USH1487H - Benzoate derivatives of taxol - Google Patents

Benzoate derivatives of taxol Download PDF

Info

Publication number
USH1487H
USH1487H US08/128,949 US12894993A USH1487H US H1487 H USH1487 H US H1487H US 12894993 A US12894993 A US 12894993A US H1487 H USH1487 H US H1487H
Authority
US
United States
Prior art keywords
compound
alkyl
formula
taxol
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US08/128,949
Other languages
English (en)
Inventor
Henry Wong
Terrence Doyle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Co
Original Assignee
Bristol Myers Squibb Co
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 Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to US08/128,949 priority Critical patent/USH1487H/en
Application granted granted Critical
Publication of USH1487H publication Critical patent/USH1487H/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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 Table
    • 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
    • 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 Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • Taxol was first isolated from the stem bark of Western Yew, Taxus brevifolia Nut. (Taxaceae) and has the following structure (with the 2'- and 7- positions indicated) ##STR5## In ongoing clinical trials sponsored by the National Cancer Institute (NCI), taxol has shown promising results in fighting advanced cases of ovarian, breast, and other cancers. A recent review article in the Journal of National Cancer Institute provides an overview on its mechanism of action, toxicology, clinical results, etc. E. Rowinsky et al., Taxol: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: 1247-1259 (1990).
  • taxol has been made more water soluble through the derivatization of the 2'- and/or 7-hydroxy group with a hydrophilic group resulting in a bioreversible form known as a prodrug.
  • Prodrugs have been shown to improve physicochemical (e.g. solubility, lipophilicity, etc.) and biological properties of many compounds.
  • One approach to form a water soluble prodrug of a hydroxy containing molecule has been to derivatize the hydroxy group into an N-substituted-(aminomethyl)benzoate ester. See for example, Bundgaard et al., J. Med.
  • This invention relates to a compound of formula I ##STR6## or a pharmaceutically acceptable salt thereof, in which R 2 is a radical of the formula ##STR7## in which R a and R b are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C 1-6 alkyl)amino; or NR a R b together represents a radical of the formula ##STR8## in which y is one to three, and R a is as defined above; R p and R r are independently same or different C 1-6 alkyl;
  • R 1 is hydrogen or a radical Z of the formula ##STR9## in which Q is --(CH 2 ) f --, optionally substituted with one to six same or different C 1-6 alkyl or C 3-6 cycloalkyl, or a carbon atom of said --(CH 2 ) f -- radical may also be a part of C 3-6 cycloalkylidene;
  • R 3 and R 4 are independently hydrogen or C 1-6 alkyl, or R 3 and R 4 taken together with the carbon atom to which they are attached form C 3-6 cycloalkylidene;
  • R 5 is --OC( ⁇ O)R, --OP ⁇ O(OH) 2 or --CH 2 OP ⁇ O(OH) 2 , in which R is C 1-6 alkyl;
  • R 6 , R 7 , R 8 and R 9 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or hydrogen, but when R 5 is --OC ( ⁇ O)R one of R 6 , R 7 , R 8 R 9 is --OP ⁇ O(OH) 2 ; f is 2 to 6;
  • n is O, and m is 1 or 0 when R 5 is --CH 2 OP ⁇ O(OH) 2 ; and n is 1 or 0, and m is 1 when R 5 is --OC( ⁇ O)R or --OP ⁇ O(OH) 2 .
  • This invention also provides pharmaceutical formulations and a method for treating mammalian tumors with a compound of formula I.
  • This invention relates to a benzoate taxol derivative of formula I ##STR10## or a pharmaceutically acceptable salt thereof, in which R 2 is a radical of the formula ##STR11## in which R a and R b are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with hydroxy, phosphono, phosphonooxy, carboxy or di(C 1-6 alkyl)amino; or NR a R b together represents a radical of the formula ##STR12## in which y is one to three, and R a is as defined above; R p and R r are independently same or different C 1-6 alkyl;
