WO1997009979A1 - Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques - Google Patents

Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques Download PDF

Info

Publication number
WO1997009979A1
WO1997009979A1 PCT/US1996/014613 US9614613W WO9709979A1 WO 1997009979 A1 WO1997009979 A1 WO 1997009979A1 US 9614613 W US9614613 W US 9614613W WO 9709979 A1 WO9709979 A1 WO 9709979A1
Authority
WO
WIPO (PCT)
Prior art keywords
rsg
heterosubstituted
hydrocarbon
heteroaryl
hydrogen
Prior art date
Application number
PCT/US1996/014613
Other languages
English (en)
Other versions
WO1997009979A9 (fr
Inventor
Robert A. Holton
Hossain Nadizadeh
Kurt G. Hofer
Li-Xi Yang
Original Assignee
Florida State University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Florida State University filed Critical Florida State University
Priority to CA002231837A priority Critical patent/CA2231837A1/fr
Priority to JP51209497A priority patent/JP2001524067A/ja
Priority to AU69746/96A priority patent/AU728057B2/en
Priority to PCT/US1996/014613 priority patent/WO1997009979A1/fr
Priority to EP96930833A priority patent/EP0855909A4/fr
Publication of WO1997009979A1 publication Critical patent/WO1997009979A1/fr
Publication of WO1997009979A9 publication Critical patent/WO1997009979A9/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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

