Merged ion channel modulating compounds and uses thereof
Merged compounds of ion channel modulating compounds, including, for example, merged compounds of the ion channel modulating compound of the following formula: (I) are described herein, as well as methods of making and using such merged compounds and pharmaceutical compositions containing such merged compounds.
1. A merged compound of the formula (IXXXa):
wherein:
indicates a bond that gives rise to either R or S stereochemistry;
R 1a is hydrogen;
R 2a is an aryloxypropanolamine side chain of a β 1 -blocker or a substituted propanol-3-yl, wherein the substituted propanol-3-yl is substituted at one or more position with a group selected from hydroxyl, phenyl, or substituted phenyl wherein the substituted phenyl is substituted with C 1 -C 8 alkyloxylalkyl group; and
R 21 and R 22 are independently selected from a substituted or unsubstituted C 1 -C 8 alkoxy group wherein the substituted C 1 -C 8 alkoxy is substituted with a hydroxyl and/or a substituted or unsubstituted amino group;
as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
2. The merged compound of claim 1 wherein R 2a is a substituted substituted propanol-3-yl, wherein the substituted propanol-3-yl is substituted at one or more position with a group selected from hydroxyl, phenyl, or substituted phenyl wherein the substituted phenyl is substituted with C 1 -C 8 alkyloxylalkyl group; and
R 21 and R 22 are independently selected from a unsubstituted C 1 -C 8 alkoxy group.
3. The merged compound of claim 2 having the following formula:
4. The merged compound of claim 2 selected from the group consisting of:
(S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
(R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
(S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
(R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
(S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
(R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
(S)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol; and
(R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol.
5. A merged compound of the formula (IXXXa):
wherein:
indicates a bond that gives rise to either R or S stereochemistry;
R 1a and R 2a are taken together with the nitrogen atom to which they are attached to form a 5 to 8-membered heterocyclic ring that is optionally substituted with a group selected from a hydroxyl;
R 21 is unsubstituted C 1 -C 8 alkoxy; and
R 22 is a substituted C 1 -C 8 alkoxy group wherein the substituted C 1 -C 8 alkoxy is substituted with a hydroxyl and/or a substituted or unsubstituted amino group;
as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
6. The merged compound of claim 5 , wherein:
R 1a and R 2a are taken together with the nitrogen atom to which they are attached to form a pyrrolidino ring that is substituted with a hydroxyl group; and
R 21 is a methoxy group.
7. The merged compound of claim 6 having the following formula:
8. The merged compound of claim 7 selected from the group consisting of:
(R)-1-((1R,2R)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol;
(S)-1-((1R,2R)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol;
(R)-1-((1S,2S)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol;
(S)-1-((1S,2S)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol;
(R)-1-((1S,2R)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol;
(S)-1-((1S,2R)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol;
(R)-1-((1R,2S)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol; and
(S)-1-((1R,2S)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)-3-methoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol.
9. A merged compound of the formula (IXXXa):
wherein:
indicates a bond that gives rise to either R or S stereochemistry;
R 1a and R 2a are taken together with the nitrogen atom to which they are attached to form a 5 to 8-membered heterocyclic ring that is substituted with an amino or substituted amino; and
R 21 and R 22 are independently selected from a substituted or unsubstituted C 1 -C 8 alkoxy group wherein the substituted C 1 -C 8 alkoxy is substituted with a hydroxyl and/or a substituted or unsubstituted amino group;
as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
10. The merged compound of claim 9 wherein:
R 1a and R 2a are taken together with the nitrogen atom to which they are attached to form a 5 to 8-membered heterocyclic ring that is substituted with a substituted amino; and
R 21 and R 22 are each an unsubstituted C 1 -C 8 alkoxy group.
11. The merged compound of claim 10 having the following formula:
12. The merged compound of claim 11 selected from the group consisting of:
1-((R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
1-((S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
1-((R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
1-((S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
1-((R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol;
1-((S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol; and
1-((R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ylamino)-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol.
13. A merged compound of the formula (IXXXa):
wherein:
wherein:
indicates a bond that gives rise to either R or S stereochemistry;
R 1a and R 2a are taken together with the nitrogen atom to which they are attached to form a 5 to 8-membered heterocyclic ring that is substituted with a substituted alkoxy group wherein the substituted alkoxy group is substituted phenethoxy; and
R 21 and R 22 are independently selected from a substituted or unsubstituted C 1 -C 8 alkoxy group wherein the substituted C 1 -C 8 alkoxy is substituted with a hydroxyl and/or a substituted or unsubstituted amino group;
as isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.
14. The merged compound of claim 13 wherein:
R 1a and R 2a are taken together with the nitrogen atom to which they are attached to form a 5 to 8-membered heterocyclic ring that is substituted with a substituted alkoxy group wherein the substituted alkoxy group is substituted phenethoxy; and
R 21 and R 22 are each an unsubstituted C 1 -C 8 alkoxy group.
15. The merged compound of claim 14 having the following formula:
16. The merged compound of claim 15 selected from the group consisting of:
1-(4-(2-((R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
1-(4-(2-((S)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
1-(4-(2-((R)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
1-(4-(2-((S)-1-((1S,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
1-(4-(2-((R)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
1-(4-(2-((S)-1-((1S,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol;
1-(4-(2-((R)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol; and
1-(4-(2-((S)-1-((1R,2S)-2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-yloxy)ethyl)phenoxy)-3-(isopropylamino)propan-2-ol.