  • R 1 is hydrogen or a radical Z of the formula ##STR13## in which Q is --(CH 2 ) f --, optionally substituted with one to six same or different C 1-6 alkyl or C 3-6 cycloalkyl, or a carbon atom of said --(CH 2 ) f -- radical may also be a part of C 3-6 cycloalkylidene;
  • R 3 and R 4 are independently hydrogen or C 1-6 alkyl, or R 3 and R 4 taken together with the carbon atom to which they are attached form C 3-6 cycloalkylidene;
  • R 5 is --OC( ⁇ O)R, --OP ⁇ O(OH) 2 or --CH 2 OP ⁇ O(OH) 2 , in which R is C 1-6 alkyl;
  • R 6 , R 7 , R 8 and R 9 are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or hydrogen, but when R 5 is --OC( ⁇ O)R, one of R 6 , R 7 , R 8 or R 9 is --OP ⁇ O(OH) 2 ; f is 2 to 6;
  • n is O, and m is 1 or 0 when R 5 is --CH 2 OP ⁇ O(OH) 2 ; and n is 1 or 0, and m is 1 when R 5 is --OC( ⁇ O)R or --OP ⁇ O(OH) 2 .
  • Some compounds of formula I may form pharmaceutically acceptable metal and amine salts in which the cation does not contribute significantly to the toxicity or biological activity of the salt and are compatible with the customary pharmaceutical vehicles and adapted for oral or parenteral administration. These salts are also part of the present invention. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, and aluminum salts. The sodium or potassium salts are preferred.
  • Amines which are capable of forming stable salts may include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or the like amines.
  • trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or the like amines.
  • Some compounds of formula I may also form pharmaceutically acceptable acid addition salts in which the anion does not contribute significantly to the toxicity of the salt and are compatible with the customary pharmaceutical vehicles and adapted for oral or parenteral administration.
  • the pharmaceutically acceptable acid addition salts include the salts of compounds of formula I with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, with organic carboxylic acids or organic sulfonic acids such as acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like acids.
  • Some compounds of the present invention may exist as zwitterionic forms.
  • Pharmaceutically acceptable salts include not only pharmaceutically acceptable metal and amine salts and pharmaceutically acceptable acid addition salts but also zwitterionic forms, which are also within the scope of this invention.
  • C 1-6 alkyl refers to straight and branched chain alkyl groups with one to six carbon atoms and such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, or the like alkyl groups;
  • C 3-6 cycloalkylidene refers to cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene;
  • C 3-6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • C 1-6 alkyloxy (alkoxy) refers to straight or branched alkyloxy groups such as methoxy
  • a compound of formula I 1 which is within the scope of formula I compounds, may be obtained by the steps comprising: [Step (1)] reacting taxol with chloromethylbenzoic anhydride of formula XXXV to afford a compound of formula XXX; and [Step (2)] reacting the compound of formula XXX with an secondary amine of the formula
  • R t and R u are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with di(C 1-6 alkyl)amino or hydroxy, or with a conventionally protected carboxy, phosphono or phosphonooxy group; or NR t R u together represents a radical of the formula ##STR14## in which y is one to three and R t is as defined above.
  • An additional step [Step (3)] of removing conventional carboxy, phosphonooxy or phosphono protecting group(s) is required if either or both R t and R u contain such protecting group(s).
  • conventional carboxy protecting groups which can be employed in the present invention to block or protect the carboxylic acid function are well-known to those skilled in the art and, preferably, said groups can be removed, if desired, by methods which do not result in any appreciable destruction of the remaining portion of the molecule.