Definitions

  • This invention relates to novel
  • radiosensitizing compounds and in particular, to
  • hypoxic cell volume is
  • hypoxic tumor cells One promising field of investigation for dealing with radioresistant hypoxic tumor cells has been the use of "radiosensitizing" compounds which selectively increase the sensitivity of hypoxic cells to radiation. This specificity to hypoxic cells is also valuable because a significant percentage of solid tumors are characterized by such cells while most normal tissue is not. Thus, treatment with such compounds serves to enhance the impact of radiation on tumor cells while having little effect on the impact of radiation on healthy cell tissue.
  • a number of heterocyclic, electron-affinic compounds, and in particular, those with oxidized nitrogen moieties, have been successfully used for the purpose of radiosensitizing hypoxic tumor cells.
  • chemotherapeutic agents to selectively enhance radiation response in tumors.
  • taxol for example, has been investigated in vitro and in vivo as a potential
  • Gynecologic Oncology 48:252-258 (1993); Steren, et al., Gynecologic Oncology, 50: 89-93 (1993); Choy et al.,
  • the present invention is directed to taxanes comprising one or more electron-affinic moieties. Such compounds provide greatly
  • the electron-affinic moiety may be attached directly, or indirectly through a linker to one of the ring atoms of the taxane or to one of the C13 side chain atoms.
  • the electron-affinic moiety may be attached to the C2, C4, C7, C9, C10, C14, C3' or C5' carbon of a taxane corresponding to the structure:
  • M comprises ammonium or is a metal
  • R 1 is hydrogen or hydroxy
  • R 2 is -OT 2 , -OCOZ 2 , -OCOOZ 2 , RSG 1 or RSG 2 ;
  • R 4 is -OT 4 , -OCOZ 4 , -OCOOZ 4 , RSG 1 or RSG 2 ;
  • R 7 is hydrogen, halogen, -OT 7 , -OCOZ 7 , -OCOOZ 7 , RSG 1 or RSG 2 ;
  • R 9 is hydrogen, keto, -OT 9 , -OCOZ 9 , -OCOOZ 9 , RSG 1 or RSG 2 ;
  • R 10 is hydrogen, keto, -OT 10 , -OCOZ 10 , -OCOOZ 10 , RSG 1 or RSG 2 ;
  • R 7 , R 9 , and R 10 independently have the alpha or beta stereochemical configuration
  • R 13 is hydroxy, protected hydroxy, keto, MO- or
  • R 14 is hydrogen, hydroxy, protected hydroxy, RSG 1 or RSG 2 ;
  • T 2 , T 4 , T 7 , T 9 and T 10 are independently hydrogen or hydroxy protecting group
  • X 1 is -OX 6 ;
  • X 2 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl or heterosubstituted heteroaryl; X 3 and X 4 are independently hydrogen,
  • X 5 is -X 10 , -OX 10 , -SX 10 , or -NX 8 X 10 ;
  • X 6 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl or hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
  • X 8 is hydrogen, hydrocarbon, heterosubstituted hydrocarbon, RSG 1 or RSG 2 ;
  • X 10 is hydrocarbon, heterosubstituted hydrocarbon, heteroaryl, heterosubstituted heteroaryl, RSG 1 or RSG 2 ;
  • Z 2 , Z 4 , Z 7 , Z 9 and Z 10 are independently hydrocarbon, heterosubstituted hydrocarbon, heteroaryl or heterosubstituted heteroaryl;
  • RSG 1 is an electron-affinic moiety
  • RSG 2 is -L- (RSG 1 ) n ;
  • L is a linker comprising a chain of 1 to 30 atoms in the chain, the atoms being selected from the group consisting of C, O, N, S, Si, and P;
  • n is an integer greater than or equal to 1.
  • the invention is also directed to
  • compositions for radiosensitizing tumor cells which contain a radiosensitizing amount of the above described taxanes or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically
  • the present invention is further directed to a process for radiosensitizing tumor cells.
  • the process comprises administering a radiosensitizing amount of the pharmaceutical composition described above to the tumor cells.
  • a method for killing tumor cells in a warm-blooded animal which includes the steps of administering to the warm-blooded animal a pharmaceutical composition as described above in an amount effective to radiosensitize the tumor cells, followed by, after a time interval sufficient to enhance radiosensitization of the tumor cells, irradiating the tumor cells with a dose of radiation effective to kill the tumor cells.
  • Fig. 1 is a graph depicting in vitro chemotherapeutic activity of taxoltere metro, taxol and taxoltere pnip on CHO cells for the studies set forth in Example 4.1.
  • Fig. 2 is a graph depicting in vitro chemotherapeutic activity of taxoltere, taxol and
  • Fig. 3 is a graph depicting in vitro chemotherapeutic radiosensitization of taxoltere metro and taxoltere pnip on CHO cells for the studies set forth in Example 4.2.
  • Fig. 4 is a graph depicting in vitro chemotherapeutic radiosensitization of taxoltere metro and taxoltere pnip on HCT 116 cells for the studies set forth in Example 4.2.
  • Fig. 5 is a graph depicting in vivo dose- response curves for taxoltere metro and taxol for the studies set forth in Example 4.4.
  • Fig. 6 is a graph depicting in vivo
  • Fig. 7 is a graph depicting the
  • Fig. 8 is a graph depicting the
  • Figs. 9 and 10 are graphs depicting the
  • Fig. 11 is a graph depicting in vivo chemotherapeutic radiosensitization of taxoltere metro, taxoltere pnip and taxol on MTG-B mammary tumors (i.p., single dose) for the studies set forth in Example 4.5.
  • Fig. 12 is a graph depicting the effects of ip taxol, taxoltere metro and taxoltere pnip +/-RT on MTG-B mammary tumors for the studies set forth in Example 4.5.
  • Figs. 13 and 14 are graphs depicting the effects of taxoltere pnip on MTG-B mammary tumors (i.v., single dose, 24% LD50) for the studies set forth in
  • Fig. 15 is a graph depicting the cure rate for taxoltere pnip (i.p., single dose) for the studies set forth in Example 4.6.
  • Figs. 16 and 17 are graphs depicting the cure rate for taxoltere pnip (i.v., single dose) for the studies set forth in Example 4.6.
  • Fig. 18 is a graph depicting the cure rate for taxoltere pnip +/- RT on MTG-B mammary tumors in vivo as a function of drug dose for the studies set forth in Example 4.6. Detailed Description of the Preferred Embodiments
  • taxanes containing electron-affinic substituents exhibit significantly greater potency than taxol as a
  • radiosensitizing agent As a result, such increased potency permits the administration of much lower dosages of these compounds for the same or even greater
  • This novel class of potent radiosensitizers comprise taxanes containing at least one, and optionally two or more electron-affinic moieties.
  • the novel class of potent radiosensitizers comprise taxanes containing at least one, and optionally two or more electron-affinic moieties.
  • radiosensitizing moieties contain electron-affinic groups which fall into one of four groups: (i) carbocyclic or heterocyclic aromatic moieties which possess one or more carbonyl, trifluoromethyl, halogen, nitro, sulfonyl, sulfinyl, phosphoryl, oxide or cyano groups,
