Cancerous B cell treatment using substituted nucleoside derivatives

A process for killing chronic lymphocytic leukemia (CLL) cells that comprises:

• (a) contacting in an aqueous medium a proliferation-inducing amount of an immune response-enhancing agent with human CLL cells that undergo blast transformation and proliferation when contacted with said immune response-enhancing agent with a proliferation-inducing amount of an immune response-enhancing agent;
• (b) maintaining said contact under biological culture conditions for a time period sufficient for said contacted CLL cells to proliferate and form blasts;
• (c) contacting said blasts with a cytotoxic amount of an anti-cancer drug;
• and
• (d) maintaining said contact with said anti-cancer drug under biological culture conditions for a time period for said contacted blast cells to die,
• said immune response-enhancing agent having a structure that corresponds to a formula ##STR15## wherein Z is O, S or N--R.sub.2 ;
• R.sub.1 contains up to about 20 atoms and has a Hammett substituent sigma constant for ionization of a meta-substituted benzoic acid that is greater than that of hydrogen;
• R.sub.2 is a radical having a length up to about that of an n-decyl group that is selected from the group consisting of C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 beta-alkenyl, phenyl-substituted C.sub.3 -C.sub.6 beta-alkenyl, benzyl, C.sub.1 -C.sub.6 alkoxybenzyl, nitrobenzyl, hydroxy C.sub.1 -C.sub.10 alkyl, polyhydroxy C.sub.1 -C.sub.10 alkyl, halo C.sub.1 -C.sub.10 alkyl, polyhalo C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.6 alkylene C.sub.1 -C.sub.6 alkylcarboxylate, C.sub.1 -C.sub.10 alkanoyl, C.sub.1 -C.sub.6 alkoxy C.sub.1 -C.sub.6 alkylenecarbonyl, and C.sub.1 -C.sub.6 alkylenecarboxamido in which the carboxamido group has the formula CONR.sub.9 R.sub.10 wherein R.sub.9 and R.sub.10 are the same or different and are selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 alkyl, or NR.sub.9 R.sub.10 together form a heterocyclic ring having five or six atoms in the ring;
• X is oxygen or sulfur;
• R.sub.3 is a radical selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy C.sub.1 -C.sub.6 alkyl, polyhydroxy C.sub.1 -C.sub.6 alkyl, phenyl, phenyl-C.sub.1 -C.sub.6 alkylene, C.sub.1 C.sub.6 alkylphenyl, C.sub.1 -C.sub.6 alkoxyphenyl, halophenyl, trifluoromethylphenyl, hydroxy, oxo (O.dbd.), C.sub.1 -C.sub.6 alkoxy, phenyl-C.sub.1 -C.sub.6 alkoxy, halo, mercapto, thioxo (S.dbd.), C.sub.1 -C.sub.6 alkylthio, phenyl-C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkanoyl (C.sub.1 -C.sub.6 acyl), C.sub.1 -C.sub.6 alkoxy carbonyl, C.sub.1 -C.sub.6 alkylene C.sub.1 -C.sub.6 alkylcarboxylate, C.sub.1 -C.sub.6 alkoxy C.sub.1 -C.sub.6 alkyl carbonyl, and C.sub.1 -C.sub.6 alkyl carboxamido in which the carboxamido group has the formula CONR.sub.9 R.sub.10 wherein R.sub.9 and R.sub.10 are the same or different and are selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 alkyl or NR.sub.9 R.sub.10 together form a heterocyclic ring having five or six atoms in the ring;
• R.sub.4 is a beta-bonded aldoglycoside radical selected from the group consisting of 1'-aldopentosidyl, 1'-aldohexosidyl, mono-deoxygenated 1'-aldopentosidyl, and mono-deoxygenated 1'-aldohexosidyl, and their O-substituted C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkanoyl, benzyl, benzoyl and C.sub.1 -C.sub.6 acetal or ketal derivatives, an O-substituent other than an acetal or ketal, if present on one oxygen, being present on all available ring substituent oxygens;
• the pharmaceutically acceptable salts of said agent;
• and
• the tautomers thereof,
• said immune response-enhancing agent being free from ionic charge in water at pH 7.2-7.4.

