WO1995001342A1 - Derives de l'ansamycine utilises comme agents anti-oncogenes et anticancereux - Google Patents

Derives de l'ansamycine utilises comme agents anti-oncogenes et anticancereux Download PDF

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Publication number
WO1995001342A1
WO1995001342A1 PCT/IB1994/000160 IB9400160W WO9501342A1 WO 1995001342 A1 WO1995001342 A1 WO 1995001342A1 IB 9400160 W IB9400160 W IB 9400160W WO 9501342 A1 WO9501342 A1 WO 9501342A1
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Prior art keywords
demethoxygeldanamycin
alkyl
group
amino
hydrogen
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PCT/IB1994/000160
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English (en)
Inventor
Randall James Gallaschun
Mikel Paul Moyer
Rodney Caughren Schnur
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Pfizer Inc.
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Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to EP94916372A priority Critical patent/EP0706516A1/fr
Priority to US08/578,671 priority patent/US5932566A/en
Publication of WO1995001342A1 publication Critical patent/WO1995001342A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to derivatives of geldanamycin, pharmaceutically acceptable salts and prodrugs of said derivatives, processes for their preparation and antitumor and oncogene product inhibiting compositions containing said derivatives, salts and prodrugs as the active ingredients.
  • Oncogene products are proteins generated by cancer genes and are involved in the transformation of normal cells into cancer cells.
  • the present invention relates to compounds of the formula
  • R 1 and R 2 are both hydrogen or R 1 and R 2 together form a single bond; wherein R 1 and R 2 are both hydrogen or R 1 and R 2 together form a single bond;
  • R 3 is hydrogen and R 4 is selected from the group consisting of
  • R 11 is selected from the group consisting of amino, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, hydroxy(C 1 -C 8 )alkyl, protected amino(C 1 -C 8 )alkyl, protected hydroxy(C 1 -C 8 )alkyl, phenyl and naphthyl; and
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, amino (C 1 -C 8 )alkyl, dimethylamino(C 1 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, phenyl and naphthyl; or R 12 and R 13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C 1 -C 4 )alkylpiperidinyl and N-(C 1 -C 4 )piperazinyl;
  • alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C 1 -C 8 )alkyl, halo, nitro, amino, azido and (C 1 -C 8 )alkoxyl;
  • J is selected from O and NOH
  • R 5 is NR 8 R 9 wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, and (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl groups selected from the group comprising imidizaloly, furyl, tetrahydrofuryl; and if comprising more than
  • R 5 is R 14 O wherein R 14 is hydrogen or (C 1 -C 4 )alkyl
  • R 6 is hydrogen or a group of the formula
  • each R 7 is independently selected from halo, azido, nitro, (C 1 -C 8 )alkyl, C 1 -C 8 alkoxyl, phenyl and naphthyl, cyano and NR 8 R 9 wherein R 8 and R 9 are as defined above; with the proviso that when R 1 and R 2 together form a single bond R 3 is hydrogen and R 4 is OR 10 wherein R 10 is hydrogen then R 5 cannot be OR 14 , wherein R 14 is hydrogen or methyl, or NR 8 R 9 wherein HNR 8 R 9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, ß-hydroxyethylamine, ß-chloroethylamine, ß-glycoxyethylamine,
  • the compounds of the invention are compounds of formula I wherein
  • R 1 and R 2 are each hydrogen
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and un
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 14 is hydrogen or (C 1 -C 6 )alkyl; with the proviso that when R 3 and R 6 are hydrogen and R 4 is OR 10 wherein R 10 is hydrogen, R 14 is not methyl; or
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cycl
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 5 is R 14 O
  • R 14 is hydrogen or (C 1 -C 8 )alkyl
  • R 6 is hydrogen, R 3 and R 4 together form a group of the formula
  • J is O or NOH; and R 5 is OR 14 or R 8 R 9 N wherein
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cycl
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 5 is R 14 O
  • R 14 is hydrogen or (C 1 -C 8 )alkyl; or d.
  • R 3 and R 4 together form a group of the formula
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cycl
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 14 is hydrogen or (C 1 -C 8 )alkyl; or or 2.