  • heterocyclic aromatic moieties containing two or more heteroatoms (iii) heterocyclic aromatic moieties containing two or more heteroatoms, (iii) metal complexes, and (iv) organo-metallic groups in which the metal is covalently bonded to carbon.
  • the carbocyclic or heterocyclic aromatic electron-affinic moieties contain one to three rings with a total of 5 to 15 ring atoms which are selected from the group consisting of C, N, S, O and P.
  • the carbocyclic or heterocyclic aromatic electron-affinic moieties contain one to two rings with one ring being presently most preferred.
  • Representative carbocyclic aromatic electron-affinic moieties include phenyl and napthyl groups containing one or more nitro, halogen, carbonyl or sulfonyl substituents, with nitro-substituted phenyl being a preferred carbocyclic aromatic electron-affinic moiety.
  • heterocyclic aromatic electron-affinic moieties include imidazoles, triazoles, pyridines, benzamides, nicotinamides, benzotriazine oxides, furans, thiophenes, oxazoles and thiozoles possessing one or more carbonyl, trifluoromethyl, halogen, nitro, sulfonyl, sulfinyl, phosphoryl, oxide or cyano groups, and preferably at least one nitro group.
  • Nitroimidazole and nitrotriazole heterocyclic aromatic electron-affinic moieties which may be
  • radiosensitizing agents of the present invention include 2-nitroimidazol-1-yl and 3-nitro-1,2,4-triazol-1-yl and other nitroimidazoles and nitrotriazoles which correspond to the following
  • E 1 is alkyl or fluoroalkyl.
  • the preparation and use of radiosensitizing agents incorporating these and other nitroimidazoles and nitrotriazoles is described in Suzuki et al., U.S. Patent Nos. 4,945,102 and 5,064,849; Kagiza et al., U.S. Patent Nos. 4,927,941, 4,977,273 and 5,304,654; Suto, U.S. Patent No. 4,954,515 and 5,036,096; Suto et al., U.S. Patent No. 4,797,397; Papadopoulou-Rosenzweig et al., U.S. Patent No. 5,294,715; Beylin et al., U.S. Patent No. 5,342,959.
  • aromatic electron-affinic moieties which may benzoate
  • radiosensitizing agents of the present invention include
  • X 1 is O or S
  • Y 1 is H, lower alkyl, lower alkoxy, acetoxy, or acetamido
  • Y 2 is -OR, -SR, -NHR, -NO 2 ,
  • Y 3 is H, Z 1 , -OR, -SR, -NHR, -O(CO)R, -NH(CO)R, -O(SO)R, or -O(POR)R; and R is hydrogen or hydrocarbon which may be optionally substituted and interrupted by an ether (-O-) linkage.
  • nicotinamides is described in Lee et al., U.S. Patent Nos. 5,032,617, 5,041,653 and 5,175,287.
  • Benzotriazine oxide heterocyclic aromatic electron-affinic moieties which may be incorporated into the radiosensitizing agents of the present invention include
  • Y 4 is H, substituted or unsubstituted lower hydrocarbon, or alkanoyl; m is O or 1; and Y 5 and Y 6 are independently hydrogen, nitro, halogen, morpholino, pyrrolidino, piperidino, substituted or unsubstituted hydrocarbon, -NH 2 , -NHR', -NR'R'O(CO)R', -NH(CO)R',
  • the metal complex electron-affinic moieties preferably comprise Pt 2+ , CO 3+ , Fe 2+ , Fe 3+ , Pd 2+ , Cu 2+ , Ti 4+ , or Zr 4+ as the metal and generally fall into two
  • metal complexes of the carbocyclic and heterocyclic aromatic electron-affinic moieties discussed above and (b) metal complexes of bidentate ligands comprising nitrogen, carbon or sulfur.
  • metal complexes of bidentate ligands correspond to the formula -BM L X k wherein B is a bidentate ligand containing
  • M L is a metal
  • X is an anionic ligand such as Cl- or -OAc
  • k is 1-4.
  • Exemplary bidentate ligands include: , , and
  • Electron-affinic metal complexes which may be incorporated into the radiosensitizing agents of the present invention include compounds of the formula:
  • heterocycles may optionally be substituted by an alkyl, amino substituted alkyl, hydroxy, alkoxy or amino group.
  • the heterocycle is pyrazole or imidazole, a ring nitrogen may be substituted by alkyl or alkoxy or hydroxy substituted alkyl and wherein one or two
  • methylenes of the alkyl may be replaced by oxygen.
  • Q is one of the following:
  • R 1 is alkyl optionally containing an amino
  • Other electron-affinic metal complexes which may be incorporated into the radiosensitizing agents of the present invention may be made by reacting an organic or inorganic platinum compound such as an alkali metal tetrahaloplatinate or cis-bis (acetonitrile) dichloroplatinum (II) with rhodamine 123 or other (+) -charged rhodamine or the like, for example, a cyanine dye such as 3,3'-diethylthiadicarbocyanine iodide or other (+) -charged cyanine dyes as described in U.S. Patent No.
  • an organic or inorganic platinum compound such as an alkali metal tetrahaloplatinate or cis-bis (acetonitrile) dichloroplatinum (II)
  • rhodamine 123 or other (+) -charged rhodamine or the like for example, a cyanine dye such as 3,3'-diethy
  • a c represents a bidentate heteroaromatic ligand containing neutral nitrogen donor atoms
  • B c represents a bidentate ligand containing neutral or negatively charged oxygen donor atoms
  • X c and Y c are the same or different neutral or negatively charged monodentate ligands
  • Z 1 and Z 2 represent the charge on the complex.
  • Radiosensitizing agents include Co (III) or Fe(III) compounds a formula
  • n has a value of 3 or 4; N is an uncharged nitrogen donor atom that is contained within a ligand; X F represents an anionic ligand; and y represents the charge on the complex; A F represents a bidentate or tetradentate negative ligand containing N or O donor atoms; D 1 and D 2 represent the same or different monodentate ligands; q represents a positive or negative charge on the complex; Z F represents a chelating mononegative negative ligand; T 1 and T 2 , which may be the same or different, represent mono-negative tridentate ligands.
  • the preparation and use of radiosensitizing agents incorporating these metal complexes is described in U.S. Patent No. 4,727,068.
  • organometallic electron-affinic moieties are aliphatic or aromatic mercury radicals.
  • the electron-affinic moieties may be directly attached to one of the carbons of the A, B, or C rings of the taxane or indirectly attached via a linker.
  • the linker comprises a chain of 0 to 30 atoms in the chain, with approximately 10 or less being preferred.
  • the chain atoms are selected from the group consisting of C, O, N, S, Si, and P and are preferably C, N or O.
  • the linker may be linear or cyclic, branched or unbranched, and may contain as substituents, one or more P, C, O, N, S, H, Si or halogen-containing substituents.
  • linker substituents include silyls, ethers, thioethers, esters, thioesters, amides, thioamides, amines, alcohol, alkyl, aryl, carbonyl, sulfonyl, phosphoryl, and halogen