  • Examples of such readily removable carboxy-protecting groups include moieties such as C 1-6 alkyl, diphenylmethyl (benzyhydryl), 2-naphthylmethyl, 4-pyridylmethyl, phenacyl, acetonyl, 2,2,2-trichloroethyl, silyl such as trimethylsilyl and t-butyldimethylsilyl, phenyl, ring substituted phenyl, e.g., 4-chlorophenyl, tolyl, and t-butylphenyl, phenyl C 1-6 alkyl, ring substituted phenyl C 1-6 alkyl, e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl (p-nitrobenzyl), 2-nitrobenzyl (o-nitrobenzyl), and triphenylmethyl (trityl), methoxymethyl, 2,2,2-trichloroethoxycarbonyl, benzyloxymethyl,
  • carboxy protecting groups well known in the art which have not been disclosed above can be found in "Protective Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, John Wiley & Sons, 2nd Edition, 1991, Chapter 5.
  • Particularly advantageous carboxy protecting groups are benzyl, p-nitrobenzyl, o-nitrobenzyl, 2,4-dimethoxybenzyl, 4-methoxybenzyl, allyl, substituted allyl, t-butyl or diphenylmethyl (DPM).
  • a conventional phosphono or phosphonooxy protecting group can be C 1-6 alkyl, benzyl, allyl or 2,2,2-trichloroethyl, with a preferred phosphono protecting group being ethyl and a preferred phosphonooxy protecting group being benzyl, allyl or 2,2,2-trichloroethyl.
  • Step (1) of Scheme I is normally conducted in the presence of a strong base, such as LDA (lithium diisopropylamide), and in an inert solvent such as 1,4-dioxane, THF, DMF, diglyme, methylene chloride, or in the like solvent under reduced temperature.
  • a strong base such as LDA (lithium diisopropylamide)
  • an inert solvent such as 1,4-dioxane, THF, DMF, diglyme, methylene chloride, or in the like solvent under reduced temperature.
  • All three methods (Methods A-C) in Example 28 may be adapted to make any of the positional isomers of a compound of formula XXX.
  • the methods for making representative 2'-[(N-substituted-4-aminomethyl)benzoate]taxols in Example 29 may be adapted to make other 2'-[(N-substituted-aminomethyl)benzoate]taxol derivative
  • R a' and R b' are independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl being optionally substituted with a conventionally protected carboxy, hydroxy, phosphonooxy, or phosphono group, or with a di(C 1-6 alkyl)amino group; or NR a' R b' together represents a radical of the formula ##STR16## in which y is one to three and R a' is as defined above, to afford a compound of formula XXXI.
  • Step (1) of Scheme II can be conducted in the same or substantially same manner as Step (2) of Scheme I.
  • R 6' , R 7' , R 8' and R 9' are independently halogen, C 1-6 alkyl, C 1-6 alkoxy or hydrogen, but when R 5' is --OC( ⁇ O)R, one of R 6' R 7' , R 8' or R 9' is --OP ⁇ O(OR 10 ) 2 ; n is O, and m is 1 or 0 when R 5' is --CH 2 OP ⁇ O(OR 10 ) 2 ; n is 1 or 0, and m is 1 when R 5' is --OC( ⁇ O)R or --OP ⁇ O(OR 10 ) 2 ; Q, R, R 3 and R 4 are as previously defined; and R 10 is a conventional phosphonooxy protecting group.
  • R d is a radical of the formula ##STR18## Subsequent removal of all protecting groups from a compound of formula XXXII in Step (3) affords a compound of formula I 2 .
  • R 10 group is benzyl, it can be removed by catalytic hydrogenolysis.
  • conventional hydroxy protecting groups are moieties which can be employed to block or protect the hydroxy function and they are well-known to those skilled in the art.
  • said groups are those which can be removed by methods resulting in no appreciable destruction to the remaining portion of the molecule.
  • hydroxy protecting groups examples include chloroacetyl, methoxymethyl, 2,2,2-trichloroethyloxymethyl, 2,2,2-trichloroethyloxycarbonyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, triphenylsilyl, and the like.
  • a particularly advantageous protecting group for the 2'-hydroxy group of taxol is benzyloxycarbonyl, which can be removed conveniently by catalytic hydrogenolysis.
  • Other suitable protecting groups which may be used are found in Chapter 2 of "Protecting Groups in Organic Synthesis", Second Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons).
  • acylating a hydroxy group with a carboxylic acid is well known in the art.
  • Particularly useful to the present invention are those which employ dehydrating agents such as dicyclohexylcarbodiimide (DCC), alkyl chloroformate and triethylamine, pyridinium salts-Bu 3 N, phenyl dichlorophosphate, DCC and an aminopyridine, 2-chloro-1,3,5-trinitrobenzene and pyridine, polyphosphate ester, chlorosulfonyl isocyanate, chlorosilanes, MeSO 2 Cl-triethylamine, Ph 3 P-CCl 4 -triethylamine, or N,N'-carbonyldiimidazole, to name a few.