  • R 1 and R 2 together form a single bond and
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 - C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cycl
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 14 is hydrogen or (C 1 -C 8 )alkyl; with the proviso that when R 10 is hydrogen then R 5 cannot be OR 14 wherein R 14 is hydrogen or methyl or NR 8 R 9 wherein HNR 8 R 9 is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptyiamine, octylamine, allylamine, ß-hydroxyethylamine, ß-chloroethylamine, ß-glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylamine, ethyleneamine, pyrrolidine,
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cycl
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 5 is R 14 O
  • R 14 is hydrogen or (C 1 -C 8 )alkyl
  • R 6 is hydrogen, R 3 and R 4 together form a group of the formula
  • J is O or NOH; and R 5 is OR 14 or NR 8 R 9 wherein
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cycl
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 5 is R 14 O, R 14 is hydrogen or (C 1 -C 8 )alkyl; or d.
  • R 6 is a group of the formula A wherein m and R 7 are defined as above; and
  • R 5 is R 14 O or R 8 R 9 N wherein i.
  • R 8 is hydrogen and R 9 is selected from the group consisting of (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 8 )alkenyl and (C 2 -C 8 )alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, optionally substituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino, acylamino, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and un
  • R 5 is R 8 R 9 N
  • R 8 and R 9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 )alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 )alkoxyl, carboxyl, amidino and acylamino;
  • R 14 is hydrogen or (C 1 -C 8 )alkyl.
  • More preferred compounds of the invention are selected from the group consisting of compounds of the formula I wherein
  • R 1 and R 2 together form a single bond
  • R 3 and R 6 are each hydrogen
  • R 1 and R 2 together form a single bond
  • R 3 and R 6 are each hydrogen
  • R 4 is fluoro or OR 10 wherein R 10 is selected from hydrogen
  • R 11 C( O)- and
  • R 12 R 13 NSO 2 NHC(O)- wherein R 11 is selected from amino, (C 1 -C 8 )alkyl, amino(C 1 - C 8 )alkyl, protected amino(C 1 -C 8 )alkyl, phenyl and naphthyl; and R 12 and R 13 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, dimethylamino(C 1 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, phenyl and naphthyl; wherein is as defined above; or R 12 and R 13 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperaz
  • R 1 and R 2 together form a single bond
  • R 3 and R 6 are each hydrogen
  • R 4 is fluoro or OR 10 wherein R 10 is selected from hydrogen
  • R 11 C( O)- and
  • R 12 R 13 NSO 2 NHC(O)- wherein R 11 is selected from amino, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, protected amino (C 1 -C 8 )alkyl, phenyl and naphthyl; and R 12 and R 13 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, amino(C 1 - C 8 )alkyl, dimethylamino(C 1 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, phenyl and naphthyl; wherein is as defined above; or R 12 and R 13 together with the nitrogen to which they are attached form a heterocylic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, pipe
  • R 1 and R 2 together form a single bond
  • R 6 is hydrogen
  • R 5 is R 8 R 9 N wherein R 8 is hydrogen and R 9 is selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl or optionally substituted (C 3 -C 6 )cycloalkyl, (C 2 - C 6 )alkenyl and (C 2 -C 6 )alkynyl wherein the substituents of said alkyl, alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C 1 -C 6 )alkoxyl, ((C 1 -C 6 ) kylthio,
  • R 1 and R 2 together form a single bond
  • R 6 is hydrogen
  • R 5 is R 8 R 9 N wherein R 8 and
  • R 9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )alkylthio, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl;
  • R 1 and R 2 together form a single bond
  • R 6 is hydrogen
  • R 5 is R 14 O wherein R 14 is hydrogen or (C 1 -C 8 )alkyl
  • R 1 and R 2 together form a single bond
  • R 3 is hydrogen
  • R 6 is a group of the formula A wherein m and R 7 are as defined above
  • R 4 is OR 10 or fluoro
  • R 11 is selected from the group consisting of amino, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, protected amino(C 1 -C 8 )alkyl, phenyl and naphthyl
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, dimethylamino(C 1 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, phenyl and naphthyl and said al
  • R 5 is R 8 R 9 N wherein R 8 is hydrogen and R 9 is selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 2 -C 6 )alkenyl and optionally substituted (C 2 -C 6 )alkynyl wherein the substituents of said alkyl and alkenyl and alkynyl groups are selected from hydroxyl, halo, cyano, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )alkylthio, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl;
  • R 1 and R 2 together form a single bond
  • R 3 is hydrogen
  • R 6 is a group of the formula A wherein m and R 7 are as defined above
  • R 4 is OR 10 or fluoro
  • R 11 is selected from the group consisting of amino, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, protected amino(C 1 -C 8 )alkyl, phenyl and naphthyl
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, dimethylamino(C 1 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, phenyl and naphthyl; and said
  • R 1 and R 2 together form a single bond
  • R 3 is hydrogen
  • R 6 is a group of the formula A wherein m and R 7 are as defined above
  • R 4 is OR 10 or fluoro
  • R 11 is selected from the group consisting of amino, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, protected amino(C 1 -C 8 )alkyl, phenyl and naphthyl
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, amino(C 1 -C 8 )alkyl, dimethylamino(C 1 -C 8 )alkyl, cyclo(C 3 -C 8 )alkyl, phenyl and naphthyl; and said
  • R 1 and R 2 are each hydrogen
  • R 6 is a group of the formula A wherein m and R 7 are as defined above
  • R 5 is R 8 R 9 N wherein R 8 and R 9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )alkylthio, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl;
  • R 1 and R 2 together form a bond
  • R 1 and R 2 together form a bond
  • R 6 is a group of the formula A wherein m and R 7 are as defined above
  • R 5 is R 8 R 9 N wherein R 8 and R 9 together with the nitrogen to which they are attached form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (C 1 -C 6 )alkoxyl, (C 1 -C 6 )alkylthio, (C 2 -C 6 )heterocycloalkyl and (C 2 -C 6 )heterocycloaryl;
  • R 1 and R 2 together form a bond
  • R 6 is a group of the formula A wherein m and R 7 are as defined above
  • R 5 is R 14 O wherein R 14 is hydrogen or (C 1 -C 8 )alkyl.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an antitumor or oncogene product inhibiting or cancer preventing or treating effective amount of a compound of the formula I, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.
  • This invention also relates to a method of inhibiting an oncogene product in a mammal, including a human, comprising administering to said mammal an oncogene product inhibiting effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • This invention also relates to a method of inhibiting an ErbB-2, src, lck, fyn or abl oncogene product in a mammal, including a human, comprising administering to said mammal an ErbB-2, src, lck, fyn or abl oncogene product inhibiting effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • This invention also relates to a method of treating or preventing cancer in a mammal, including a human, comprising administering to said mammal an antitumor or oncogene product inhibiting effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • This invention also relates to a method of preventing or inhibiting the growth of a tumor in a mammal, including a human, comprising administering to said mammal an antitumor effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • This invention also relates to a method of inhibiting growth factors that play an important role in uncontrolled cell proliferation such as the EGF receptor, the NGF receptor, the PDGF receptor and the insulin receptor in a mammal, including a human, comprising administering to said mammal a growth factor inhibiting effective amount of a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof.
  • the pharmaceutically acceptable salts of the present invention are those which are non-toxic at the dosages administered. Since compounds of the invention may contain basic groups, acid addition salts are possible. Pharmaceutically acceptable acid addition salts include, for example, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, maleate, mesylate, fumarate, citrate, acid citrate, tartrate, bitartrate, succinate, gluconate and saccharate salts.
  • Typical pharmaceutically acceptable anions include the acetate; benzenesulfonate; benzoate; bicarbonate; bitartrate; bromide; calcium edetate; camsylate; carbonate; chloride; citrate; dihydrochloride; edetate; edisylate; estolate; esylate; fumarate; gluceptate; gluconate; glutamate; glycollylarsnilate; hexylresorcinate; hydroxynaphthoate; iodide; isothionate; lactate; lactobionate; malate; maleate; mandelate; mesylate; methylbromide; methylnitrate; methylsulfate; mucate; napsylate; nitrate; pamoate (embonate); pantothenate; phosphate; polygalacturonate; salicylate; stearate; subacetate; succinate; sulfate; t
  • alkyl, alkoxy, and alkenyl moieties referred to herein may comprise linear, branched and cyclic moieties and combinations thereof and the term "halo" includes fluoro, chloro, bromo and iodo. It will be understood, however that a group comprising only 1 or 2 atoms cannot be branched or cyclic.
  • alkyl groups are methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl and cyclohexyl.
  • optionally substituted means comprising from zero to the maximum number of substituents, e.g., 3 for a methyl group, 1 for a hexyl group and 5 for a phenyl group.
  • the active compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compound 2 is formed by condensation of the geldanamyacin or 4,5-dihydrogeldanamyacin 1 with an amine R 8 R 9 NH.