  • the linker comprises a hydrocarbon segment consisting of 1 to 6 carbon atoms. It may additionally comprise a carbonyl, ester, thioester, amide, carbonate, thiocarbonate, carbamate, or ether segment. If a non-hydrocarbon segment is included; the non-hydrocarbon segment preferably comprises one or more ether, carbonate or carbonyl moieties as the non-hydrocarbon segment.
  • h is 1-3
  • R 4 is H, hydrocarbon or substituted hydrocarbon
  • R 5 is hydrocarbon or substituted
  • the carbonyl or ester linkage of the above structures may be replaced by thioester or amide linkages.
  • many of these radicals may serve as ligands for the previously
  • the radiosensitizing compounds of the present invention are prepared by linking the electron-affinic moiety to the C2, C4 , C7, C9, C10, C14, C3', or C5' carbons of a taxane.
  • the starting material may be 10-deacetyl baccatin III, baccatin III, or another naturally occurring taxane such as 14-hydroxy-10-deacetylbaccatin III.
  • the taxane may be synthesized from commodity chemicals as set forth in PCT Patent
  • Taxanes having C13 side chains which incorporate electron-affinic moieties at C3' and/or C5' may be prepared through the use of ⁇ -lactams having the desired substituents and reacting the ⁇ -lactam and a C13 metal or ammonium alkoxide of a suitably substituted taxane as more fully described in U.S. Patent 5,430,160.
  • the ⁇ -lactams have the following structural formula:
  • the alkoxide has the tetracyclic taxane nucleus and corresponds to the
  • M is a metal or tetraalkylammonium and R 1 , R 2 , R 4 , R 7 , R 9 , R 10 , and R 14 are as previously defined.
  • the electron-affinic moieties can be attached to the C2, C4, C7, C9, C10, and C14 positions of a taxane by a variety of methods. For purposes of illustration, the attachment method will first be described with respect to the C7 position. As will be described
  • Metronidazole a well known radiosensitizer, and other electron-affinic moieties can be attached via a carbonate linkage by treating baccatin III 2 with
  • This method can be used for the preparation of a series of similar radiosensitizing taxanes having different radiosensitizing groups.
  • the intermediate 7-carbonylimidazolide 2a reacts smoothly with alcohols to provide the desired radiosensitizing taxanes in which the radiosensitizing group is attached via a carbonate linkage, as in taxoltere metro.
  • alcohols 6 through 9 will react with the carbonylimidazolide substituent of 2a to yield four other taxanes having radiosensitizing groups linked to C7.
  • Attachment of the radiosensitizing group is then followed by attachment of a side chain at C13 in the same manner as it was accomplished for taxoltere metro.
  • the attachment of a metal atom or metal complex tethered at the C7 position of the taxane core can be accomplished by reacting an allylchloroformate with a taxane having an available C7 hydroxy group and a
  • the ester analog of 11 can be prepared by the direct acylation of the C7 hydroxyl group of a 2' hydroxy protected taxane with an acid chloride to produce ester 12. Hydroboration of the allyl ester followed by
  • Similar chemistry can be used to attach a bidentate ligand to the C7 position, and the metal complex (e.g., platinum) of the bidentate ligand can then be prepared by introducing an appropriate metallic reactant (e.g., PtCl 2 or PtCl 2 (SMe 2 ) 2 ).
  • an appropriate metallic reactant e.g., PtCl 2 or PtCl 2 (SMe 2 ) 2 .
  • the bidentate ligand can also incorporate an electron-affinic ligand, and the Pt (II) complex of 13 can be made in this way.
  • the length and nature of the linker between the taxane and the electron-affinic group may be altered. It is possible to prepare analogs in which the electron- affinic group is both closer and further away from the taxane than it is in taxoltere metro. An analog with a longer linker can easily be synthesized by incorporating a dicarboxylic acid diester instead of the carbonate between the taxane and metronidazole, e.g., 14. The p- nitrobenzyl ether 15 and the corresponding p- nitrobenzoate are radiosensitizing taxanes in which the electron-affinic group is very close to the taxane.
  • hydroboration of 10 gives an alcohol, the mesylate of which reacts with, for example, 2-nitro imidazole to provide 16, and the epoxide derived by peracid treatment of 10 reacts with, for example, 2-nitro imidazole to provide 17.
  • Ester analogs of 16 and 17 can be similarly prepared starting from 12.
  • radiosensitizing taxanes having multiple radiosensitizing groups attached to a single linker.
  • reaction of 2-nitro imidazole with glycidyl chloride at somewhat elevated temperature provides alcohol 18, which then reacts with 2a and with ⁇ -lactam 4 to give radiosensitizing taxane 19.
  • Electron-affinic moieties can be attached to the C10 position of a taxane possessing a C10 hydroxy group, such as 10-DAB, by the methods discussed for attaching the electron-affinic moieties to the C7
  • taxanes having a C10 keto substituent can be prepared by oxidation of 10-desacetyl taxanes.
  • Taxanes which are dihydro substituted at C10 can be prepared by reacting a C10 hydroxy or acyloxy substituted taxane with samarium diiodide.
  • Taxanes having acyloxy substituents other than acetate can be prepared by reacting the C10 hydroxy substituent of 10-deacetyl baccatin III with any standard acylating agent such as anhydrides, acid chlorides, acyl imidazoles or other activated carboxyl derivatives. Taxanes having a C10 carbonate substituent can be prepared by using an analogous chloroformate instead of the acid chloride.
  • Electron-affinic moieties can be attached to the C9 position of a taxane possessing a C9 hydroxy group by the methods discussed for attaching the electron-affinic moieties to the C7 position.
  • the C9 the C9 keto substituent of taxol, 10-DAB, baccatin III or can be selectively reduced to yield the corresponding C9 ⁇ -hydroxy derivative with a borohydride, preferably tetrabutylammonium borohydride (Bu 4 NBH 4 ) or triacetoxy-borohydride.
  • the C9 ⁇ -hydroxy derivative can then be protected at C7 with a hydroxy protecting group and the C9 hydroxy group can be acylated following the methods described herein for acylation of the C7 hydroxy group.
  • reaction of 7-protected-9 ⁇ -hydroxy derivative with KH causes the acetate group (or other acyloxy group) to migrate from C10 to C9 and the hydroxy group to migrate from C9 to C10, thereby yielding a 10-desacetyl derivative, which can be acylated as described elsewhere herein.
  • substituted taxanes can be prepared by tin hydride reduction of the C7 xanthate.
  • C7 fluoro-substituted taxanes can be prepared by treatment of C13-triethylsilyl-protected baccatin III with 2-chloro-1,1,2-trifluorotriethylamine at room temperature in THF