  • dehydrating agents such as dicyclohexylcarbodiimide (DCC), alkyl chloroformate and triethylamine, pyridinium salts-Bu 3 N, phenyl dich
  • More particularly advantageous dehydrating system is comprised of DCC and 4-dimethylaminopyridine (4-DMAP).
  • a compound of formula I 3 which is within the scope of compounds of formula I, may be made by acylating the 2'-hydroxy group of taxol with an acid of formula XXXIV [Step (1), Scheme III]. Subsequent acylation of the 7-hydroxy group with an acid of formula XXV or IX in Step (2) generates a compound of formula XXXIII. Removal of all protecting groups from a compound of formula XXXIII affords a compound of formula I 4 , which is further within the scope of formula I compounds. ##STR19##
  • synthesis of acids of formula IX can be made by a wide variety of methods.
  • synthesis of an acid of formula IX' which is within the scope of the acids of formula IX, may be made by the sequence of steps as shown in Scheme A.
  • R 6' , R 7' , R 8' , and R 9' preferably are independently hydrogen or C 1-6 alkyl; R, R 3 and R 4 are as previously defined.
  • Step (a) involves acid promoted transesterification of an acrylic acid ester with a phenol derivative of formula II and subsequent ring cyclization to afford a compound of formula III.
  • the reaction is usually conducted in an inert organic solvent such as benzene, toluene or xylene, and the preferred catalyst is concentrated sulfuric acid.
  • the reaction is normally conducted at an elevated temperature, preferably at or above the boiling point of benzene.
  • Step (b) a lactone of formula III is being reduced.
  • the reduction is normally conducted in an inert solvent such as 1,4-dioxane, diglyme, tetrahydrofuran (THF) or diethyl ether.
  • a suitable reducing agent is lithium aluminum hydride.
  • Other metal aluminum hydrides known to reduce lactones to alcohols may be employed as well.
  • Step (c) involves the protection of the free alkylhydroxy group in a compound of formula IV to afford a compound of formula V in which R 12 is a conventional hydroxy protecting group.
  • R 12 is a conventional hydroxy protecting group.
  • t-butyldimethylsilyl group on a hydroxy group can be accomplished by reacting the hydroxy group with t-butyldimethylsilyl chloride in an inert solvent such as diethyl ether, 1,4-dioxane, diglyme, chloroform, DMF, THF, or methylene chloride, and also in the presence of an amine base such as imidazole, 4-dimethylaminopyridine, or triethylamine, N,N-diisopropylethylamine, or any other tri(C 1-6 )alkylamines.
  • an inert solvent such as diethyl ether, 1,4-dioxane, diglyme, chloroform, DMF, THF, or methylene chloride
  • an amine base such as imidazole, 4-dimethylaminopyridine, or triethylamine, N,N-diisopropylethylamine, or any other tri
  • Step (d) the phenolic hydroxy group of a compound of formula V is phosphorylated with a compound of formula XXIV to afford a compound of formula VI in which R 10 is a phosphonooxy protecting group defined above.
  • R 10 is a phosphonooxy protecting group defined above.
  • a preferred R 10 radical is benzyl.
  • the addition of dibenzylphosphono group is effected by reacting a phenolic salt of a compound of formula V with tetrabenzylpyrophosphate that in turn can be made from dibenzylphosphate and at least 0.5 equivalent of DCC.
  • Step (d) is normally conducted in an inert aprotic solvent, such as 1,4-dioxane, diglyme, DMF or THF.
  • the cation of the phenolic salt of a compound of formula V can be sodium, potassium, lithium, calcium, benzyltriethylammonium or tetraethylammonium, tetrabutylammonium or any other tetra(C 1-6 )alkylammonium.
  • the formation of the phenolic salt can be effected by removing the phenolic proton by a base such as potassium carbonate, potassium hydroxide, potassium hydride, sodium hydride, sodium hydroxide, sodium carbonate, or a quaternary ammonium hydroxide such as tetrabutylammonium hydroxide or benzyltriethylammonium hydroxide.
  • Step (e) the hydroxy protecting group R 12 is removed.
