Small molecule inhibition of RNA/ligand binding

A compound having the formula:

• ##STR44## wherein R.sup.18 is 3-pyridylmethyl and R.sup.19 is 3-N,N-diethylaminopropyl, or R.sup.18 is 3-pyridylmethyl and R.sup.19 is an alkyl group having from about 3 to about 6 carbon atoms;
• wherein said alkyl group is substituted with a dialkylamino group in which each alkyl group has from 2 to about 4 carbon atoms;
• or a pharmaceutically acceptable salt thereof;
• and
• a pharmaceutically acceptable diluent or carrier.

A pharmaceutical composition comprising a compound having the formula:

• ##STR47## wherein Y is oxygen or sulfur;
• wherein R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, C.sub.2 to C.sub.7 alkyl, and a heterocyclic ring having 3-10 ring atoms;
• wherein the heterocyclic ring is optionally substituted with C.sub.1 -C.sub.6 alkyl groups;
• wherein the hetero atoms are N, O, or S;
• and
• wherein when R.sup.16 and R.sup.17 are alkyl groups, the alkyl groups are substituted with at least one radical selected from the group consisting of C.sub.1 to C.sub.6 dialkylamino, (C.sub.1 to C.sub.6 alkyl)(aryl)amino, di(C.sub.1 14 C.sub.6 alkyl)amino(C.sub.1 -C.sub.6 alkyl)aryl, C.sub.3 -C.sub.8 dicycloalkylamino, (C.sub.1 to C.sub.6 alkyl)(C.sub.3 -C.sub.8 cycloalkyl)amino, and heterocyclic having 5 to about 7 ring atoms wherein the hetero atoms are N, O, or S;
• and
• wherein R.sup.16 and R.sup.17 can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• or
• a pharmaceutically acceptable salt thereof;
• and
• a pharmaceutically acceptable diluent or earlier.

A composition comprising a compound having the formula:

• ##STR49## wherein each R.sup.20 is independently an alkyl group having from about 3 to about 7 carbon atoms;
• wherein said alkyl group is substituted with a dialkylamino group in which each alkyl group has from 1 to about 4 carbon atoms;
• or a pharmaceutically acceptable salt thereof;
• and
• a pharmaceutically acceptable diluent or carrier.

A composition comprising a compound having the formula:

• ##STR50## wherein each R.sup.21 is independently an alkyl group having from about 3 to about 6 carbon atoms;
• wherein said alkyl group is substituted with a dialkylamino group in which each alkyl group has from 2 to about 4 carbon atoms, a 2-(1-methyl-2-pyrrolidinyl)ethyl group, or a 3-(2-methylpiperidino)propyl group;
• or a pharmaceutically acceptable salt thereof;
• and
• a pharmaceutically acceptable diluent or carrier.

A composition comprising a compound having the formula:

• ##STR52## wherein R.sup.18 is 3-pyridylmethyl and R.sup.19 is 3-N,N-diethylaminopropyl, or R.sup.18 is 3-pyridylmethyl and R.sup.19 is an alkyl group having from about 3 to about 6 carbon atoms;
• wherein said alkyl group is substituted with a dialkylamino group in which each alkyl group has from 2 to about 4 carbon atoms;
• or a pharmaceutically acceptable salt thereof;
• and
• a pharmaceutically acceptable diluent or carrier.

A composition comprising a compound having the formula:

• ##STR53## wherein R.sup.18 is 2-(1-methyl-2-pyrrolidinyl)ethyl and R.sup.19 is 3-N,N-diethylaminopropyl, or R.sup.18 is 2-(1-methyl-2-pyrrolidinyl)ethyl and R.sup.19 is an alkyl group having from about 3 to about 6 carbon atoms wherein said alkyl group is substituted with a dialkylamino group in which each alkyl group has from 2 to about 4 carbon atoms;
• or a pharmaceutically acceptable salt thereof;
• and
• a pharmaceutically acceptable diluent or carrier.

A method for inhibiting HIV Rev protein binding to RNA containing a Rev-responsive element, which comprises contacting the RNA with a compound having the formula:

• ##STR55## wherein Y is oxygen or sulfur;
• wherein R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, C.sub.2 to C.sub.7 alkyl, and a heterocyclic ring having 3-10 ring atoms;
• wherein the heterocyclic ring is optionally substituted with C.sub.1 -C.sub.6 alkyl groups;
• wherein the hetero atoms are N, O, or S;
• and
• wherein when R.sup.16 and R.sup.17 are alkyl groups, the alkyl groups are substituted with at least one radical selected from the group consisting of C.sub.1 to C.sub.6 dialkylamino, (C.sub.1 to C.sub.6 alkyl)(aryl)amino, di(C.sub.1 .varies.C.sub.6 alkyl)amino(C.sub.1 -C.sub.3 alkyl)aryl, C.sub.3 -C.sub.8 dicycloalkylamino, (C.sub.1 to C.sub.6 alkyl)(C.sub.3 -C.sub.8 cycloalkyl)amino, and heterocyclic having 5 to about 7 ring atoms wherein the hetero atoms are N, O, or S;
• and
• wherein R.sup.16 and R.sup.17 can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• or a pharmaceutically acceptable salt thereof, and a
• pharmaceutically acceptable diluent or carrier.

