Novel prodrugs of N-H bond-containing compounds and methods of making thereof

A compound having the following formula,

• 57
• wherein Z1 and Z2 are residues of an N—H bond-containing pharmaceutical compound, R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.

A compound having the following formula,

• 58
• wherein Z1, Z2 and Z3 are residues of an N—H bond-containing pharmaceutical compound, R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.

A compound having the following formula,

• 59
• wherein Z1 and Z2 are residues of an N—H bond-containing pharmaceutical compound, R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.

A method of making a prodrug of an N—H bond-containing pharmaceutical compound comprising the reaction illustrated in Reaction Scheme I,

• 60
• wherein M is a pharmaceutically acceptable organic or inorganic cation and X is any good leaving group,
• wherein R1 and R2 are residues of an N—H bond-containing pharmaceutical compound, R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms.

A method of making a prodrug of an N—H bond-containing pharmaceutical compound comprising the reaction illustrated in Reaction Scheme II

• 61
• wherein X is any good leaving group,
• wherein R1 and R2 are residues of an N—H bond-containing pharmaceutical compound, R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms.

A method of making a prodrug of an N—H bond-containing pharmaceutical compound comprising the reaction illustrated in Reaction Scheme III

• 62
• wherein M is a pharmaceutically acceptable organic or inorganic cation and X is any good leaving group,
• wherein R1 and R2 are residues of an N—H bond-containing pharmaceutical compound, R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms.

A method of making a prodrug of an N—H bond-containing pharmaceutical compound comprising the reaction illustrated in Reaction Scheme IV

• 63
• wherein X is any good leaving group,
• wherein R1 and R2 are residues of an N—H bond-containing pharmaceutical compound, R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms.

An N—S prodrug having the following formula,

• 64
• wherein R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.

An N—S prodrug having the following formula,

• 65
• wherein R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.

An N—S prodrug having the following formula,

• 66
• wherein R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.

An N—S prodrug having the following formula,

• 67
• wherein R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• f) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.

An N—S prodrug having the following formula,

• 68
• wherein R is one of a hydrogen, inorganic residue and an organic residue selected from the group consisting of:
• a) straight-chain substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• b) branched substituted or unsubstituted aliphatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• c) substituted or unsubstituted acyl groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• d) substituted or unsubstituted aromatic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• e) substituted or unsubstituted cyclic groups, with or without any additional polar or non-polar functional groups and/or heteroatoms;
• and
• d) any combination of a), b), c), d) and e) with or without additional polar or non-polar functional groups and/or heteroatoms;
• and pharmaceutically acceptable salts thereof.