Pro-drug forms of digoxin and method of preparing and using same

Claim 1

A pro-drug of digoxin having the formula: ##STR8## wherein R represents a member selected from the group consisting of a hydrogen atom, a residue of any naturally occurring protein amino acid, and a ##STR9## group, wherein X and Y, which may be the same or different, each represent a member selected from the group consisting of a methyl group and an ethyl group, or wherein X and Y may form a (CH 2 ) 4 or (CH 2 ) 5 heterocyclic ring with the N atom to which each of X and Y are attached, and a non-toxic inorganic or organic pharmaceutically acceptable acid addition salt thereof, with the proviso that: when R is a member other than a hydrogen atom, all of said R's must be the same member.

Claim 36

A method for treating cardiac insufficiency in a warm-blooded animal which comprises orally administering thereto, an effective cardiotonic amount of a pro-drug of digoxin having the following formula: ##STR14## wherein R represents a member selected from the group consisting of a hydrogen atom, a residue of any naturally occurring protein amino acid, and a ##STR15## group, wherein X and Y, which may be the same or different, each represent a member selected from the group consisting of a methyl group and an ethyl group, or wherein X and Y may form a (CH 2 ) 4 or (CH 2 ) 5 heterocyclic ring with the N atom to which they are attached, and a non-toxic inorganic or organic pharmaceutically acceptable acid addition salt thereof, with the proviso that: when R is a member other than a hydrogen atom, all of said R's must be the same member.

Claim 37

A method for treating cardiac insufficiency in a warm-blooded animal which comprises orally administering thereto, an effective cardiotonic amount of a pro-drug of digoxin having the following formula: ##STR14## wherein R represents a member selected from the group consisting of a hydrogen atom, a residue of any naturally occurring protein amino acid, and a ##STR15## group, wherein X and Y, which may be the same or different, each represent a member selected from the group consisting of a methyl group and an ethyl group, or wherein X and Y may form a (CH 2 ) 4 or (CH 2 ) 5 heterocyclic ring with the N atom to which they are attached, and a non-toxic inorganic or organic pharmaceutically acceptable acid addition salt thereof, with the proviso that: when R is a member other than a hydrogen atom, all of said R's must be the same member.

Claim 56

A method for preparing a pro-drug compound of digoxin having the formula: ##STR16## where R represents a ##STR17## group, wherein X and Y, which may be the same or different, each represent a member selected from the group consisting of a methyl group and an ethyl group, or wherein X and Y may form a (CH 2 ) 4 or (CH 2 ) 5 heterocyclic ring with the N atom to which each of X and Y are attached, with the proviso that when R is a member other than a hydrogen atom, all of said R's must be the same member which comprises the steps of (1) reacting, in the presence of a suitable organic coupling agent and a weak organic base-solvent, a stoichiometric amount of digoxin with a stoichiometric amount of an N,N-dialkylamino acid having the formula ##STR18## or its pharmaceutically acceptable acid addition salt, wherein X and Y, which may be the same or different, each represent a member selected from the group consisting of a methyl group and an ethyl group, or wherein X and Y may form a (CH 2 ) 4 or (CH 2 ) 5 heterocyclic ring with the N atom to which they are attached, said reaction being carried out at room temperature, standard pressure and over a period of time of from one hour to four days, and wherein the mole ratio of said N,N-dialkylamino acid to said coupling agent ranges from 1:1 to 1:5, and (2) removing the final product thus formed during the reaction of step (1) above from the reaction mixture.

Claim 57

A method for preparing a pro-drug compound of digoxin having the formula: ##STR16## where R represents a ##STR17## group, wherein X and Y, which may be the same or different, each represent a member selected from the group consisting of a methyl group and an ethyl group, or wherein X and Y may form a (CH 2 ) 4 or (CH 2 ) 5 heterocyclic ring with the N atom to which each of X and Y are attached, with the proviso that when R is a member other than a hydrogen atom, all of said R's must be the same member which comprises the steps of (1) reacting, in the presence of a suitable organic coupling agent and a weak organic base-solvent, a stoichiometric amount of digoxin with a stoichiometric amount of an N,N-dialkylamino acid having the formula ##STR18## or its pharmaceutically acceptable acid addition salt, wherein X and Y, which may be the same or different, each represent a member selected from the group consisting of a methyl group and an ethyl group, or wherein X and Y may form a (CH 2 ) 4 or (CH 2 ) 5 heterocyclic ring with the N atom to which they are attached, said reaction being carried out at room temperature, standard pressure and over a period of time of from one hour to four days, and wherein the mole ratio of said N,N-dialkylamino acid to said coupling agent ranges from 1:1 to 1:5, and (2) removing the final product thus formed during the reaction of step (1) above from the reaction mixture.