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
  • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

• the present invention is directed to new taxane derivatives endowed with antitumor activity, to a process for their preparation and to pharmaceutical compositions containing them.
• the taxane family of diterpenes includes Paclitaxel (also named taxol in several publications) , isolated and characterized from an extract of bark of Taxus brevifolia L., and Cephalomannine (see J.Chem.Soc. Chem.Comm. 102, 1979); other taxane analogues are also known and were prepared by semisynthesis starting from 10-deacetyl baccatin III, extracted from the needles of Taxus baccata L. (see ani et al. , J.Am.Chem.Soc.
• taxol is a very potent anticancer drug and is already applied with success to the treatment of platinum- resistant ovarian cancer. Nevertheless there is a continuous need for more potent compounds having the broadest possible spectrum of activity on different cancer types.
• the present invention provides taxane derivatives modified at the 7-position of the taxane skeleton (taxol numbering) . More especially, the invention provides taxane derivatives of formula
• R represents azido, cyano, lH-tetrazol-5-yl or a residue of formula NR 7 R g wherein R 7 and R 8 independently represent hydrogen or a C,-C 6 alkyl, C,-C 8 alkanoyl or C 7 -C n aroyl group,*
• R 2 represents a hydrogen atom, hydroxy group or a group of formula -OCOR' , -OR', -OS0 2 R' , -OCONR'R", -OCONHR, or -OCOOR' wherein R' and R' ' each independently represent C]-C 6 alkyl, preferably methyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkynyl or a phenyl group, optionally substituted with one, two or three substituents which may be the same or different and which are selected from a halogen atom, C,-C 6 alkyl, C ⁇ -C 6 alkoxy and -CF 3 groups,*
• R 3 is -COR' ' ' or -COOR' ' ' wherein R' ' ' represents C,-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkynyl or a phenyl group, optionally substituted with one, two or three substituents which may be the same or different and which are selected from a halogen atom, C]-C 6 alkyl, C,-C 6 alkoxy and -CF 3 groups,- and
• R 4 is C]-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl or a radical of the formula -W-R x in which W is a bond, C 2 -C 6 alkenediyl or - ⁇ CH 2 ) n - where n is from 1 to 6 such as from 2 to 4 and R x is naphthyl, phenyl or heteroaryl optionally substituted with one, two or three substituents which may be the same or different and which are selected from C,-C 6 alkyl, Cj-C 6 alkoxy, halogen and -CF 3 groups, or a pharmaceutically acceptable salt thereof.
• R' ' ' represents phenyl, tert-butyl, l-methyl- l- propenyl or n-pentyl,* more preferably phenyl.
• R 4 is phenyl.
• the wavy lines indicate that the hydroxy group at the 2' -position and the substituent at the 7-position may be in the or ⁇ configuration, or both, i.e. a mixture of stereoisomers is present.
• a C ! *-C 6 alkyl group is a straight or branched alkyl group, preferably a C,-C 4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
• a C 2 -C 6 alkenyl group is a straight or branched alkenyl group, preferably a C 2 -C 5 alkenyl group e.g. vinyl, allyl, crotyl, 2-methyl-1- propenyl, 1-methyl-1-propenyl, butenyl or pentenyl.
• a C 3 -C 6 cycloalkyl group is a saturated carbocyclic group of 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclohexyl.
• a halogen is preferably fluorine, chlorine, bromine or iodine.
• a heteroaryl group is preferably a 3- to 6-membered, saturated or unsaturated heterocyclyl ring which contains at least one, for example 1, 2 or 3, heteroatoms selected from 0, S and N and which is optionally fused to a second 5- or 6-membered, saturated or unsaturated heterocyclyl group containing one or more, for example 1, 2 or 3, heteroatoms or to a cycloalkyl group or to an aryl group.
• the 3- to 6- membered heterocyclyl ring may be a 3-, 4-, 5- or 6- membered such ring.
• a cycloalkyl group is generally a said C 3 -C 6 cycloalkyl group.
• An aryl group is generally phenyl (Ph) or naphthyl.
• heterocyclyl groups are pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,thienyl, furyl, aziridinyl, oxiranyl, azetidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyranyl, pyridazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, chromenyl, indolyl, indolizinyl, isoindolyl, cinnolinyl, indazolyl and purinyl.
