Water soluble prodrugs of secondary and tertiary amine containing drugs and methods of making thereof

• US 5,985,856 A
• Filed: 12/30/1998
• Issued: 11/16/1999
• Est. Priority Date: 12/31/1997
• Status: Expired due to Fees

• Current Assignee: University of Kansas
• Original Assignee: University of Kansas
• Inventors: Krise, Jeffrey P., Georg, Ingrid Gunda, Zygmunt, Jan J., Stella, Valentino
• Primary Examiner(s): Ambrose, Michael G.
• Application Number:
  US09/222,858
• Time in Patent Office: 321 Days
• Field of Search: 514/80, 514/85, 514/100, 514/114, 540/542, 544/337, 549/220
• US Class Current: 514/80
• CPC Class Codes: C07F 9/091 with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/650952 having the nitrogen atoms in the positions 1 and 4
• CPC Class Codes: C07F 9/65517 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

The present invention is drawn to water soluble derivatives aliphatic acid aromatic secondary and tertiary amine containing drugs. The present invention is further drawn to methods of making water soluble derivatives of aliphatic and aromatic secondary and tertiary amine containing drugs.

Claims

1. N-phosphoryloxymethyl prodrugs of tertiary amine containing drugs having the following formula VIa or VIb, ##STR28## wherein R₁, R₂ and R₃ are substituents which comprise the parent tertiary amine, R₄ and R₅ are each hydrogen or an organic residue selected from the group consisting of a straight-chain, substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, and a substituted or unsubstituted cyclic group, R₄ and R₅ may contain one or more heteroatoms and may also be joined to form a ring, R₆ is a group double bonded to the carbon spacer, which is an organic residue as defined for R₄ and R₅, and X is an organic or inorganic cation, and A represents an anion.

2. The prodrug of claim 1 wherein R₄ and R₅ are each selected from the group consisting of --CH₃, --C₂ CH₃, phenyl, benzyl, and cyclohexane.

3. The prodrug of claim 1 wherein X is selected from the group consisting of sodium, potassium, ammonium and other pharmaceutically acceptable cations.

4. The prodrug of claim 1 wherein the aqueous solubility of the compound is at least 5 mg/ml.

5. A composition containing an N-phosphoryloxymethyl prodrug of tertiary amine containing drugs having the following formula VI, ##STR29## wherein R₁, R₂ and R₃ are substituents which comprise the parent tertiary amine, R₄ and R₅ are each hydrogen or an organic residue selected from the group consisting of a straight-chain, substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, and a substituted or unsubstituted cyclic group, R₄ and R₅ may contain one or more heteroatoms and may also be joined to form a ring, and X is an organic or inorganic cation, A represents an anion, and a pharmaceutically acceptable carrier thereof.

6. The composition of claim 5 wherein the pharmaceutically acceptable carrier is aqueous.

7. The composition of claim 5 wherein the pH of the composition is a physiological acceptable pH range.

8. The composition of claim 5 for intravenous, oral or parenteral administration.

9. The composition of claim 5 wherein the composition is lyophilized.

10. A method of making a soluble prodrug of a tertiary amine containing parent drug comprising derivatization of a prodrug moiety of formula VII ##STR30## wherein A represents a leaving group, R₄ and R₅ are each hydrogen or an organic residue selected from the group consisting of a straight-chain, substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, and a substituted or unsubstituted cyclic group, R₄ and R₅ may contain one or more heteroatoms and may also be joined to form a ring, and Y is a phosphate protecting group,

through the nucleophilic attack of a tertiary amine causing the displacement of A, followed by the removal of the protecting groups.

11. The method of claim 10 wherein A is selected from the group consisting of chlorine, bromine, iodine, tosylate, florine, acetate, hydroxyl and triflate.

12. The method of claim 10 herein Y is a phosphate protecting groups that temporarily blocks the reactive phosphate moiety and permits selective displacement with the nucleophilic deplacement reaction.

13. The method of claim 10 wherein Y is selected from the group consisting of benzyl, tertiary butyl and isopropyl, ethyl and β

-cyanoethyl.

14. A method of making a soluble prodrug of a tertiary amine containing parent drug comprising reaction of a compound of the following Formula VIII ##STR31## wherein R₄ and R₅ are each an organic or inorganic residue, and W and Z are leaving groups, with a tertiary amine to displace one of either W or Z and reacting the remaining leaving group with a protected phosphate.

15. The method of claim 14 wherein the W and Z are each independently selected from the group consisting of chlorine, bromine, iodine, tosylate, fluorine, acetate, hydroxyl and triflate.