  • baccatin III can be prepared by treatment of baccatin III with methanesulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydrochloride. Taxanes having C7 acyloxy substituents can be prepared as set forth in the
  • Taxanes having alternative C2 and/or C4 esters or carbonates which optionally may contain an electron- affinic moiety as described elsewhere herein can be prepared using baccatin III and 10 -DAB as starting materials.
  • the C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol (s) using reducing agents such as LAH or Red-Al, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.
  • the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride.
  • a suitable base such as LDA
  • an acylating agent such as an acid chloride.
  • the coresponding carbonates can be prepared by substituting a chloroformate for the analogous acid chloride.
  • Baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can be prepared as set forth in Reaction Schemes C 2 -1 to C 2 -5. To simplify the description, 10 -DAB is used as the starting material and only the ester products are shown. It should be understood, however, that other starting materials and reactants may be substituted to yield the other C2 and C4 substituted compounds disclosed herein.
  • nucleophilic agent e.g., Grignard reagents or
  • triol 21 Deprotonation of triol 21 with LDA followed by introduction of an acid chloride selectively gives the C4 ester.
  • LDA liquid-dimethylethyl ether
  • an acid chloride acetyl chloride
  • triol 21 was converted to 1,2 diol 24 as set forth in Reaction Scheme C 2 -2 wherein Z 4 is as defined elsewhere herein.
  • Triol 21 can also readily be converted to the 1,2 carbonate 22.
  • Acetylation of carbonate 22 under vigorous standard conditions provides carbonate 25 as described in Reaction Scheme C 2 -3; addition of
  • alkyllithiums or Grignard reagents to carbonate 22 provides the C2 ester 24 having a free hydroxyl group at C4 as set forth in Reaction Scheme C 2 -1.
  • baccatin III may be used as a starting material and reacted as shown in Reaction Scheme C 2 -5. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 29.
  • Tetraol 29 is converted to carbonate 30 using Cl 2 CO and pyridine, and carbonate 30 is acylated at C10 with an acid chloride and pyridine to produce carbonate 31 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 31 under vigorous standard conditions provides carbonate 32 which is then reacted with alkyl lithiums to provide the baccatin III
  • Taxanes having radiosensitizing groups at the C14 position may be prepared using the same or similar methods as those described elsewhere herein with respect to attaching radiosensitizing groups to the C7 position of the taxane.
  • the starting material for these compounds may be, for example, a hydroxylated taxane (14 -hydroxy-10-deacetylbaccatin III) which has been discovered in an extract of yew needles (C&EN. p 36-37, April 12, 1993).
  • Derivatives of this hydroxylated taxane having the various C2, C4, C7 , C9, C10, C3' and C5' functional groups described above may also be
  • taxane radiosensitizers of the present invention can be combined with various excipient vehicles and/or adjuvants well known in this art which serve as pharmaceutically acceptable carriers to permit drug administration in the form of, e.g., injections,
  • compositions containing a
  • radiosensitizing amount of the described substituted diamine compounds may be administered by any acceptable means which results in the radiosensitization of tumor cells.
  • administration can be oral, parenteral, subcutaneous, intravenous, intramuscular and/or intraperitoneal.
  • the pharmaceutical composition containing the radiosensitizing diamines are administered in an amount effective to radiosensitize the tumor cells (in the range of 1 to 100 mg/kg for humans).
  • the specific dosage administered will be dependent upon such factors as the general health and physical condition of the patient as well as his age and weight, the stage of the patient's disease condition, and the existence of any concurrent treatments.
  • the tumor cells After administration of the radiosensitizing composition to the tumor cells and the passage of a time interval sufficient to enhance radiosensitization of the tumor cells, the tumor cells are irradiated with a dose of radiation effective to destroy the tumor cells.
  • the patient will receive a total radiation dosage of about 60 to 76 Gy over seven to eight weeks, each individual radiation dose to be given within
  • hydrocarbon moieties described herein are 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. Preferably, these moieties comprise 1 to 20 carbon atoms.
  • alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
  • lower alkenyl containing from two to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl,
  • lower alkynyl containing from two to six 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. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
  • aryl moieties described herein contain from 6 to 20 carbon atoms and include phenyl. They may be hydrocarbon or heterosubstituted with the various
  • Phenyl is the more
  • heteroaryl moieties described are heterocyclic compounds or radicals which are analogous to aromatic compounds or radicals and which contain a total of 5 to 20 atoms, usually 5 or 6 ring atoms, and at least one atom other than carbon, such as furyl, thienyl, pyridyl and the like.
  • the heteroaryl moieties may be substituted with hydrocarbon, heterosubstituted
  • hydrocarbon or hetero-atom containing substituents with the hetero-atoms being selected from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, and halogens.
  • substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; amino; and amido.
  • heterosubstituted hydrocarbon moieties described herein are hydrocarbon 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 lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro ; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl;
  • acyloxy nitro; amino; and amido.
  • the acyl moieties described herein contain hydrocarbon, substituted hydrocarbon or heteroaryl moieties.
  • alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon moieties.
  • taxane denotes compounds containing the A, B and C rings (with numbering of the ring positions shown herein):
  • Ac means acetyl; "AIBN” means azo-(bis)-isobutyronitrile; "Ar” means aryl; "BMDA” means BrMgNiPr 2 ; “BOC” means butyloxycarbonyl; “BOM” means benzyloxymethyl; “10-DAB” means 10-desacetylbaccatin III; “DBU” means diazabicycloundecane; "DMAP” means
  • DDQ means dicyano- dichloroquinone
  • DMF means dimethylformamide
  • Et means ethyl
  • FAR means 2-chloro-1,1,2-trifluorotriethylamine
