-desacetoxytaxol derivatives |
US5227400A (en) * | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
US5714513A (en) * | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
US5721268A (en) * | 1991-09-23 | 1998-02-24 | Florida State University | C7 taxane derivatives and pharmaceutical compositions containing them |
US5567614A (en) * | 1992-01-15 | 1996-10-22 | E.R. Squibb & Sons, Inc. | Enzymatic processes for resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes |
US5879929A (en) * | 1993-07-14 | 1999-03-09 | Bristol-Myers Squibb Company | Enzymatic processes for the resolution of enantiomeric mixtures of lactams useful as intermediates in the preparation of taxanes |
US5780653A (en) * | 1995-06-07 | 1998-07-14 | Vivorx Pharmaceuticals, Inc. | Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers |
US5811452A (en) * | 1997-01-08 | 1998-09-22 | The Research Foundation Of State University Of New York | Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof |
US5912264A (en) * | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
Also Published As
Publication number | Publication date |
---|---|
HK1047937A1 (en) | 2003-03-14 |
HUP0200752A3 (en) | 2005-02-28 |
ZA200108056B (en) | 2003-12-01 |
IL145643A0 (en) | 2002-06-30 |
US20030060638A1 (en) | 2003-03-27 |
NO20014757L (en) | 2001-11-29 |
WO2001057028A1 (en) | 2001-08-09 |
CA2368510A1 (en) | 2001-08-09 |
ATE392422T1 (en) | 2008-05-15 |
US6359154B2 (en) | 2002-03-19 |
PL350024A1 (en) | 2002-10-21 |
US20010051640A1 (en) | 2001-12-13 |
DK1165549T3 (en) | 2008-08-11 |
PT1165549E (en) | 2008-06-20 |
AU3330201A (en) | 2001-08-14 |
BR0104355A (en) | 2002-01-02 |
HUP0200752A2 (en) | 2002-10-28 |
CN1362956A (en) | 2002-08-07 |
US6750245B2 (en) | 2004-06-15 |
AU778991B2 (en) | 2004-12-23 |
CZ20013521A3 (en) | 2002-03-13 |
JP2003522168A (en) | 2003-07-22 |
DE60133600T2 (en) | 2009-06-10 |
NO20014757D0 (en) | 2001-10-01 |
MXPA01009923A (en) | 2003-08-01 |
DE60133600D1 (en) | 2008-05-29 |
EP1165549A1 (en) | 2002-01-02 |
ES2305056T3 (en) | 2008-11-01 |
EP1165549B1 (en) | 2008-04-16 |
NZ514410A (en) | 2005-01-28 |
KR20020002417A (en) | 2002-01-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7157474B2 (en) | C10 heterosubstituted acetate taxane compositions | |
US6610860B2 (en) | C7 ester substituted taxanes | |
US7183312B2 (en) | Taxanes having a C7 heterosubstituted acetate substituent | |
US7256213B2 (en) | Taxanes having a C10 carbonate substituent | |
US7226944B2 (en) | Taxanes having a C7 carbonate substituent | |
US7230013B2 (en) | C10 carbamoyloxy substituted taxane compositions | |
US6649632B2 (en) | C10 ester substituted taxanes | |
US6359154B2 (en) | C7 carbamoyloxy substituted taxanes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |