WO1999032109A1 - Paclitaxels portant un substituant 7-desoxy-6-azote - Google Patents

Paclitaxels portant un substituant 7-desoxy-6-azote Download PDF

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WO1999032109A1
WO1999032109A1 PCT/US1998/025872 US9825872W WO9932109A1 WO 1999032109 A1 WO1999032109 A1 WO 1999032109A1 US 9825872 W US9825872 W US 9825872W WO 9932109 A1 WO9932109 A1 WO 9932109A1
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och
nhc
compound
alkyl
hydroxy
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PCT/US1998/025872
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Mark D. Wittman
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Bristol-Myers Squibb Company
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Priority to AU17128/99A priority Critical patent/AU1712899A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6551—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a four-membered ring
    • C07F9/65512—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a four-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention concerns antitumor compounds. More particularly, the invention provides novel paclitaxel derivatives, pharmaceutical formulations thereof, and their use as antitumor agents.
  • Taxol® (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It has recently been approved for the treatment of refractory advanced ovarian cancer and breast cancer; and studies involving other cancers have shown promising results. The results of paclitaxel clinical studies are reviewed by numerous authors, such as by Rowinsky and Donehower in "The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics," Pharmac. Ther.. 52:35-84, 1991; by Spencer and Faulds in "Paclitaxel, A Review of its Pharmacodynamic and
  • Taxotere® (docetaxel) has also been found to have good antitumor activity.
  • the structures of paclitaxel and Taxotere® are shown below along with the conventional numbering system for molecules belonging to the class; such numbering system is also employed in this application.
  • This invention describes novel antitumor compounds in which the C-6 position of the taxane core is linked by a direct bond to a nitrogen atom.
  • This invention relates to novel antitumor compounds represented by formula I, or pharmaceutically acceptable salt thereof
  • R is hydrogen, Ci- 6 alkyl, C 2 -6 alkenyl, C 2 - 6 alkynyl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkenyl, cyclic 3-7 membered ring containing either one or two heteroatoms, heteroaryl or -Z 1 -R 3 ;
  • Z 1 is a direct bond, Ci- 6 alkyl, or -O-C 1 - 6 alkyl;
  • R 3 is aryl, substituted aryl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkenyl, cyclic 3-7 membered ring containing either one or two heteroatoms, or heteroaryl;
  • n is 0-3, -OC(0)CH 2 CH 2 C(0)OCH 2 CH 2 ⁇ H or -OC(0)-Z-C(0)-R';
  • R' is -OH, -OH base, -NR' 2 R' 3 , -OR' 3 , -SR' 3 or -OCH 2 C(0)NR' 4 R' 5 *
  • R' 2 is -H or -CH 3 ;
  • R' 3 is -(CH 2 ) n NR' 6 R'7 or where n is 1-3;
  • R' 4 is -H or - -C alkyl
  • R' 5 is -H, -Cj-C alkyl, benzyl, hydroxyethyl, -CH 2 C0 2 H or dimethylaminoethyl;
  • R' 6 and R' 7 are independently -H, -CH 3 , -CH 2 CH 3 , benzyl or R' 6 and R' 7 together with the nitrogen of NR' 6 R' 7 form a pyrrolidino, piperidino, morpholino, or N-methylpiperizino group;
  • R' ⁇ is -CH 3 , -CH 2 CH 3 or benzyl
  • X " is halide; base is NH 3 , (HOC 2 H 4 ) 3 N, N(CH 3 ) 3 , CH 3 N(C 2 H 4 ) 2 NH, NH 2 (CH 2 ) 6 NH 2 , N- methylglucamine, NaOH or KOH;
  • R F and R G are independently -H or -C C 3 alkyl, or R F and R G taken ttooggeetthheerr wwiitthh tthhee nniittrrooggeenn ooff NNRR RR ffoorrmm aa ] pyrrolidino, piperidino, morpholino or N-methylpiperizino groups;
  • Y+ is Na+ or N+(Bu) ⁇
  • R 6 and R 6' are independently hydrogen, N 3/ NH 2 , NHR, N(R) 2 , NHC(0)R, NHC(0)OR, NHC(0)NHR, NHC(0)N(R) 2 , NHS0 2 R, NHS(0)R, NHPO 2 OR, NHPO 2 NHR or NR a R b where R a and R b together with the nitrogen atom form a heteroaryl ring or a heterocyclic ring;
  • R 7 is hydrogen
  • R 19 is methyl
  • R 10 is hydrogen, hydroxy, -OC(0)R x , -OC(0)OR x , -0-C ⁇ _ 6 alkyl,
  • R x is Ci- 6 alkyl, C 2 _ 6 alkenyl, C _6 alkynyl, C 3 - 6 cyclo alkyl, any of which groups can be optionally substituted with one to six of the same or different halogen atoms or with one or more hydroxy groups.
  • a preferred embodiment are compounds wherein
  • R is phenyl, p-fluorophenyl, p-chlorophenyl, p-Tolyl, isopropyl, isopropenyl, isobutenyl, isobutyl, cyclopropyl, furyl, or thienyl;
  • RA is -NHC(0)Ph, or -NHC(0)0-(C ⁇ _ 6 alkyl);
  • R B is hydroxy
  • R 2 is phenyl
  • R 4 is methyl
  • R 9 and R 9' together form an oxo (keto) group
  • RI O is hydroxy or -OC(0)CH 3 ;
  • R 19 is methyl
  • R is phenyl or p-fluorophenyl
  • R A is -NHC(0)Ph, NHC(0)0-t- butyl or -NHC(0)0-isopropyl
  • R 6' is hydrogen
  • R 10 is -OC(0)CH 3 .
  • Another aspect of the present invention provides a method for inhibiting tumor in a mammalian host which comprises administering to said mammalian host an antitumor effective amount of a compound of formula I.
  • a pharmaceutical formulation which comprises an antitumor effective amount of a compound of formula I in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
  • C carbon atoms a particular group can contain.
  • Ci-6 alkyl means a straight or branched saturated carbon chain having from one to six carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl, and n-hexyl.
  • Ci-6 alkyl can also refer to Ci-6 alkylene which bridges two groups; examples include propane-l,3-diyl, butane- 1,4-diyl, 2-methyl- butane-l,4-diyl, etc.
  • C2-6 alkenyl means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from two to six carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl.
  • C2-6 alkenyl can also refer to C2-6 alkenediyl which bridges two groups; examples include ethylene-l,2-diyl (vinylene), 2-methyl-2-butene- 1,4-diyl, 2-hexene-l,6-diyl, etc.
  • C2-6 alkynyl means a straight or branched carbon chain having at least one carbon-carbon triple bond, and from two to six carbon atoms; examples include ethynyl, propynyl, butynyl, and hexynyl.
  • Aryl means aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and naphthyl.
  • Substituted aryl means aryl independently substituted with one to five (but preferably one to three) groups selected from C ⁇ _6 alkanoyloxy, hydroxy, halogen, C . alkyl, trifluoromethyl, C ⁇ _6 alkoxy, aryl, C2-6 alkenyl, C ⁇ .g alkanoyl, nitro, amino, cyano, azido, C * i-6 alkylamino, di-Ci-6 alkylamino, and amido.
  • Halogen means fluorine, chlorine, bromine, and iodine.
  • Heterocyclic means a 3 to 6-membered non-aromatic ring containing at least one and up to three non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples include piperadine, pyrrolidine, morpholine, piperazine and like rings.
  • Heteroaryl means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen.
  • heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, and like rings.
  • Hydroxy protecting groups include, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates
  • Ph means phenyl
  • ipr means isopropyl
  • DAST means diethylamino sulfur trifluoride.
  • the substituents of the substituted alkyl, alkenyl, alkynyl, aryl, heterocyclic and heteroaryl groups and moieties described herein, may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and /or may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.
  • taxane or “taxane core” refers to moieties with a framework of the structure:
  • cyclopropane group which can be constituted from R' and R*" of formula I can alternatively be referred to as "7b,8b-methano” group as in Tetrahedron Letters, Vol 35, No 43, pp 7893-7896 (1994) or as "cyclopropa” group as in U.S. Patent No. 5,254,580 issued October 19, 1993.
  • the new products that have the general formula I display a significant inhibitory effect with regard to abnormal cell proliferation, and have therapeutic properties that make it possible to treat patients who have pathological conditions associated with an abnormal cell proliferation.
  • the pathological conditions include the abnormal cellular proliferation of malignant or non-malignant cells in various tissues and /or organs, including, non-limitatively, muscle, bone and /or conjunctive tissues; the skin, brain, lungs and sexual organs; the lymphatic and /or renal system; mammary cells and /or blood cells; the liver, digestive system, and pancreas; and the thyroid and /or adrenal glands.
  • pathological conditions can also include psoriasis; solid tumors; ovarian, breast, brain, prostate, colon, stomach, kidney, and /or testicular cancer, Karposi's sarcoma; cholangiocarcinoma; choriocarcinoma; neuroblastoma; Wilm's tumor, Hodgkin's disease; melanomas; multiple myelomas; chronic lymphocytic leukemias; and acute or chronic granulocytic lymphomas.
  • novel products in accordance with the invention are particularly useful in the treatment of non-Hodgkin's lymphoma, multiple myeloma, melanoma, and ovarian, urothelial, oesophageal, lung, and breast cancers.
  • the products in accordance with the invention can be utilized to prevent or delay the appearance or reappearance, or to treat these pathological conditions.
  • the compounds of formula I are useful in treating and /or preventing polycystic kidney diseases (PKD) and rheumatoid arthritis.
  • the compounds of this invention can be made by techniques from the conventional organic chemistry repertoire.
  • Schemes I - VI which depict processes that compounds within the scope of formula I can be made, are only shown for the purpose of illustration and are not to be construed as limiting the processes to make the compounds by any other methods.
  • the preparation of a diol intermediate 4 is shown in Scheme I.
  • the starting material is a taxane analog suitably protected to leave the most reactive hydroxy group at C-7.
  • Compound 1 in Scheme I is protected at the 2' hydroxy group at the sidechain with a triethylsilyl ether.
  • the preparation of intermediates such as 1 are now well known in the art.
  • the synthesis of diol 4 utilizes precursor 6,7-olefin analogs 3 which is also now well known in the art.
  • Compound 3 can be formed directly from intermediate's 1 upon treatment with a reagent such as DAST as described in the U.S. patent 5,380,751.
  • a reagent such as DAST as described in the U.S. patent 5,380,751.
  • the synthesis of olefin 3 described in Scheme I proceeds through the 7-trifluoromethanesulfonate (triflate) intermediates 2 which are prepared as shown in step A. Elimination of the triflate (step B) provides the desired olefins 3.
  • the preparation of 7-0 triflates and their conversion into cyclopropanes and olefins has been divulged by Johnson, R.A., et ah, Taxol chemistry. 7-O-Tri ⁇ ates as precursors to olefins and cyclopropanes. Tetrahedron Letters, 1994. 35(43): p. 7893-7896 & by the same authors in WO 94/29288.
  • the olefin 3 is then hydroxylated with Osmium tetroxide (step C) which is used in either stoichiometric quantities or catalytically in the presence of a cooxidant such as N-methyl morpholine-N oxide (NMO).
  • a cooxidant such as N-methyl morpholine-N oxide (NMO).
  • NMO N-methyl morpholine-N oxide
  • a trialkyl germane such as tri-n-butyl germane provides the C-7 deoxy compound 6 with little, if any, competitive formation of the C-6 deoxy material.
  • a trialkyl tin hydride could be utilized in place of the germanium reagent.
  • the use of the tin hydride reagent also results in competitive deoxygenation at C-10 which produces mixtures which must be separated.
  • the tin reagent is the method of choice for producing C 7 and 10 deoxy -6-substituted analogs if these are the desired targets.
  • the use of trialkyl germane to suppress an unwanted side reaction is not precedented.
  • step E is a 7-deoxy-6-alpha- hydroxy intermediate 6 which is protected at the sidechain.
  • Scheme III illustrates the preparation of the C-6 trifluoromethanesulfonate (triflate or Tf) 7 from the C-6 hydroxy compound 6. The conversion is carried out as shown in Step f using
  • Triflic anhydride and 4-N,N-Dimethylamino pyridine (DMAP) as a catalyst Triflic anhydride and 4-N,N-Dimethylamino pyridine (DMAP) as a catalyst.
  • DMAP 4-N,N-Dimethylamino pyridine
  • the conditions described in the experimental are preferred. While a number of nonprotic organic solvents can be utilized successfully for this reaction, the preferred solvent is dichloromethane.
  • step G illustrates a direct displacement of the trifluromethanesulfonate of Compound 7 to produce the imidazolide Compound 8.
  • This reaction illustrates the use of heterocyclic compounds which contain an NH group as nucleophiles to displace the triflate grouping.
  • the 2' trialkylsilyl protecting group present in Compound 8 can be removed using triethylamine trihydrofluoride in THF to provide la which is a compound claimed in this invention.
  • step I illustrates the use of azide ion as a nucleophile to give Compound 9.
  • a 7-hydroxyl group is present in UK patent application GB 2,296,239A 6-azido structures are claimed but in all cases a 7-hydroxyl group is present. In the present invention the C-7 position is deoxygenated which provides a unique activity advantage.
  • the trialkylsilyl group can be removed as in step H above to give Compound lb which is a compound claimed in this invention.
  • Compound 9 serves as the starting material for the preparation of C-6 derivatives Ic an Id as illustrated in Scheme VI steps J and K.
  • Tf - -S-CF 3 Step A Tf 2 0, DMAP, CH 2 CI 2 O
  • hydroxy protecting group preferably trialkylsilyl group. It is to be understood that hydroxy protecting group may be a carbonate or ester group -C(0)OR x or -C(0)R x . Thus when such a group is employed as a hydroxy protecting group, it may either be removed to generate the free hydroxy protecting group or it may remain as a part of the final product.
  • the relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule.
  • the nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq).
  • the solvents employed for taking NMR spectra are acetone-d ⁇ (deuterated acetone).
  • DMSO-d ⁇ perdeuterodimethylsulfoxide
  • D2O deuterated water
  • CDCI3 deuterochloroform
  • IR infrared
  • spectral description include only absorption wave numbers (cm'l) having functional group identification value.
  • Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth.
  • THF tetrahydrofuran
  • HMDS hexamethyldisilazane
  • MeOTf methyltriflate
  • NMO morpholine-N-oxide
  • DHQ 2PHAL
  • LRMS low resolution mass spectrometry
  • ESI electrospray ionization
  • Paclitaxel (15g, 17.57 mmol) was dissolved in a solution of 60mL of pyridine and 60mL of dichloromethane and then the mixture was cooled to 0°C. Triethylsilyl chloride (11.8mL, 70.3 mmol) and the reaction was stirred for 90 min at 0°. The reaction was diluted with ethyl acetate, washed successively with water and then brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using 2:1 hexane/ethyl acetate as eluent to provide 17.0g (99%) of the title compound.
  • Paclitaxel 146.0 mg, 0.17 mmol was dissolved in dry N,N- dimethylformamide (1 mL). To this solution imidazole (116.1 mg, 1.7 mmol) and t-butyldimethylsilyl chloride (128.8 mg, 0.85 mmol) were added successively and the mixture was stirred at 60°C for 1 hour. The reaction mixture was then diluted with ethyl acetate (2 mL), followed by water. The aqueous layer was washed with additional ethyl acetate (2 X 2 mL).
  • the alcohol 1 (17g, 17.5 mmol) and DMAP (8.55g, 70mmol) was dissolved in dichloromethane and then the mixture was cooled to 0°C.
  • Trifluoromethanesulfonic anhydride (3.39mL, 20.1 mmol) was added via syringe and then reaction was allowed to warm to ambient temperature. The reaction was stirred for 2 hours, was diluted with ethyl acetate, washed successively with water and then brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
  • the triflate 2 (17. g, 16mmol) was dissolved in 75 mL of dry THF and then 12.18g (80mmol) of DBU was added. The reaction was heated at reflux for 2 hours and then diluted with ethyl acetate. The organic layer was washed five times with water and then brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was dissovled in methylene chloride and then 16 mmol of imidazole and 8 mmol of triethylsilyl chloride were added.
  • the reaction was stirred for 1.5h at ambient temperature, diluted with ethyl acetate, washed with two portions of water, dried over anhydrous magnesium sulfate and concentrated in vacuo.
  • the crude material was purified by flash chromatography over silica gel using 2:1 hexane/ethyl acetate as eluent to provide 15.0g (99%) of the title compound.
  • the diol 4 (1.773g, 1.809 mmol), thiocarbonyldiimidazole(0.996 g, 5.427 mmol), DMAP(0.618 g, 5.065 mmol) were dissolved in 50 mL THF and allowed to stir overnight. The reaction was diluted with EtOAc, washed with NaHC ⁇ 3, and brine. The solution was dried over MgS ⁇ 4 , filtered, and concentrated. The residue was chromatographed over silica gel (1:1 hexane/ethyl acetate) to yield 1.646 g of product 5 (89%).
  • the thiocarbonate 5 (0.200 g, 0.196 mmol), AIBN(cat), (aza- isobutyrylnitrile (catalytic)) and Bu3GeH(0.479 g, 1.96 mmol) were dissolved in 3 mL toluene under Argon.
  • the reaction mixture was frozen, dried in vacuo, and thawed three times to remove ⁇ 2-
  • the reaction was heated to 85°C for 1 hr..
  • the reaction mixture was concentrated and chromatographed over silica gel (1.5:1 hexane/ethyl acetate) to yield 0.137 g of product 6 (72%).
  • the alcohol 6 (0.950 g, 0.98 mmol) and DMAP (0.479 g, 3.92 mmol) were dissolved in 10 mL of dichloromethane and cooled to 0°C under nitrogen. Triflic anhydride ( 198 ⁇ L, 1.18 mmol) was added via syringe, and the reaction was allowed to stir at 0°C for 10 min.
  • the crude reaction mixture was placed directly onto a vacuum funnel containing a 1.5 inch plug of silica gel wet with hexanes, and eluted with (3:1 hexanes / ethyl acetate) to provide the triflate 7 (0.842 g 78%) as a white powder.
  • the solution was diluted with ethyl acetate and washed with saturated bicarbonate solution and brine, and dried over MgS ⁇ 4 .
  • the solution was concentrated and the residue chromatographed over silica gel using hexane/ ethyl acetate (1.5:1) to give 134 mg of product (42%).
  • the residue in 5 mL of THF was stirred for 24 hours with Et 3 N 3HF (35 ⁇ L) diluted with ethyl acetate and washed with water and brine.
  • the solution was diluted with ethyl acetate and washed with saturated bicarbonate solution and brine, and dried over MgS ⁇ 4 .
  • the solution was concentrated and the residue chromatographed over silica gel using hexane/ ethyl acetate (1:1) to give 165 mg of product (58%).
  • the compounds of this invention exhibit antitumor activities in in vivo and /or in vitro models.
  • the following test describes the in vitro test used to evaluate some representative compounds of this invention.
  • the epoxide taxane derivatives possessed cytoxicity in vitro against human colon carcinoma cells HCT-116. Cytoxicity was assessed in HCT- 116 human colon carcinoma cells by MTS (3-(4,5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium, inner salt) assay as reported in T.L. Riss, et. al., "Comparison of MTT, XTT, and a novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assays.," Mol. Biol. Cell 3 (Suppl.):184a, 1992.
  • Cytoxicity was determined after a 72 h exposure by MTS assay.
  • another aspect of the instant invention concerns a method for inhibiting human and /or other mammalian tumors which comprises administering to a tumor bearing host an antitumor effective amount of a compound of formula I.
  • the compound of formula I of the present invention may be used in a manner similar to that of paclitaxel, e.g. see Physician's Desk Reference, 49th Edition, Medical Economics, p 682, 1995.
  • the dosage, mode and schedule of administration for the compound of this invention are not particularly restricted; an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering the compound of the present invention.
  • the compound of formula I may be administered via any suitable route of administration, parenterally or orally.
  • Parenteral administration includes intravenous, intraperitoneal, intramuscular, and subcutaneous administration.
  • the doses utilized to implement the methods in accordance with the invention are the ones that make it possible to administer prophylactic treatment or to evoke a maximal therapeutic response.
  • the doses vary, depending on the type of administration, the particular product selected, and the personal characteristics of the subject to be treated. In general, the doses are the ones that are therapeutically effective for the treatment of disorders caused by abnormal cell proliferation.
  • the products in accordance with the invention can be administered as often as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to relatively high or low doses, and then require mild maintenance or no maintenance dose at all. Via the iv route, the dosage may be, for example, in the range of about 20 to about 500 mg/m ⁇ over 1 to 100 hours.
  • the dosage may be in the range of 5- lOOOmg/kg/day of body weight.
  • the actual dose used will vary according to the particular composition formulated, the route of administration, and the particular site, host and type of tumor being treated. Many factors that modify the action of the drug will be taken into account in determining the dosage including age, weight, sex, diet and the physical condition of the patient.
  • compositions containing an antitumor effective amount of compound of formula I in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
  • the compositions can be prepared in accordance with conventional methods. Examples of formulating paclitaxel or derivatives thereof may be found in, for example, United States Patents Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compound of this invention.
  • compound of formula I may be formulated in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms.
  • sterile solid compositions for example, freeze dried and, if desired, combined with other pharmaceutically acceptable excipients.
  • Such solid compositions can be reconstituted with sterile water, physiological saline, or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like, or some other sterile injectable medium immediately before use for parenteral administration.
  • Typical of pharmaceutically acceptable carriers are, for example, manitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid.
  • the pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.
  • auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.