  • This reaction is generally carried out by mixing the amine and the ansamycin in an inert solvent such as chloroform, methylene chloride, N,N-dimethylformamide (DMF), pyridine, acetonitrile, tetrahydrofuran (THF) or a lower alcohol, preferably chloroform or methylene chloride, at a temperature from about ambient temperature to the reflux temperature of the solvent, preferably from about ambient temperature to about 65°C.
  • an inert solvent such as chloroform, methylene chloride, N,N-dimethylformamide (DMF), pyridine, acetonitrile, tetrahydrofuran (THF) or a lower alcohol, preferably chloroform or methylene chloride
  • the conversion of 1 or 2 to 3 is generally carried out by oxidizing 2 with standard oxidizing reagents such as pyridinium chlorochromate in methylene chloride, pyridinium dichromate in DMF, oxalyl chloride/dimethyl sulfoxide (DMSO) in methylene chloride, Dess-Martin periodinane in chloroform, and Jones reagent in acetone, preferably Dess-Martin periodinane in chloroform at reflux.
  • DMSO oxalyl chloride/dimethyl sulfoxide
  • Jones reagent in acetone
  • Dess-Martin periodinane in chloroform at reflux.
  • these reagents can be used with additional, inert solvents and at temperatures ranging from -60°C to the reflux temperature of the solvent.
  • the conversion of 3 to 4 is generally carried out by reacting 3 with hydroxylamine hydrochloride in the presence of a base (e.g., sodium acetate, pyridine, sodium carbonate, sodium hydroxide, potassium carbonate, and triethylamine) in water or a lower alcohol solvent at about 0°C to about 100°C.
  • a base e.g., sodium acetate, pyridine, sodium carbonate, sodium hydroxide, potassium carbonate, and triethylamine
  • 3 is combined with hydroxylamine hydrochloride in the presence of triethylamine in ethanol at room temperature.
  • the conversion of 3 to 5 is generally carried out under standard reductive amination conditions such as combining the amine and 3 in an inert solvent (e.g., halogenated (C 1 -C 6 ) alkanes and (C 1 -C 6 )alcohols) with a suitable reducing agent (e.g., sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and formic acid), optionally in the presence of a dehydrating agent (e.g., sodium sulfate, molecular sieves, and calcium sulfate), at temperatures ranging from about ambient temperature to the reflux temperature of the solvent.
  • a suitable reducing agent e.g., sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and formic acid
  • a dehydrating agent e.g., sodium sulfate, molecular sieves, and calcium sulfate
  • the reaction is carried out by combining 3,
  • compound 1 or 2 can be selectively 22-N-alkylated to afford 6 by treatment with a base, such as a (C 1 -C 6 ) alkoxide, in a polar solvent, for instance dimethylformamide or dimethyl sulfoxide, followed by reaction with an appropriate alkylating agent, for example, an alkyl halide. Reaction temperatures are maintained between about 5 and about 65°C, optimally from about 5 to about 25°C.
  • the compound 1 or 2 can be reacted with anhydrous potassium carbonate and the alkyl halide in acetone at reflux.
  • Compound 7 can be prepared by treating compound 1 or 2 with diethylaminosulfurtrifluoride (DAST).
  • DAST diethylaminosulfurtrifluoride
  • This reaction is performed in an inert solvent (e.g., methylene chloride, chloroform and dichloroethane) at low temperature of about -78 to about 0°C, preferably from about -78 to about -50°C.
  • an inert solvent e.g., methylene chloride, chloroform and dichloroethane
  • the reaction is quenched at low temperature with dilute aqueous base, for example 5% sodium bicarbonate.
  • Compound 1 or 2 can be converted to 11-O-acyl or 11-O-sulfonyl derivatives by treatment with acylating or sulfonating agents in the presence of non-nucleophilic bases.
  • the acylating agents include acid anhydrides, halides and isocyanates.
  • Sulfonating agents include sulfonyl halides and anhydrides.
  • Solvents used in these reactions include a wide variety of aprotic polar and non-polar media, for example, acetone, chloroform, ethyl acetate, DMF, pyridine, tetrahydrofuran. Bases used include 1 ,8-diazabicyclo[5.440]undec-7-ene (DBU), triethylamine and 4-dimethylaminopyridine. If desired, compounds 3-7 wherein R 5 is R 14 O may be converted to compounds 3-7 wherein R 5 is R 8 R 9 N by the method for converting 1 to 2 in Scheme 1.