  • fluoride ion or mineral acid in alcohol may be used for its removal.
  • the source of the fluoride ion can be from tetrabutylammonium fluoride.
  • the removal with fluoride is conducted in an inert solvent such as THF, methylene chloride, 1,4-dioxane, DMF, chloroform, or in the like inert solvent; and preferably the reaction medium is buffered by a weak acid such as acetic acid.
  • An example of mineral acid in alcohol is hydrochloric acid in isopropanol.
  • Step (f) entails the oxidation of the hydroxy group to the aldehyde group.
  • a wide array of reagents are available for oxidizing a primary alcohol to an aldehyde, which may also be used to effect Step (f).
  • Some examples include: dipyridine Cr(VI) oxide (Collin's reagent), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), ceric ammonium nitrate (CAN), Na 2 Cr 2 O 7 in water, N-iodosuccinimide and Bu 4 N + I - , Ag 2 CO 3 -on-celite, N-methylmorpholine-n-oxide, a Ru complex, etc.
  • Step (f) is pyridinium chlorochromate (PCC) in methylene chloride.
  • Step (g) involves a further oxidation of an aldehyde of formula VIII into an acid of formula IX'.
  • Many reagents are known to convert an aldehyde to an acid.
  • Step (g) Some examples include: potassium permanganate, Ag 2 O-water, m-chloroperbenzoic acid, Jones reagent (chromic and sulfuric acid in water), etc.
  • the oxidation in Step (g) is preferably done by using the Jones reagent in acetone.
  • a compound of formula IV can be directly converted to a compound of formula VII by employing the method specified above for Step (d). Furthermore, a compound of formula VII can be directly converted to a compound of formula IX' with the Jones reagent.
  • Step (a) a quinone of formula X is reduced to a hydroquinone of formula XI by a standard quinone reduction method such as by employing sodium hydrosulfite.
  • the annulation in Step (b) can be effected using the same or substantially the same condition described for Step (a) of Scheme A.
  • Step (c) The phenolic hydroxy group in a compound of formula XII is protected in Step (c) to afford a compound of formula XIII.
  • a suitable phenol protecting group R 11 for the purpose of Step (c) is benzyl.
  • Other well-known phenol protecting groups such as those enumerated in pp. 144-170 of "Protecting Groups in Organic Synthesis", Second Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons), may also be used.
  • the reduction in Step (d) can be conducted in the same or substantially the same manner as described for Step (b) of Scheme A.
  • Step (h) the conversion of a compound of formula XVII to a compound of formula XVIII can be effected in the same or substantially the same way as described for Step (d) of Scheme A.
  • a preferred R 10 radical is again benzyl.
  • the removal of R 12 hydroxy protecting group from a compound of formula XVIII can be carried out in the same or substantially same manner as described for Step (e) of Scheme A.
  • the oxidation of the alcohol group to the carboxylic group in Step (j) can be done with the Jones reagent.
  • a compound of formula XXII may be reacted with bis(allyloxy)(diisopropylamino)phosphine or dibenzyloxy(diisopropylamino)phosphine in the presence of a base, such as 1H-tetrazole; and the resulting addition product is subsequently oxidized, for example by m-chloroperbenzoic acid.
  • a base such as 1H-tetrazole
  • NMR nuclear magnetic resonance
  • the nature of the shifts as to multiplicity is reported as broad singlet (bs), broad doublet (bd), broad triplet (bt), broad quartet (bq), 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 DMSO-d 6 (perdeuterodimethylsulfoxide), D 2 O (deuterated water), CDCl 3 (deuterochloroform) and other conventional deuterated solvents.
  • the infrared (IR) spectral description include only absorption wave numbers (cm -1 ) having functional group identification value.
  • Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth.
  • hexane and hexanes may be used interchangeably.
  • tetrabenzylpyrophosphate (XXIVa) (14.5 g, 26.93 mmol, 1.5 eq.; pyrophosphate XXIVa was prepared from dibenzylphosphate and DCC) all at once.