  • iPr means isopropyl
  • LAH means lithium aluminum hydride
  • LDA means lithium diisopropylamide
  • LHMDS means lithium hexamethyldisilazide
  • LTMP means lithium tetramethylpiperidide
  • mCPBA means metachloro- perbenzoic acid
  • Me means methyl
  • MOP means 2-methoxy-2-propyl
  • Ms means CH 3 SO 2 -
  • Ph means phenyl
  • protected hydroxy means -OP or -OT wherein P or T is a hydroxy protecting group
  • py means pyridine
  • R means lower alkyl unless otherwise defined
  • tetrabutylammonium fluoride "tBu” and “t-Bu” means tert- butyl; "TBS” means Me 2 t-BuSi-; "TES" means triethylsilyl; “Tf” means -SO 2 CF 3 ; “TMS” means trimethyl-silyl; “TPAP” means tetrapropylammonium perruthenate; and “Ts” means toluenesulfonyl.
  • “Hydroxy protecting group” includes, but is not limited to, acetals having two to ten carbons, ketals having two to ten carbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and
  • trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether,
  • esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl;
  • the solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added.
  • the mixture was partitioned between saturated aqueous NaHC0 3 and 60/40 ethyl acetate/hexane.
  • taxoltere metro concentrations of taxol, taxoltere metro, or taxoltere p-nip at 37 °C for 24 hours.
  • Cell survival was evaluated by the colony forming assay.
  • both taxoltere metro and taxoltere p-nip are much more efficient than taxol in killing CHO and HCT-116 cells.
  • taxoltere metro is about 15 times
  • taxoltere p-nip is about 45 times, more effective than taxol in killing CHO cells
  • taxoltere metro is about 10 times
  • taxoltere p-nip is about 30 times, more effective than taxol in killing HCT-116 cells.
  • both taxoltere metro and taxoltere p-nip exhibit significantly stronger ability than taxol to kill both types of cells at every drug dose point.
  • Figures 3 and 4 show the results of experiments in which cells were subjected to different radiation doses in the presence or absence of drugs. Both taxoltere metro and taxoltere p-nip strongly radiosensitize both CHO and
  • HCT-116 cells although taxol does not.
  • the sensitizer enhancement ratio (SER) is 2.3 for 100 nM taxoltere metro and 1.6 for taxoltere p-nip.
  • SER sensitizer enhancement ratio
  • taxoltere metro shows a SER of 1.2 at the (low) dose of 10 nM
  • taxoltere p-nip has a SER of 1.5.
  • At each radiation dose point there is a significantly enhanced decrease in the surviving fraction for the taxoltere metro and taxoltere p-nip treated groups, but not for the taxol treated groups.
  • HCT-116 cells are more sensitive to both taxoltere metro and taxoltere p-nip than CHO cells, hence lower concentrations of the drugs are required for a significant enhancement of radiation induced cell killing.
  • the LD 50/5 for i.p. taxoltere metro is 249.67 mg/kg, compared with 140.97 mg/kg for i.p. taxol.
  • the death of mice in the taxol treated groups occurred sooner than the death of mice in the taxoltere metro treated groups.
  • Severe toxic symptoms such as the constriction of pupils and the contraction of erectile tissue of hair follicles (resulting in rough hair) were observed 24 hours after drug administration in the taxol treated groups, but not in the taxoltere metro treated groups.
  • the acute toxicity of taxoltere metro is significantly lower than that of taxol.
  • the LD 50/5 values are 79.13 mg/kg for i.p. administration of taxoltere p-nip and 134.16 mg/kg for i.v. administration of taxoltere p-nip.
  • the data strongly demonstrate that taxoltere p-nip is significantly less toxic when administered i.v. than it is when administered i.p. 4.4. In vivo chemotherapeutic activity.
  • Taxol, taxoltere metro, and taxoltere p-nip were selected from the group consisting of taxol, taxoltere metro, and taxoltere p-nip.
  • taxol-metro is much more effective than taxol in increasing the life span of mammary tumor-bearing mice.
  • the survival time for control mice was 13 days.
  • taxol increased the survival time by 31% to 17 days
  • taxoltere metro increased the survival time by 123% to 29 days.
  • Taxoltere p-nip ( Figure 6) is substantially more potent, increasing the life span by 1015% to 145 days (dose-response data not shown because only a single dose (40% of LD 50/5 ) was studied).
  • taxoltere metro was 4 times
  • taxoltere p-nip was 33 times, more effective than taxol.
  • taxoltere p-nip were administered to MTG-B tumor bearing C3H/Hej mice have been carried out. In the first of these, drugs were administered on a q7d ⁇ 4 schedule
  • MTG-B tumor bearing C3H/Hej mice received single equitoxic drug doses i.p. (40% of LD 50/5 ) .
  • the mice were placed in a lead holder (with the tumor-bearing hind leg exposed), and the tumor was subjected to a 22 Gy Xray dose (Figure 11).
  • Figure 12 tumor doubling times (TDT) of 3.5 days
  • control 8.5 days (22 Gy Xray exposure alone), 14.5 days (taxol alone), 19.5 days (taxol plus 22 Gy Xray), 20.5 days (taxoltere metro alone), and 29.5 days
  • Taxoltere metro two hours prior to irradiation (data not shown). Taxoltere p-nip alone (TDT 3D 36.5 days) is even more effective in delaying tumor growth (Figure 12), and the combination of taxoltere p-nip plus 22 Gy produced a TDT of 65 days.
  • Cure Rates are defined by the U.S. National Cancer Institute as tumor-free survival for at least twice the survival time of control tumor-bearing mice, therefore we have used 28 days tumor- free to define a "cure” in this system.
  • the cure rate is 40% for mice treated i.p. with taxoltere p-nip alone at a single dose, and 75% for the combination of taxoltere p-nip and 22 Gy ( Figure 15). Similarly, a single i.v.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des taxanes renfermant des groupes fonctionnels à effet radiosensibilisant, à affinité électronique, ainsi qu'à leurs préparations pharmaceutiques et aux procédés de fabrication et d'utilisation de cette nouvelle classe de substances qui augmentent considérablement la sensibilité des cellules tumorales aux radiations.
PCT/US1996/014613 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques WO1997009979A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002231837A CA2231837A1 (fr) 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
JP51209497A JP2001524067A (ja) 1995-09-13 1996-09-13 放射線感作性タキサン類およびその医薬製剤
AU69746/96A AU728057B2 (en) 1995-09-13 1996-09-13 Radiosensitizing taxanes and their pharmaceutical preparations
PCT/US1996/014613 WO1997009979A1 (fr) 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
EP96930833A EP0855909A4 (fr) 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US60/003,687 1995-09-13
PCT/US1996/014613 WO1997009979A1 (fr) 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques

Publications (2)

Publication Number Publication Date
WO1997009979A1 true WO1997009979A1 (fr) 1997-03-20
WO1997009979A9 WO1997009979A9 (fr) 1997-06-05

Family

ID=22255772

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/014613 WO1997009979A1 (fr) 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques

Country Status (2)

Country Link
CA (1) CA2231837A1 (fr)
WO (1) WO1997009979A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6359154B2 (en) 2000-02-02 2002-03-19 Fsu Research Foundation, Inc. C7 carbamoyloxy substituted taxanes
US6515151B1 (en) 1992-12-23 2003-02-04 Bristol-Myers Squibb Company Method for the preparation of novel sidechain-bearing taxanes and intermediates thereof
EP1301500A1 (fr) * 2000-06-22 2003-04-16 Nitromed, Inc. Taxanes nitroses et nitrosyles, compositions et procedes d'utilisation
US6596737B2 (en) 2000-02-02 2003-07-22 Fsu Research Foundation, Inc. C10 carbamoyloxy substituted taxanes
US6610860B2 (en) 2000-02-02 2003-08-26 Fsu Research Foundation, Inc. C7 ester substituted taxanes
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US6660866B2 (en) 2000-02-02 2003-12-09 Psu Research Foundation, Inc. C10 carbonate substituted taxanes
US6664275B2 (en) 2000-02-02 2003-12-16 Fsu Research Foundation, Inc. C10 heterosubstituted acetate taxanes
US6673833B2 (en) 2000-02-02 2004-01-06 Fsu Research Foundation, Inc. C7 heterosubstituted acetate taxanes
US6780879B2 (en) 2000-02-02 2004-08-24 Fsu Research Foundation, Inc. C7 carbonate substituted taxanes
US6906040B2 (en) 2000-09-22 2005-06-14 Bristol-Myers Squibb Company Method for reducing toxicity of combined chemotherapies
US7091190B2 (en) 1996-09-17 2006-08-15 Avanir Pharmaceuticals Synergistic inhibition of viral replication by long-chain hydrocarbons and nucleoside analogs
US7160919B2 (en) 2004-03-05 2007-01-09 Florida State University Research Foundation, Inc. C7 lactyloxy-substituted taxanes
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2029563A4 (fr) * 2006-06-12 2009-12-02 Canada Inc 6570763 Voie semi-synthétique pour la préparation de paclitaxel, docétaxel et 10-désacétylbaccatine iii à partir de 9-dihydro-13-acétylbaccatine iii
US7847111B2 (en) 2006-06-19 2010-12-07 Canada Inc. Semi-synthetic route for the preparation of paclitaxel, docetaxel, and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466834A (en) * 1991-09-23 1995-11-14 Florida State University Preparation of substituted isoserine esters using metal alkoxides and .beta.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466834A (en) * 1991-09-23 1995-11-14 Florida State University Preparation of substituted isoserine esters using metal alkoxides and .beta.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0855909A4 *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6515151B1 (en) 1992-12-23 2003-02-04 Bristol-Myers Squibb Company Method for the preparation of novel sidechain-bearing taxanes and intermediates thereof
US7091190B2 (en) 1996-09-17 2006-08-15 Avanir Pharmaceuticals Synergistic inhibition of viral replication by long-chain hydrocarbons and nucleoside analogs
US6906088B2 (en) 2000-02-02 2005-06-14 Fsu Research Foundation, Inc. Taxanes having a C10 carbamoyloxy substituent
US6610860B2 (en) 2000-02-02 2003-08-26 Fsu Research Foundation, Inc. C7 ester substituted taxanes
US6992104B2 (en) 2000-02-02 2006-01-31 Fsu Research Foundation, Inc. C7 carbonate taxane compositions
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US6660866B2 (en) 2000-02-02 2003-12-09 Psu Research Foundation, Inc. C10 carbonate substituted taxanes
US6664275B2 (en) 2000-02-02 2003-12-16 Fsu Research Foundation, Inc. C10 heterosubstituted acetate taxanes
US6673833B2 (en) 2000-02-02 2004-01-06 Fsu Research Foundation, Inc. C7 heterosubstituted acetate taxanes
US6359154B2 (en) 2000-02-02 2002-03-19 Fsu Research Foundation, Inc. C7 carbamoyloxy substituted taxanes
US6750245B2 (en) 2000-02-02 2004-06-15 Fsu Research Foundation, Inc. C7 carbamate substituted taxanes
US6780879B2 (en) 2000-02-02 2004-08-24 Fsu Research Foundation, Inc. C7 carbonate substituted taxanes
US6861446B2 (en) 2000-02-02 2005-03-01 Fsu Research Foundation, Inc. C7 heterosubstituted acetate taxane compositions
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
US6872837B2 (en) 2000-02-02 2005-03-29 Fsu Research Foundation, Inc. Taxanes having a c10 Heterosubstituted acetate substituent
US7256213B2 (en) 2000-02-02 2007-08-14 Florida State University Research Foundation, Inc. Taxanes having a C10 carbonate substituent
US7230013B2 (en) 2000-02-02 2007-06-12 Florida State University Research Foundation, Inc. C10 carbamoyloxy substituted taxane compositions
US6596737B2 (en) 2000-02-02 2003-07-22 Fsu Research Foundation, Inc. C10 carbamoyloxy substituted taxanes
US7226944B2 (en) 2000-02-02 2007-06-05 Fsu Research Foundation, Inc. Taxanes having a C7 carbonate substituent
US7056946B2 (en) 2000-02-02 2006-06-06 Fsu Research Foundation, Inc. C10 carbonate taxane compositions
US7186849B2 (en) 2000-02-02 2007-03-06 Fsu Research Foundation, Inc. C7 ester substituted taxanes
US7157474B2 (en) 2000-02-02 2007-01-02 Fsu Research Foundation, Inc. C10 heterosubstituted acetate taxane compositions
US7183312B2 (en) 2000-02-02 2007-02-27 Fsu Research Foundation, Inc. Taxanes having a C7 heterosubstituted acetate substituent
EP1301500A1 (fr) * 2000-06-22 2003-04-16 Nitromed, Inc. Taxanes nitroses et nitrosyles, compositions et procedes d'utilisation
AU2001270070B2 (en) * 2000-06-22 2006-03-16 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
US6869973B2 (en) 2000-06-22 2005-03-22 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
EP1301500A4 (fr) * 2000-06-22 2004-03-31 Nitromed Inc Taxanes nitroses et nitrosyles, compositions et procedes d'utilisation
US6906040B2 (en) 2000-09-22 2005-06-14 Bristol-Myers Squibb Company Method for reducing toxicity of combined chemotherapies
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8003812B2 (en) 2004-02-13 2011-08-23 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US7160919B2 (en) 2004-03-05 2007-01-09 Florida State University Research Foundation, Inc. C7 lactyloxy-substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