  • DBU 1,8-diazabicyclo[5.440]undec-7-ene
  • the compounds of formula I and their pharmaceutically acceptable salts are useful as antitumor agents (including, but not limited to anticancer agents) and oncogene product inhibitors. They are useful, for example, in inhibiting the ErbB-2, src, lck, fyn and abl oncogene products. They are also useful in inhibiting certain growth factors that play an important role in uncontrolled cell proliferation such as the EGF receptor, the NGF receptor, the PDGF receptor and the insulin receptor.
  • the ability of the active compounds to inhibit the ErbB-2 oncogene product may be determined by the following method for determining the p185 concentrations in SKBr3 cells.
  • SKBr3 human breast cancer cells obtained from the ATCC, Rockville, Maryland were seeded in 8 well tissue culture plates (9.5 cm 2 /well, Falcon, Becton Dickenson, Lincoln Park, NJ) at 5 ⁇ 10 5 cells/well in 2 ml McCoys medium, supplemented with 10% fetal calf serum and glutamine. Cells were allowed to attach overnight at 37°C in a 5% CO 2 atmosphere.
  • the compounds are dissolved in DMSO and tested over a range of concentrations by addition to the medium, followed by incubation at 37°C for 6 hours. At the end of the incubation, the medium is aspirated from the well, and the cells are washed twice with 2 ml of TNK buffer (50 mM tris (hydroxymethyl)aminomethane hydrochloride, 140 mM NaCI, 3.3 mM KCl, 0.5 mM sodium orthovanadate, adjusted to pH 7.4).
  • TNK buffer 50 mM tris (hydroxymethyl)aminomethane hydrochloride, 140 mM NaCI, 3.3 mM KCl, 0.5 mM sodium orthovanadate, adjusted to pH 7.4
  • the cells are then lysed by addition of 250 ⁇ I boiling Laemmli sample buffer (140 mM tris(hydroxymethyl)aminomethane hydrochloric acid, pH 6.8, 5.7% sodium dodecyl sulfate, 29% glycerol) with shaking.
  • the cell lysate is transferred to a tube and then placed in a boiling water bath for 5 mins.
  • the lysates are then sonicated with a probe sonicator and stored at -70 °C until analysis.
  • the p185 concentration of each sample may be determined by standard immunoblotting procedures essentially as described by Hariow and Lane (Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988).
  • a standard portion of each sample is mixed with dithiothreitol (10% added of a 1 M solution), and then a portion corresponding to ⁇ 10 ⁇ g of protein is blotted onto a nitrocellulose membrane (BA-S, Schleicher and Schuell, Keene, New Hampshire) equilibrated with rinse buffer (10 mM Tris hydrochloric acid pH 7.4, 150 mM NaCI) by use of a dot blot apparatus (Mini-fold, Schleicher and Schuell, Keene, New Hampshire) with an underlayer of filter paper.
  • rinse buffer 10 mM Tris hydrochloric acid pH 7.4, 150 mM NaCI
  • the wells are rinsed with 200 ⁇ I of a rinse buffer, blocked by incubation with a blocking buffer (5% bovine serum albumin, 1% ovalbumin in rinse buffer), and then incubated for 4 to 12 hours with a 1 :1000 dilution of NT1 , an affinity purified rabbit polyclonal antibody raised by standard methods (Hariow and Lane, Antibodies. A Laboratory Manual, Cold Spring Harbor Laboratory, 1988) against a peptide representing the C-terminal domain of human p185 (sequence, TAENPEYLGLDVPV, by the standard 1 letter amino acid code).
  • a blocking buffer 5% bovine serum albumin, 1% ovalbumin in rinse buffer
  • the membrane is then rinsed twice for 10 minutes with rinse buffer and once for 10 minutes in rinse buffer with 0.05% Triton X-100, and then twice more for 10 minutes in rinse buffer.
  • the membrane is then incubated with a 1 :3000 dilution of horseradish peroxidase labeled donkey anti-rabbit antibody (Amersham, Arlington Heights, Illinois) in a rinse buffer with shaking for 20-45 minutes.
  • the membrane is then again rinsed twice for 10 minutes in the rinse buffer, once for 10 minutes in the rinse buffer with 0.05% Triton X-100, and then twice more for 10 minutes in the rinse buffer.