  • the reaction mixture was continued to be stirred at 65° C. for 10 min. Subsequently, it was diluted with EtOAc (300 mL), washed with brine (4 ⁇ 100 mL), and dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated in vacuo to obtain compound VIa as a crude product which was purified on a silica gel column.
  • the Jones reagent was prepared by dissolving CrO 3 (26.72 g) in "concentrated sulfuric acid (23 mL) and diluted with water to a volume of 100 mL" (see Fieser and Fieser “Reagents for Organic Synthesis” Vol 1, p 142, John Wiley, New York, 1967).
  • Table 1 lists taxol derivatives whose specific syntheses are described in the Examples.
  • mice Balb/c x DBA/2 F 1 hybrid mice were implanted intraperitoneally, as described by William Rose in Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Antitumor Drugs, Cancer Treatment Reports, 65, No. 3-4 (1981), with 0.5 mL of a 2% (w/v) brei of M109 lung carcinoma.
  • mice were treated with compound under study by receiving intraperitoneal injections of various doses on either Days 1, 5 and 9 post-tumor implant or Days 5 and 8 post-implant. Mice were followed daily for survival until approximately 75-90 days post-tumor implant. One group of mice per experiment remained untreated and served as the control group. Median survival times of compound-treated (T) mice were compared to the median survial time of the control (C) mice. The ratio of the two values for each compound-treated group of mice was multiplied by 100 and expressed as a percentage (i.e. % T/C) in Table 2 for certain representative compounds.
  • Another aspect of the instant invention concerns with a method for inhibiting mammalian tumors sensitive to a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides pharmaceutical compositions (formulations) containing a compound of formula I in combination with one or more pharmaceutically acceptable, inert or physiologically active, carriers, excipients, diluents or adjuvants.
  • pharmaceutically acceptable, inert or physiologically active, carriers, excipients, diluents or adjuvants are described in numerous literatures, for example in U.S. Pat. Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compounds of this invention.
  • the new compounds are administrable in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms.
  • the pharmaceutical preparation which contains the compound is conveniently admixed with a nontoxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier, usually about 0.01 mg up to 2500 mg, or higher per dosage unit, preferably 50-500 mg.
  • a nontoxic pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic carrier usually about 0.01 mg up to 2500 mg, or higher per dosage unit, preferably 50-500 mg.
  • 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, and other conventionally employed acceptable carriers.
  • 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.
  • the compounds of the invention can also be freeze dried and, if desired, combined with other pharmaceutically acceptable excipients to prepare formulations suitable for parenteral, injectable administration.
  • the formulation can be reconstituted in water (normal, saline), or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like.
  • the dose to be administered whether a single dose, multiple dose, or a daily dose, will of course vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient and the nature of the patient's condition.
  • the dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects.
  • the dosage to be administered will be generally in the range of 0.8 to 8 mg/kg of body weight or about 50-275 mg/m 2 of the patient.
  • An oncologist skilled in the art of cancer treatment will able to ascertain, without undue experimentations, appropriate protocols for effective administration of the compounds of this present invention by referring to the earlier studies of taxol and its derivatives.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)
US08/128,949 1992-05-06 1993-09-29 Benzoate derivatives of taxol Abandoned USH1487H (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US08/128,949 USH1487H (en) 1992-05-06 1993-09-29 Benzoate derivatives of taxol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87966192A 1992-05-06 1992-05-06
US08/128,949 USH1487H (en) 1992-05-06 1993-09-29 Benzoate derivatives of taxol

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US87966192A Continuation 1992-05-06 1992-05-06

Publications (1)

Publication Number Publication Date
USH1487H true USH1487H (en) 1995-09-05

Family

ID=25374616

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/128,949 Abandoned USH1487H (en) 1992-05-06 1993-09-29 Benzoate derivatives of taxol

Country Status (4)

Country Link
US (1) USH1487H (ja)
EP (1) EP0569281A1 (ja)
JP (1) JPH069600A (ja)
CA (1) CA2095375A1 (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589502A (en) * 1994-11-17 1996-12-31 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
US20220378735A1 (en) * 2019-12-03 2022-12-01 Shenyang Pharmaceutical University Cabazitaxel weakly- alkaline derivative and formulation thereof

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW467896B (en) 1993-03-19 2001-12-11 Bristol Myers Squibb Co Novel β-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes
GB9405400D0 (en) * 1994-03-18 1994-05-04 Erba Carlo Spa Taxane derivatives
US5489589A (en) * 1994-12-07 1996-02-06 Bristol-Myers Squibb Company Amino acid derivatives of paclitaxel
US5760251A (en) * 1995-08-11 1998-06-02 Sepracor, Inc. Taxol process and compounds
US5977163A (en) 1996-03-12 1999-11-02 Pg-Txl Company, L. P. Water soluble paclitaxel prodrugs
EP0868422A1 (de) * 1996-09-24 1998-10-07 Marigen S.A. Ultramikroemulsionen aus spontan dispergierbaren konzentraten mit antitumoral und antiviral wirksamen estern von baccatin-iii-verbindungen
WO1998017656A1 (en) 1996-10-24 1998-04-30 Institute Armand-Frappier A family of canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof
PL368945A1 (en) 2001-11-30 2005-04-04 Bristol-Myers Squibb Company Paclitaxel solvates
KR101975843B1 (ko) 2008-05-23 2019-05-09 더 유니버시티 오브 브리티쉬 콜롬비아 리포좀 나노입자에 사용하기 위한 변형된 약물
CN102617517B (zh) * 2011-01-27 2015-11-18 李勤耕 一类新的7,10-o,o-二甲多西紫杉醇衍生物及其应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623486A (en) * 1985-05-29 1986-11-18 Pfizer Inc. [4-substituted benzoyloxy]-N-substituted-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides having anti-arthritic activity
US4814470A (en) * 1986-07-17 1989-03-21 Rhone-Poulenc Sante Taxol derivatives, their preparation and pharmaceutical compositions containing them
US4942184A (en) * 1988-03-07 1990-07-17 The United States Of America As Represented By The Department Of Health And Human Services Water soluble, antineoplastic derivatives of taxol
US4960790A (en) * 1989-03-09 1990-10-02 University Of Kansas Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof
EP0400971A2 (en) * 1989-05-31 1990-12-05 Florida State University Method for preparation of taxol
US5015744A (en) * 1989-11-14 1991-05-14 Florida State University Method for preparation of taxol using an oxazinone
US5059699A (en) * 1990-08-28 1991-10-22 Virginia Tech Intellectual Properties, Inc. Water soluble derivatives of taxol
US5272171A (en) * 1992-02-13 1993-12-21 Bristol-Myers Squibb Company Phosphonooxy and carbonate derivatives of taxol

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623486A (en) * 1985-05-29 1986-11-18 Pfizer Inc. [4-substituted benzoyloxy]-N-substituted-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides having anti-arthritic activity
US4814470A (en) * 1986-07-17 1989-03-21 Rhone-Poulenc Sante Taxol derivatives, their preparation and pharmaceutical compositions containing them
US4942184A (en) * 1988-03-07 1990-07-17 The United States Of America As Represented By The Department Of Health And Human Services Water soluble, antineoplastic derivatives of taxol
US4960790A (en) * 1989-03-09 1990-10-02 University Of Kansas Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof
EP0400971A2 (en) * 1989-05-31 1990-12-05 Florida State University Method for preparation of taxol
US5015744A (en) * 1989-11-14 1991-05-14 Florida State University Method for preparation of taxol using an oxazinone
US5059699A (en) * 1990-08-28 1991-10-22 Virginia Tech Intellectual Properties, Inc. Water soluble derivatives of taxol
US5272171A (en) * 1992-02-13 1993-12-21 Bristol-Myers Squibb Company Phosphonooxy and carbonate derivatives of taxol