• a C 2 -C 6 alkynyl group can be a straight or branched alkynyl group preferably a C 2 -C 4 alkynyl group such as ethynyl, propargyl, 1-propynyl, 1-butynyl or 2- butynyl.
• a C 7 -C,, aroyl group is intended to include benzoyl or naphthoyl residues.
• a C,-C 6 alkoxy group can be a straight chain or branched alkoxy1 group, preferably a C,-C 4 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy.
• a C,-C 8 alkanoyl group can be a straight chain or branched alkanoyl group, preferably a C,-C 5 alkanoyl group such as methanoyl (Ac) , ethanoyl, n-propanoyl, isopropanoyl, n-butanoyl, tert-butanoyl or n-pentanoyl.
• the pharmaceutically acceptable salts include the hydrochloride salt, the hydrobromide salt and the sulphate salt.
• Preferred compounds of the invention are the taxane derivatives of formula I wherein R, represents azido, cyano, 1H- tetrazol-5-yl or a residue of formula NR 7 R 8 wherein R 7 and R 8 independently represent hydrogen or a C]-C 4 alkyl, C,-C 5 alkanoyl, benzoyl or naphthoyl group,* R 2 represents a hydrogen atom, hydroxy group or a group of formula -OCOR' , -OR', -OS0 2 R' , -OCONR'R", -OCONHR, or -OCOOR' wherein R' and R' ' each independently represent Cj-C 4 alkyl, C 2 -C 5 alkenyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkynyl or a phenyl group optional
• R 4 is C,-C 4 alkyl, C 2 -C 5 alkenyl, C 3 -C 6 cycloalkyl or a radical of the formula -W-R x in which is a bond, C 2 -C 4 alkenediyl or -
• n is from 2 to 4 and R x is naphthyl, phenyl or heteroaryl optionally substituted with one, two or three substituents which may be the same or different and which are selected from C,-C 4 alkyl, C j - , alkoxy, halogen and -CF 3 groups; or a pharmaceutically salt thereof.
• R' and/or R" is methyl in a taxane derivative of formula I.
• R' ' ' is phenyl, tert-butyl, 1-methyl-l- propenyl or n-pentyl.
• Preferred compounds of the invention are: 7-deoxy-7-epi-azido-taxol, 7-deoxy-7-epi-amino-taxol, 7-deoxy-7-cyano-taxol and 7-deoxy-7- (lH-tetrazol-5-yl) -taxol.
• the present invention also provides a process for the preparation of taxane derivatives of formula I, as above defined, or a pharmaceutically acceptable salt thereof.
• structures of formula I can be obtained by a substitution process from a taxane derivative having a suitable leaving group at the 7-position (like triflate, mesylate, tresylate, etc.) and with an optional hydroxy protecting group at the 2'-position (like the acetyl group) .
• the present invention provides a process for preparing a taxane derivative of formula I or a pharmaceutically acceptable salt thereof, the process comprising
• R 2 , R 3 and R 4 are as defined above, R' 5 is a hydrogen atom or a hydroxy protecting group R 5 and R 6 is a leaving group, thereby to form a taxane derivative having at the 7-position an azido, cyano or lH-tetrazol-5-yl group,*
• the leaving group R 6 can for example be CH 3 S0 2 0-, CF 3 S0 2 0-, CF 3 CH 2 S0 2 0- or another suitable leaving group.
• the substitution reaction at the 7-position is typically achieved by reacting a compound of formula II with an azide or cyanide ion.
• the azide is typically sodium azide.
• the cyanide is typically potassium cyanide.
• the reaction may be performed in aprotic dipolar solvents, e.g. dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) and the like, as well as in phase-transfer catalysis conditions in the presence of a quaternary ammonium salt (for example tricaprylylmethylammonium chloride (Aliquat 336)) and in an apolar organic solvent (for example toluene, benzene, dichloromethane, chloroform, etc) .
• the reaction temperature may vary from 0°C to 120°C.