  • the p185 is then visualized with the ECL Detection Kit (Amersham, Arlington Heights, Illinois) and recorded with Hyperfilm-ECL (Amersham, Arlington Heights, Illinois). The p185 is then estimated by densitometric analysis of the film. IC 50 values are determined by reference to the p185 content of samples of cells exposed only to vehicle (DMSO) and measured as described.
  • the ability of the active compounds to inhibit the ErbB-2 oncogene product may be determined by following the method of Kamps et al., Oncogene, 2, 305-315 (1988) for determining the phosphorylation of p185 in SKBR3 and other ErbB-2 transformed cell lines.
  • the compounds of the formula I and their pharmaceutically acceptable salts are used as antiproliferative agents, such as anticancer agents, they can be administered to a mammalian subject either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally.
  • Parenteral administration includes intracenous, intramuscular, intraperitoneal, subcutaneous and topical.
  • the active compounds are administered in dosages ranging from about 0.1 mg to about 20 mg per kg of body weight as needed (e.g., every 4 to 6 hours), preferably from about 0.1 to about 15 mg per kg of body weight; variations will necessarily occur depending upon the condition of the subject being treated and the particular compound and dosage form being administered. It is to be noted that these compounds may be administered in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
  • the active compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in, e. g., the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • the hard capsules for oral use may also be presented as gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or whereas the soft capsules may be presented as gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • the soft capsules may be presented as gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil; a mineral oil such as liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides such as example soy bean and lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulation may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the active compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols.
  • creams, ointments, Jellies, solutions or suspensions, etc., containing the active compounds of the invention are employed.
  • the active compounds of the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer.
  • the preferred composition for inhalation is a powder which may be formulated as a cartridge from which the powder composition may be inhaled with the aid of a suitable device.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • One or more other active compounds may be added to the formulations described above to provide formulations for combination therapy.
  • Such compounds include cytostatic, cytotoxic and antiemetic agents conventionally used in cancer chemotherapy, such as adriamycin.
  • High pressure liquid chromatography was performed at 1.0 ml/minute with 254 nm detection on a 250 ⁇ 4.6 mm Dupont Zorbax Sil (trademark) column eluted isocratically by a two-pump/mixer system supplying the indicated mixture of 1% methanol in ethyl acetate and hexanes respectively. Samples to be thus analyzed are dissolved in an HPLC eluent. The HPLC retention times are reported followed by the ethylacetate/hexane ratio in parentheses.
  • concentration in vacuo and “coevaporated” refer to removal of solvent at water aspirator pressure on a rotary evaporator with a bath temperature of less than 40°C.
  • Examples 2-14 were prepared from 4,5-dihydrogeldanamycin and the appropriate amines using the conditions described above.
  • DAST diethylaminosulfurtrifluoride
  • 3 mL of methylene chloride was added to a flame dried flask under nitrogen and cooled to -68°C with an external dry ice/acetone bath.
  • 17-Azetidine-1-yl-4,5-dihydro-17-demethoxygeldanamycin (0.188 g, 0.320 mmol) dissolved in 15 mL of methylene chloride was added dropwise. After 0.5 hour 5 mL of 5% aqueous NaHC0 3 was added slowly at about -68 °C. After warming to room temperature the product was extracted into 100 mL of methylene chloride.
  • Propargylamine hydrochloride (0.200 gm, 2.180 mmol) and triethylamine (0.2206 gm, 2.180 mmol, 0.303 mL) were added to a flame dried flask under nitrogen and slurried in 5mL chloroform. After 10 minutes geldanamycin (0.200 gm, 0.3567 mmol) was added to the mixture and the reaction was stirred at room temperature overnight. The solution changed from a pale yellow color to a dark orange/red color. The reaction mixture was diluted with 50 mL chloroform and washed with 3 ⁇ 25 mL 1 N hydrochloric acid.
  • Examples 26-31 were prepared from geldanamycin and the appropriate amines by the method of Example 1 above.
  • Examples 33 to 45 were prepared by the method of Example 32 from the appropriately substituted phenacyl bromides.
  • the residue obtained upon evaporation of the ethyl acetate was further purified by preparative HPLC using a Zorbax column eluted with a mixture comprising 59:1 :40 ethyl acetate:methanol:hexanes.