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
David G. I. Kingston et al, "The Chemistry of Taxol, A Clinically Useful Anticancer Agent," Journal of Natural Products, 1990, vol. 53, No. 1, pp. 1-12.
David G. I. Kingston et al, The Chemistry of Taxol, A Clinically Useful Anticancer Agent, Journal of Natural Products, 1990, vol. 53, No. 1, pp. 1 12. *
Ejvind Jensen et al, "Design of a water-soluble, solution-stable and biolabile prodrug of mentronidazole for parenteral administration: N-substituted aminomethylbenzoate esters," International Journal of Pharmaceutics, 1990, vol. 58, 143-153.
Ejvind Jensen et al, Design of a water soluble, solution stable and biolabile prodrug of mentronidazole for parenteral administration: N substituted aminomethylbenzoate esters, International Journal of Pharmaceutics, 1990, vol. 58, 143 153. *
H. M. Deutsch et al, "Synthesis of Congeners and Prodrugs. 3. Water-Soluble Prodrugs of Taxol with Potent Antitumor Activity," Journal of Medicinal Chemistry, 1989, vol. 32, No. 4, pp. 788-792.
H. M. Deutsch et al, Synthesis of Congeners and Prodrugs. 3. Water Soluble Prodrugs of Taxol with Potent Antitumor Activity, Journal of Medicinal Chemistry, 1989, vol. 32, No. 4, pp. 788 792. *
Hans Bundgaard et al, "A Novel Solution-Stable, Water-Soluble Prodrug Type for Drugs Containing a Hydroxyl or an NH-Acidic Group," Journal of Medicinal Chemistry, 1989, vol. 32, pp. 2503-2507.
Hans Bundgaard et al, A Novel Solution Stable, Water Soluble Prodrug Type for Drugs Containing a Hydroxyl or an NH Acidic Group, Journal of Medicinal Chemistry, 1989, vol. 32, pp. 2503 2507. *
Kent L. Amsberry et al., "The Lactonization of 2'-Hydroxyhydrocinnamic Acid Amides: A Potential Prodrug for Amines," Journal of Organic Chemistry, 1990, vol. 55, pp. 5867-5877.
Kent L. Amsberry et al., The Lactonization of 2 Hydroxyhydrocinnamic Acid Amides: A Potential Prodrug for Amines, Journal of Organic Chemistry, 1990, vol. 55, pp. 5867 5877. *
Neal F. Magri et al, "Modified Taxols, 2. Oxidation Products of Taxol," Journal of Organic Chemistry, 1986, vol. 51, pp. 797-802.
Neal F. Magri et al, "Modified Taxols, 4. Synthesis and Biological Activity of Taxols Modified in the Side Chain," Journal of Natural Products, 1988, vol. 51, No. 2, pp. 298-306.
Neal F. Magri et al, Modified Taxols, 2. Oxidation Products of Taxol, Journal of Organic Chemistry, 1986, vol. 51, pp. 797 802. *
Neal F. Magri et al, Modified Taxols, 4. Synthesis and Biological Activity of Taxols Modified in the Side Chain, Journal of Natural Products, 1988, vol. 51, No. 2, pp. 298 306. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589502A (en) * 1994-11-17 1996-12-31 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
US5608073A (en) * 1994-11-17 1997-03-04 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
US20220378735A1 (en) * 2019-12-03 2022-12-01 Shenyang Pharmaceutical University Cabazitaxel weakly- alkaline derivative and formulation thereof

Also Published As

Publication number Publication date
CA2095375A1 (en) 1993-11-07
EP0569281A1 (en) 1993-11-10
JPH069600A (ja) 1994-01-18

Similar Documents

Publication Publication Date Title
US5272171A (en) Phosphonooxy and carbonate derivatives of taxol
JP3410518B2 (ja) デオキシパクリタキセル類
USH1487H (en) Benzoate derivatives of taxol
US5294637A (en) Fluoro taxols
US5395850A (en) 6,7-epoxy paclitaxels
EP0600517B1 (en) 6,7-Modified paclitaxels
KR102880398B1 (ko) 일루딘 유사체, 이의 용도, 및 이의 합성 방법
US5756776A (en) Semi-synthetic taxanes with anti-tumoural activity
US5856580A (en) Total synthesis of antitumor acylfulvenes
US5478854A (en) Deoxy taxols
EP0577083B1 (en) 7,8-cyclopropataxanes with antitumor action
US5739359A (en) Methods for preparing 1-deoxy paclitaxels
US5773464A (en) C-10 epoxy taxanes
US5767296A (en) Deacetoxytaxol derivatives
JPH03115279A (ja) 窒素を脱保護した４―アシルオキシアゼチジン―２―オン
JP3208517B2 (ja) ７，８−シクロプロパタキサン類
Asenjo et al. Polycyclic Hydroxyquinones. Part 29. Regioselective Reactions of 5-sulphur-substituted furan-2 (5H)-one anions with naphthoquinone monoketals. Application to the synthesis of anthracyclinone precursors
JPH0356481A (ja) 一重項酸素酸化による４―アシルオキシアゼチジンの製造方法
JPWO2002020621A1 (ja) テトラフェニルポルフィリン誘導体およびそれからなる組成物
RU2131874C1 (ru) Фторотаксолы, промежуточные соединения, фармацевтическая композиция и способ лечения
KR20050053599A (ko) 미리아포론의 전합성
CZ7594A3 (en) Process for preparing phosphonium salts
HK1019878B (en) Total synthesis of antitumor acylfulvenes

Legal Events

Date Code Title Description
STCF Information on status: patent grant

Free format text: PATENTED CASE