[go: up one dir, main page]

WO1997009979A9 - Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques - Google Patents

Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques

Info

Publication number
WO1997009979A9
WO1997009979A9 PCT/US1996/014613 US9614613W WO9709979A9 WO 1997009979 A9 WO1997009979 A9 WO 1997009979A9 US 9614613 W US9614613 W US 9614613W WO 9709979 A9 WO9709979 A9 WO 9709979A9
Authority
WO
WIPO (PCT)
Prior art keywords
rsg
hydrogen
hydrocarbon
heterosubstituted
heteroaryl
Prior art date
Application number
PCT/US1996/014613
Other languages
English (en)
Other versions
WO1997009979A1 (fr
Filing date
Publication date
Application filed filed Critical
Priority to AU69746/96A priority Critical patent/AU728057B2/en
Priority to JP51209497A priority patent/JP2001524067A/ja
Priority to EP96930833A priority patent/EP0855909A4/fr
Priority to CA002231837A priority patent/CA2231837A1/fr
Priority to PCT/US1996/014613 priority patent/WO1997009979A1/fr
Priority claimed from PCT/US1996/014613 external-priority patent/WO1997009979A1/fr
Publication of WO1997009979A1 publication Critical patent/WO1997009979A1/fr
Publication of WO1997009979A9 publication Critical patent/WO1997009979A9/fr

Links

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-, RSG 1 or RSG 2 ;
  • R 4 is -OT 4 , -OCOZ 4 , -OCOOZ 4 , RSG ⁇ 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. In general, fhe
  • 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 E 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)dichloroplatindum (II) with rhodamine 123 or other (+)-charged rhodamine or the like, for example, a cyafline 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)dichloroplatindum (II)
  • rhodamine 123 or other (+)-charged rhodamine or the like for example, a cyafline dye such as
  • 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 protected 2' hydroxy group to produce derivative 10 wherein X 3 and X 5 are as previously defined and P is a hydroxy protecting group. Hydroboration of the allyl carbonate substituent followed by treatment of the borane with mercuric acetate and sodium chloride and
  • 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 /3-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 triacetoxyborohydride.
  • 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.
  • 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-; “BOC” means butyloxycarbonyl; “BOM” means benzyloxymethyl; “10-DAB” means 10-desacetylbaccatin III; “DBU” means diazabicycloundecane; "DMAP" means
  • DDQ dicyanodichloroquinone
  • DMF 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 metachloroperbenzoic 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
  • 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 NaHCO 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 m 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 m which cells were subjected to different radiation doses m 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 tne (low) dose of 10 nM
  • taxoltere p-nip has a SER of 1.5.
  • HCT-116 cells are more sensitive to bota 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 metro uses this schedule to greatly extende ⁇ , with taxoltere metro producing the better results. Efficacy is positively correlated with frequency of iniection (i.e., smaller intervals between injections) On both schedules, taxoltere metro and taxoltere p-nip exhibit significantly stronger antitumor effects than taxol.
  • MTG-B tumor bearing C3H/Hej mice received single equitoxic drug doses i.p. (40% of LD 50/5 ).
  • a lead holder with the tumor-bearing hind leg exposed
  • the tumor was subjected to a 22 Gy Xray dose ( Figure 11).
  • TDT tumor doubling times
  • 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.

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
AU69746/96A AU728057B2 (en) 1995-09-13 1996-09-13 Radiosensitizing taxanes and their pharmaceutical preparations
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
EP96930833A EP0855909A4 (fr) 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
CA002231837A CA2231837A1 (fr) 1995-09-13 1996-09-13 Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
PCT/US1996/014613 WO1997009979A1 (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 WO1997009979A1 (fr) 1997-03-20
WO1997009979A9 true 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)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5973160A (en) 1992-12-23 1999-10-26 Poss; Michael A. Methods for the preparation of novel sidechain-bearing taxanes
US6440980B1 (en) 1996-09-17 2002-08-27 Avanir Pharmaceuticals Synergistic inhibition of viral replication by long-chain hydrocarbons and nucleoside analogs
AU783422B2 (en) 2000-02-02 2005-10-27 Florida State University Research Foundation, Inc. C10 carbamoyloxy substituted taxanes as antitumor agents
GEP20043239B (en) 2000-02-02 2004-05-25 Florida State Univ Research Foundation Us C10 Carbonate Substituted Taxanes as Antitumor Agents
CO5280224A1 (es) 2000-02-02 2003-05-30 Univ Florida State Res Found Taxanos sustituidos con ester en c7, utiles como agentes antitumorales y composiciones farmaceuticas que los contienen
PL350027A1 (en) 2000-02-02 2002-10-21 Univ Florida State Res Found C10 heterosubstituted acetate taxanes as antitumor agents
US6780879B2 (en) 2000-02-02 2004-08-24 Fsu Research Foundation, Inc. C7 carbonate substituted taxanes
HUP0200651A3 (en) 2000-02-02 2002-10-28 Univ Florida State Res Found C7 heterosubstituted acetate taxanes as antitumor agents and pharmaceutical compositions containing them
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
DE60133600T2 (de) 2000-02-02 2009-06-10 Florida State University Research Foundation, Inc., Tallahassee C7-carbamoyloxysubstituierte taxane als antitumormittel
JP2004501143A (ja) * 2000-06-22 2004-01-15 ニトロメド　インコーポレーテッド ニトロソ化およびニトロシル化タキサン、組成物および使用方法
CZ2003837A3 (cs) 2000-09-22 2004-12-15 Bristol-Myers Squibb Company Způsob pro snížení toxicity při kombinovaných chemoterapiích
PE20050693A1 (es) 2004-02-13 2005-09-27 Univ Florida State Res Found Taxanos sustituidos con esteres de ciclopentilo en c10
SV2006002036A (es) 2004-03-05 2006-03-16 Univ Florida State Res Found Taxanos con sustituyente lactiloxilo en el c7
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
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284864A (en) * 1991-09-23 1994-02-08 Florida State University Butenyl substituted taxanes and pharmaceutical compositions containing them

Similar Documents

Publication Publication Date Title
US5780653A (en) Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers
WO1997009979A9 (fr) Taxanes a effet radiosensibilisant et leurs preparations pharmaceutiques
WO1997009979A1 (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
DE69204951T2 (de) Furyl- und Thienyl-substituierte Taxane als Antitumormittel.
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
PL166893B1 (pl) Sposób wytwarzania pochodnych taksanu PL PL
JPH08225558A (ja) パクリタクセルのアミノ酸誘導体
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
EP1688415A1 (fr) Agents cytotoxiques comprenant des taxanes modifiés en position C2
JPH08503218A (ja) ブテニル置換タキサンおよび組成物
AU686137B2 (en) C9 taxane derivatives and pharmaceutical compositions containing them
AU728057B2 (en) Radiosensitizing taxanes and their pharmaceutical preparations
CZ285294A3 (en) Novel derivatives of taxan, process of their preparation and pharmaceutical composition containing thereof
WO2020228463A1 (fr) Procédé de préparation et d'utilisation de dérivés de noscapine anti-leucémie substitués au sélénium
US6362217B2 (en) Taxane anticancer agents
CN101062925A (zh) 紫杉醇衍生物、其制备方法和其药物组合物与用途
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