  • 17-Amino-17-demethoxygeldanamycin (0.500 g, 0.92 mmol) was dissolved in 25 mL of acetone (stored over potassium carbonate) and 1.27 g potassium carbonate was added (9.17 mmol, 10 eq). The reaction was stirred in the dark for 24 hours, filtered, concentrated in vacuo to a residue which was flash chromatographed through silica gel using 69:1 :30 ethyl acetate:methanol:hexanes.
  • Example 18 17-Azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.342 mmol) was added to a flame dried flask under nitrogen and dissolved in 15 mL of methylene chloride. The mixture was cooled to -68°C with an external dry ice/acetone bath and then a solution of DAST (0.055g, 0.342 mmol, 0.045 mL) in 2.5 mL of methylene chloride was added dropwise. After 1 hour 5 mL of 5% aqueous NaHCO 3 was addded slowly and the product extracted into 100 mL of methylene chloride.
  • DAST 0.055g, 0.342 mmol, 0.045 mL
  • Examples 52-58 were prepared by the method of Example 51 from the appropriately substituted 17-amino-17-demethoxygeldanamycin derivatives.
  • Example 59 The title compound of Example 59 (0.307 g, 0.546 mmol) was slurried in 6 mL of chloroform and treated with (S)-2-hydroxypropylamine (0.205 g, 2.73 mmol) at 22°C for 16 hours. The reaction mixture was diluted with 50 mL of chloroform and washed with 3 ⁇ 50 mL of brine and 3 ⁇ 50 mL of water. The organic layer was dried with
  • 17-Allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen.
  • Sodium isocyanate (0.311 g, 0.4.78 mmol) and trifluoroacetic acid (0.545 g, 4.78 mmol, 0.368 mL) were added during 10 minutes. After stirring for 16 hours at room temperature, the reaction mixture was diluted with 200 mL of water and extracted with 3 ⁇ 150 mL of chloroform.
  • Example 18 17-Azetidin-1-yl-17-demethoxygeldanamycin, the title compound of Example 18, (0.200 g, 0.341 mmol) was dissolved in 6 mL of dry methylene chloride and treated with N-BOC- ⁇ -alanine (0.077 g, 0.409 mmol), dicyclohexylcarbodiimide (0.084 g, 0.409 mmol) and dimethylaminopyridine (DMAP) (0.050 g, 0.409 mmol).
  • N-BOC- ⁇ -alanine 0.077 g, 0.409 mmol
  • dicyclohexylcarbodiimide 0.084 g, 0.409 mmol
  • DMAP dimethylaminopyridine
  • Example 63 The title compound of Example 63 (0.020 g, 0.026mmol) was dissolved in 0.5 mL of anhydrous dimethylformamide and treated with 4-azidobenzoic acid N-hydroxysuccinimide ester (0.007 g, 0.025 mmol) and triethylamine (0.0025 g, 0.025 mmol, 0.0034 mL). After three hours the reaction mixture was diluted with 200 mL of ethyl acetate and washed with 2 ⁇ 100 mL of water, 1 N hydrochloric acid, and brine. The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo to a residue.
  • 17-Allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.080 mg, 0.564 mmol, 0.049 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, isopropyl amine (0.066 g, 1.13 mmol, 0.096 mL) was added and the reaction mixture allowed to warm to room temperature during one hour. The reaction mixture was diluted with 100 mL of chloroform and extracted with 10 mL of water.
  • the aqueous layer was back extracted with 3 ⁇ 100 mL of chloroform.
  • the pooled organic layers were extracted with 3 ⁇ 75 mL of 1 N NaOH.
  • the combined basic layers were washed with 3 ⁇ 100 mL of chloroform.
  • the aqueous layer was acidified to pH 3 with 1 N hydrochloric acid and extracted with 3 ⁇ 100 ml of chloroform.
  • These latter organic extracts were pooled, washed with 2 ⁇ 100 mL of brine, dried with sodium sulfate , filtered and evaporated in vacuo to a solid, 0.213 g.
  • isopropylamine (0.044 g, 0.75 mmol, 0.064 mL) was added and the reaction mixture allowed to warm to room temperature during one hour.
  • the reaction mixture was diluted with 100 mL of methylene chloride and extracted with 2 ⁇ 100 mL of 1 N NaOH.
  • the combined basic layers were washed with 3 ⁇ 150 mL of methylene chloride and then acidified to pH 3 with 1 N hydrochloric acid.