Also Published As

Publication number Publication date
CA2231837A1 (fr) 1997-03-20

Similar Documents

Publication Publication Date Title
US5780653A (en) Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers
WO1997009979A1 (fr) Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
WO1997009979A9 (fr) Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
JP3182231B2 (ja) 新規な置換されたタキサン及びそれらを含有する薬剤組成物
JP3217156B2 (ja) 新規なフリル及びチエニル置換されたタキサン及びそれらを含有する薬剤組成物
JP3217155B2 (ja) 新規なアルコキシ置換されたタキサン及びそれらを含有する薬剤組成物
JP3360186B2 (ja) ６，７位を修飾したパクリタキセル類
CA2158454C (fr) Taxanes a chaine laretale furyle ou thienyle
JP6873221B2 (ja) ベンズアミド及びニコチンアミド化合物及びこれを使用する方法
SK282162B6 (sk) Spôsob prípravy derivátov taxánu, deriváty taxánu, deriváty oxazolínu ako medziprodukty na prípravu derivátov taxánu a spôsob ich prípravy
JPH03223258A (ja) ２―ニトロイミダゾール誘導体、その製造法及びこれを有効成分とする放射線増感剤
AU689099B2 (en) C7 taxane derivatives and pharmaceutical compositions containing them
US7067552B2 (en) Radiosensitizing taxanes and their pharmaceutical preparations
CA2147984C (fr) Derives de substitution butenyliques de taxanes; composition a base de ces derives
EP1688415A1 (fr) Agents cytotoxiques comprenant des taxanes modifiés en position C2
AU686137B2 (en) C9 taxane derivatives and pharmaceutical compositions containing them
IL107555A (en) Texans with a side chain converted to alkyl and pharmaceuticals containing them
AU728057B2 (en) Radiosensitizing taxanes and their pharmaceutical preparations
PT690711E (pt) Taxanos possuindo uma cadeia lateral substituida com amino
AU702492B2 (en) Beta-lactams useful in the preparation of taxanes having a pyridyl substituted side-chain
RU2419622C2 (ru) Производные таксола с противоопухолевой активностью
CA2147854C (fr) Taxanes possedant une chaine laterale avec substitution alkylique; compositions pharmaceutiques qui en renferment
CA2156908C (fr) Derives c9 du taxane; compositions pharmaceutiques a base de ces derives

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 96197661.6

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN CZ FI HU JP KR NO NZ PL RU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i
COP Corrected version of pamphlet

Free format text: PAGES 1/18-18/18,DRAWINGS,REPLACED BY NEW PAGES BEARING THE SAME NUMBER;DUE TO LATE TRANSMITTAL BY HTE RECEIVING OFFICE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2231837

Country of ref document: CA

Ref document number: 2231837

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1996930833

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1996930833

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1996930833

Country of ref document: EP