• the reduction of the 7-azido group may be carried out by heterogeneous catalytic hydrogenation (using for example palladium on charcoal) or by means of the Staudinger reaction (triphenyl phosphine in a solvent mixture like tetrahydrofuran (THF) /water) .
• the amino derivatization may be carried out using literature methods,- for example reductive alkylation or acylation.
• the reaction of the 7-cyano derivative to give a tetrazolyl derivative can be performed using literature methods, for example with trialkyltin azide in toluene.
• the removal of the hydroxy protecting group R 3 can be carried out under standard conditions such as hydrolysis or hydrogenolysis or utilizing tetrabutylammonium fluoride for silyl groups.
• the protecting group is acetyl, it may be removed by treatment with sodium bicarbonate in MeOH/H 2 0 or with diethylamine in methanol.
• the separation of the isomers which are a and ⁇ configuration at the 2'- and 7-positions may be carried out by analogy with known methods.
• Taxane derivatives of formula III wherein R : , R 2 , R 3 , R 4 and R 5 are as defined above are novel and within the scope of the present invention.
• a process for the preparation of taxane derivatives of formula III comprises:
• the taxane derivatives of formula II are either known compounds (for example the mesylate of formula II, where R 3 is -CO-phenyl, R 4 is phenyl, R 6 is -OS0 2 CH 3 , R 2 is 0-acetyl and R 5 is acetyl [see J.Na .Prod.51, 298 (1988)]), or may be prepared from known compounds using established methods.
• compounds of formula II can be used as starting materials where R 3 is -CO-phenyl, R 4 is phenyl, R 6 is hydroxy, R 2 is O-acetyl and R 5 is acetyl [see Bioch.Bioph.Res .Comm.124, 329 (1984) or Journal.Nat.
• the cytotoxic activity of the compounds has been evaluated on B16-F10 murine melanoma cell line which was responsive to taxol.
• the mode of action of the compound was also tested on the tubulin assembly-disassembly assay in comparison with taxol.
• the cuvette (1 cm path) containing tubulin (lmg/ml) and l mM GTP was shifted to 37°C and continuous turbidity measurements were made at 340 nm on a Perkin-Elmer 557 double wavelength, double beam spectrophotometer equipped with an automatic recorder and a thermostatically regulated sample chamber. After 30 minutes, 4 mM CaCl 2 was added and depolymerisation was measured for 10 minutes as decreased turbidity. At regular intervals of 15 minutes scaled doses of the tested compounds were added and variations in the turbidity were monitored. Data are expressed as percentage of repolymerization induced by the tested compounds. The results are shown in Table I.
• the taxane derivatives of formula I are thus antitumor agents.
• a human or animal suffering from a tumor may thus be treated by a method which comprises the administration thereto of an effective amount of a taxane derivative of formula I or II according to the invention.
• the condition of the human or animal may thereby be improved.
• tumors examples include sarcomas, carcinomas, lymphomas, neuroblastomas, melanomas, myelomas, Wilms tumor, leukemias and adenocarcinomas.
• the taxane derivatives of formulae I and II can be used to treat ovarian cancer, platinum-resistant ovarian cancer, metastatic breast cancer, non-small cell lung cancer, and head and neck cancer.
• the invention also provides a pharmaceutical composition which comprises, as active ingredient, a compound of formula I or II according to the invention and a pharmaceutically acceptable carrier or diluent.
• the composition of the invention is usually prepared following conventional methods and is administered in a pharmaceutically suitable form. Administration can be made by any of the accepted ways for administration of antitumor agents such as intravenous, intramuscular or subcutaneous injection or topical application.
• the active compound may be, e.g., dissolved in a vehicle consisting of a mixture of polyoxyethylated castor oil (Chremophor EL) 50% and ethanol 50% and then diluted with glucose 5% solution at the desired concentration, or in other pharmaceutically suitable carriers.
• Chophor EL polyoxyethylated castor oil
• the amount of the active compound administered depends on the treated subject, for example on age, weight, sex etc., and also on the severity of the affliction.
• the method of administration depends on the judgement of the prescribing physician.
• a suitable dosage for an average 70 kg person may range from about O.Olg to about lg per day.

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• 1995
  • 1995-11-02 JP JP8515042A patent/JPH09507864A/ja not_active Withdrawn
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