  • the acidic aqueous layer was extracted with 3 ⁇ 150 mL of methylene chloride.
  • 17-Allylamino-11-azetidin-1-ylsulfamylcarbonyl-17-demethoxygeldanamycin 17-Allylamino-17-demethoxygeldanamycin (0.200 g, 0.341 mmol) was dissolved in 5 mL of methylene chloride and cooled to 0°C in a flame dried flask under nitrogen. Chlorosulfonylisocyanide (0.053 mg, 0.376 mmol, 0.033 mL) was added dropwise during 10 minutes. After stirring for one hour in the cold, azetidine (0.043 g, 0.75 mmol, 0.051 mL) was added and the reaction mixture allowed to warm to room temperature during one hour.
  • 17-Allylamino-17-demethoxygeldanamycin (90 mg, 0.15 mmol) was dissolved in CHCI 3 (4 mL) to which was added the Dess-Martin periodinane (382 mg, 0.90 mmol) and the reaction heated to reflux. After 1 hour the reaction was complete and the reaction mixture diluted with CHCI 3 . The organic layer was washed with aqueous Na 2 S 2 O 3 , saturated aqueous sodium bicarbonate and dried over sodium sulfate.

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Abstract

L'invention se rapporte à un composé de formule (I) dans laquelle R?1, R2, R3, R4, R5 et R6¿ ont la définition figurant dans la définition, ainsi qu'à ses sels et promédicaments pharmaceutiquement acceptables; l'invention se rapporte également aux procédés et produits intermédiaires servant à la préparation dudit composé, à ses compositions pharmaceutiques et aux méthodes de traitement l'utilisant. Les composés de formule (I) sont utiles pour l'inhibition des produits d'oncogènes ainsi qu'en tant qu'agents antitumoraux et anticancéreux.
PCT/IB1994/000160 1993-06-29 1994-06-16 Derives de l'ansamycine utilises comme agents anti-oncogenes et anticancereux WO1995001342A1 (fr)

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WO2000003737A2 (fr) 1998-07-17 2000-01-27 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Medicaments solubles a l'eau et procedes de preparation de ceux-ci
WO2002036574A1 (fr) * 2000-11-06 2002-05-10 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derives de geldanamycine utiles dans le traitement du cancer
WO2002079167A1 (fr) * 2001-03-30 2002-10-10 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Derive de geldanamycine et procede de traitement du cancer a l'aide de celui-ci
EP1420747A2 (fr) * 2001-08-06 2004-05-26 Kosan Biosciences, Inc. Ansamycine benzoquinone
EP1435939A2 (fr) * 2001-09-24 2004-07-14 Conforma Therapeutic Corporation Procede de preparation de 17-allyl amino geldanamycine (17-aag) et d'autres ansamycines
US6855705B1 (en) 2003-11-12 2005-02-15 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6870049B1 (en) 2003-11-12 2005-03-22 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6875863B1 (en) 2003-11-12 2005-04-05 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6887993B1 (en) 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2005063714A1 (fr) 2003-12-23 2005-07-14 Infinity Pharmaceuticals, Inc Analogues d'ansamycines contenant de la benzoquinone pour le traitement du cancer
WO2007009007A2 (fr) * 2005-07-13 2007-01-18 Infinity Discovery, Inc. Methodes de traitement utilisant des ansamycines d'hydroquinone
EP1923061A1 (fr) 2001-09-24 2008-05-21 Conforma Therapeutic Corporation Procédé pour la préparation de 17-allyl amino geldanamycine (17-AAG) et autres ansamycines
WO2008073424A2 (fr) * 2006-12-12 2008-06-19 Infinity Discovery, Inc. Formulations d'ansamycine et leurs procédés d'utilisation
US7465718B2 (en) 2002-02-08 2008-12-16 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
US8778921B2 (en) 2008-10-15 2014-07-15 Infinity Pharmaceuticals, Inc. Ansamycin hydroquinone compositions

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CA2518836A1 (fr) * 2003-03-13 2004-09-30 Conforma Therapeutics Corporation Preparations medicamenteuses contenant des triglycerides a longue chaine et a chaine moyenne

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FI943100A (fi) 1994-12-30
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CA2166320A1 (fr) 1995-01-12
FI943100A0 (fi) 1994-06-28
EP0706516A1 (fr) 1996-04-17

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