Abstract

L'invention concerne de nouveaux dérivés du paclitaxel et leur utilisation comme agents antitumoraux, ainsi que des compositions pharmaceutiques.
PCT/US1998/025872 1997-12-23 1998-12-04 Paclitaxels portant un substituant 7-desoxy-6-azote WO1999032109A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17128/99A AU1712899A (en) 1997-12-23 1998-12-04 7-deoxy-6-nitrogen substituted paclitaxels

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6862997P 1997-12-23 1997-12-23
US60/068,629 1997-12-23

Publications (1)

Publication Number Publication Date
WO1999032109A1 true WO1999032109A1 (fr) 1999-07-01

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/025872 WO1999032109A1 (fr) 1997-12-23 1998-12-04 Paclitaxels portant un substituant 7-desoxy-6-azote

Country Status (2)

Country Link
AU (1) AU1712899A (fr)
WO (1) WO1999032109A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4206221A (en) * 1979-01-03 1980-06-03 The United States Of America As Represented By The Secretary Of Agriculture Cephalomannine and its use in treating leukemic tumors
US4876399A (en) * 1987-11-02 1989-10-24 Research Corporation Technologies, Inc. Taxols, their preparation and intermediates thereof
US5380751A (en) * 1992-12-04 1995-01-10 Bristol-Myers Squibb Company 6,7-modified paclitaxels
US5677462A (en) * 1992-10-05 1997-10-14 Rhone-Poulenc Rorer, S.A. Process for preparing taxane derivatives
US5710287A (en) * 1991-09-23 1998-01-20 Florida State University Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them
US5780653A (en) * 1995-06-07 1998-07-14 Vivorx Pharmaceuticals, Inc. Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers
US5840929A (en) * 1995-04-14 1998-11-24 Bristol-Myers Squibb Company C4 methoxy ether derivatives of paclitaxel

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4206221A (en) * 1979-01-03 1980-06-03 The United States Of America As Represented By The Secretary Of Agriculture Cephalomannine and its use in treating leukemic tumors
US4876399A (en) * 1987-11-02 1989-10-24 Research Corporation Technologies, Inc. Taxols, their preparation and intermediates thereof
US5710287A (en) * 1991-09-23 1998-01-20 Florida State University Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them
US5677462A (en) * 1992-10-05 1997-10-14 Rhone-Poulenc Rorer, S.A. Process for preparing taxane derivatives
US5380751A (en) * 1992-12-04 1995-01-10 Bristol-Myers Squibb Company 6,7-modified paclitaxels
US5840929A (en) * 1995-04-14 1998-11-24 Bristol-Myers Squibb Company C4 methoxy ether derivatives of paclitaxel
US5780653A (en) * 1995-06-07 1998-07-14 Vivorx Pharmaceuticals, Inc. Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR

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