Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-03-25
1999-08-03
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540461, C07D23314, A61K 3133
Patent
active
059325666
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
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.
Geldanamycin is an antibiotic whose preparation and users were described in U.S. Pat. No. 3,595,955 (incorporated herein by reference).
Co-pending U.S. Patent application Ser. No. 07/817,235, filed Jan. 6, 1992 and assigned to Pfizer Inc. describes fermentation processes for preparing 4,5-dihydrogeldanamycin and its 18,21-hydroquinone.
Other derivatives of geldanamycin, and their use as antitumor agents are described in U.S. Pat. No. 4,261,989.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## and pharmaceutically acceptable salts and prodrugs thereof here nafter, also, referred to as the active compounds; wherein R.sup.1 and R.sup.2 are both hydrogen or R.sup.1 and R.sup.2 together form a single bond; to as the active compounds; together form a single bond;
R.sup.3 is hydrogen and R.sup.4 is selected from the group consisting of --OR.sup.10, --NHR.sup.8 and halo;
wherein R.sup.10 is selected from the group consisting of hydrogen, R.sup.11 C(.dbd.O)--, R.sup.11 SO.sub.2 -- and R.sup.12 R.sup.13 NSO.sub.2 NHC(.dbd.O)--;
wherein R.sup.11 is selected from the group consisting of amino, (C.sub.1 -C.sub.8)alkyl, amino(C.sub.1 -C.sub.8)alkyl, hydroxy(C.sub.1 -C.sub.8)alkyl, protected amino(C.sub.1 -C.sub.8)alkyl, protected hydroxy(C.sub.1 -C.sub.8)alkyl, phenyl and naphthyl; and
R.sup.12 and R.sup.13 are each independently selected from the group consisting of hydyrogen, (C.sub.1 -C.sub.8)alkyl, amino(C.sub.1 -C.sub.8)alkyl, dimethylamino(C.sub.1 -C.sub.8)alkyl, cyclo(C.sub.3 -C.sub.8)alkyl, phenyl and naphthyl; or R.sup.12 and R.sup.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.sub.1 -C.sub.4)alkylpiperidinyl and N-(C.sub.1 -C.sub.4)piperazinyl;
and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C.sub.1 -C.sub.8)alkyl, halo, nitro, amino, azido and (C.sub.1 -C.sub.8)alkoxyl;
R.sup.5 is NR.sup.8 R.sup.9 wherein R.sup.8 and R.sup.9 are each independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.8)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.2 -C.sub.8)alkenyl and (C.sub.2 -C.sub.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.sub.1 -C.sub.8)alkylthio, optionally substituted amino, hydroxyl, (C.sub.1 -C.sub.8)alkoxyfl, carboxyl, amidino, acylamino, and (C.sub.2 -C.sub.6)heterocycloalkyl and (C.sub.2 -C.sub.6)heterocycloaryl groups selected from the group comprising imidizaloly, furyl, tetrahydrofuryl; and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or R.sup.8 and R.sup.9 together with the nitrogen to which they are attached form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl; -C.sub.4)alkyl;
and R.sup.6 is hydrogen or a group of the formula ##STR3## wherein m is 0 or an integer from 1-5 and each R.sup.7 is independently selected from halo, azido, nitro, (C.sub.1 -C.sub.8)alkyl, C.sub.1 -C.sub.8 alkoxyl, phenyl and naphthyl, cyano and NR.sup.8 R.sup.9 wherein R.sup.6 and R.sup.9 are as defined above; with the proviso that when R.sup.1 arid R.sup.2 together form a single bond R.sup.3 is hydrogen and R.sup.4 is OR.sup.10 wherein R.sup.10 is hydrogen then R.sup.5 cannot be OR.sup.14, whe
Gallaschun Randall James
Moyer Mikel Paul
Schnur Rodney Caughren
Appleman Jolene W.
Ford John M.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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