A method for inhibiting HIV Rev protein binding to RNA containing a Rev-responsive element, which comprises contacting the RNA with a compound having the formula:

• ##STR56## wherein Y is sulfur;
• wherein R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, C.sub.2 to C.sub.7 alkyl, and a heterocyclic ring having 3-10 ring atoms;
• wherein the heterocyclic ring is optionally substituted with C.sub.1 -C.sub.6 alkyl groups;
• wherein the hetero atoms comprise N, and optionally O, or S;
• and
• wherein when R.sup.16 and R.sup.17 are alkyl groups, the alkyl groups are substituted with at least one radical selected from the group consisting of C.sub.1 to C.sub.6 dialkylamino, (C.sub.1 to C.sub.6 alkyl)(aryl)amino, di(C.sub.1 -C.sub.6 alkyl)amino(C.sub.1 -C.sub.3 alkyl)aryl, C.sub.3 -C.sub.8 dicycloalkylamino, (C.sub.1 to C.sub.6 alkyl)(C.sub.3 -C.sub.8 cycloalkyl)amino, and heterocyclic having 5 to about 7 ring atoms wherein the hetero atoms are N, O, or S;
• and
• wherein R.sup.16 and R.sup.17 can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• or a pharmaceutically acceptable salt thereof, and a
• pharmaceutically acceptable diluent or carrier.

A method for inhibiting RNA-protein interaction, which comprises contacting the RNA with a compound having the formula:

• ##STR57## wherein Y is oxygen or sulfur;
• wherein R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, C.sub.2 to C.sub.7 alkyl, and a heterocyclic ring having 3-10 ring atoms;
• wherein the heterocyclic ting is optionally substituted with C.sub.1 -C.sub.6 alkyl groups;
• wherein the hetero atoms are N, O, or S;
• and
• wherein when R.sup.16 and R.sup.17 are alkyl groups, the alkyl groups are substituted with at least one radical selected from the group consisting of C.sub.1 to C.sub.6 dialkylamino, (C.sub.1 to C.sub.6 alkyl)(aryl)amino, di(C.sub.1 -C.sub.6 alkyl)amino(C.sub.1 -C.sub.3 alkyl)aryl, C.sub.3 -C.sub.8 dicycloalkylamino, (C.sub.1 to C.sub.6 alkyl)(C.sub.3 -C.sub.8 cycloalkyl)amino, and heterocyclic having 5 to about 7 ring atoms wherein the hetero atoms are N, O, or S;
• and
• wherein R.sup.16 and R.sup.17 can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• or
• a pharmaceutically acceptable salt thereof, and
• a pharmaceutically acceptable diluent or carrier.

A method of inhibiting retroviral replication in a cell infected with a retrovirus, which comprises contacting said retroviral-infected cell with a compound having the formula:

• ##STR58## wherein Y is oxygen or sulfur;
• wherein R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen, C.sub.2 to C.sub.7 alkyl, and a heterocyclic ring having 3-10 ring atoms;
• wherein the heterocyclic ring is optionally substituted with C.sub.1 -C.sub.6 alkyl groups;
• wherein the hetero atoms are N, O, or S;
• and
• wherein when R.sup.16 and R.sup.17 are alkyl groups, the alkyl groups are substituted with at least one radical selected from the group consisting of C.sub.1 to C.sub.6 dialkylamino, (C.sub.1 to C.sub.6 alkyl)(aryl)amino, di(C.sub.1 -C.sub.6 alkyl)amino(C.sub.1 -C.sub.3 alkyl)aryl, C.sub.3 -C.sub.8 dicycloalkylamino, (C.sub.1 to C.sub.6 alkyl)(C.sub.3 -C.sub.8 cycloalkyl)amino, and heterocyclic having 5 to about 7 ring atoms wherein the hetero atoms are N, O, or S;
• and
• wherein R.sup.16 and R.sup.17 can be optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
• or
• a pharmaceutically acceptable salt thereof, and
• a pharmaceutically acceptable diluent or carrier.