A process for killing cancerous B cells that comprises:

• (a) contacting in an aqueous medium a CLL cell proliferation-inducing amount of an immune response-enhancing agent with cancerous B cells of a host mammal that undergo blast transformation and proliferation when contacted with an immune response-enhancing agent;
• (b) maintaining said contact under biological culture conditions for a time period sufficient for said contacted cancerous B cells to proliferate and form blasts, and for the contacted cancerous B cells to die;
• said immune response-enhancing agent having a structure that corresponds to a formula ##STR17## wherein Z is O, S or N--R.sub.2 ;
• R.sub.1 contains up to about 20 atoms and has a Hammett substituent sigma constant for ionization of a meta-substituted benzoic acid that is greater than that of hydrogen;
• R.sub.2 is a radical having a length up to about that of an n-decyl group that is selected from the group consisting of C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.10 beta-alkenyl, phenyl-substituted C.sub.3 -C.sub.6 beta-alkenyl, benzyl, C.sub.1 -C.sub.6 alkoxybenzyl, nitrobenzyl, hydroxy C.sub.1 -C.sub.10 alkyl, polyhydroxy C.sub.1 -C.sub.10 alkyl, halo C.sub.1 -C.sub.10 alkyl, polyhalo C.sub.1 -C.sub.10 alkyl, C.sub.1 -C.sub.6 alkylene C.sub.1 -C.sub.6 alkylcarboxylate, C.sub.1 -C.sub.10 alkanoyl, C.sub.1 -C.sub.6 alkoxy C.sub.1 -C.sub.6 alkylenecarbonyl, and C.sub.1 -C.sub.6 alkylenecarboxamido in which the carboxamido group has the formula CONR.sub.9 R.sub.10 wherein R.sub.9 and R.sub.10 are the same or different and are selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 alkyl or NR.sub.9 R.sub.10 together form a heterocyclic ring having five or six atoms in the ring;
• X is oxygen or sulfur;
• R.sub.3 is a radical selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy C.sub.1 -C.sub.6 alkyl, polyhydroxy C.sub.1 -C.sub.6 alkyl, phenyl, phenyl-C.sub.1 -C.sub.6 alkylene, C.sub.1 -C.sub.6 alkylphenyl, C.sub.1 -C.sub.6 alkoxyphenyl, halophenyl, trifluoromethylphenyl, hydroxy, oxo (O.dbd.), C.sub.1 -C.sub.6 alkoxy, phenyl-C.sub.1 -C.sub.6 alkoxy, halo, mercapto, thioxo (S.dbd.) , C.sub.1 -C.sub.6 alkylthio, phenyl-C.sub.1 -C.sub.6 alkylthio, C.sub.1 -C.sub.6 alkanoyl (C.sub.1 -C.sub.6 acyl), C.sub.1 -C.sub.6 alkoxy carbonyl, C.sub.1 -C.sub.6 alkylene C.sub.1 -C.sub.6 alkylcarboxylate, C.sub.1 -C.sub.6 alkoxy C.sub.1 -C.sub.6 alkyl carbonyl, and C.sub.1 -C.sub.6 alkyl carboxamido in which the carboxamido group has the formula CONR.sub.9 R.sub.10 wherein R.sub.9 and R.sub.10 are the same or different and are selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 alkyl, or NR.sub.9 R.sub.10 together form a heterocyclic ring having five or six atoms in the ring;
• R.sub.4 is a beta-bonded aldoglycoside radical selected from the group consisting of 1'-aldopentosidyl, 1'-aldohexosidyl, mono-deoxygenated 1'-aldopentosidyl, and mono-deoxygenated 1'-aldohexosidyl, and their O-substituted C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkanoyl, benzyl, benzoyl and C.sub.1 -C.sub.6 acetal or ketal derivatives, an O-substituent other than an acetal or ketal, if present on one oxygen, being present on all available ring substituent oxygens;
• the pharmaceutically acceptable salts of said agent;
• and
• the tautomers thereof,
• said immune response-enhancing agent being free from ionic charge in water at pH 7.2-7.4.