Quaternary ammonium salt prodrugs

• US 9,670,200 B2
• Filed: 12/23/2010
• Issued: 06/06/2017
• Est. Priority Date: 01/07/2010
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: Remenar, Julius F., Almarsson, rn, Blumberg, Laura Cook
• Primary Examiner(s): Grazier, Nyeemah A
• Application Number:
  US12/978,178
• Publication Number:
  US 20110178068A1
• Time in Patent Office: 2,357 Days
• Field of Search: None
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/452 Piperidinium derivatives pancuronium A61K31/58
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 221/18 Ring systems of four or more rings
• CPC Class Codes: C07D 307/87 Benzo [c] furans; Hydrogenated benzo [c] furans
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/044 with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 495/04 Ortho-condensed 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 invention provides a method of sustained delivery of a tertiary amine-containing parent drug comprising administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile quaternary ammonium salts of tertiary amine-containing parent drugs (or tertiary imine-containing parent drugs) that are derivatized through aldehyde-linked prodrug moieties that reduce the solubility of the prodrug compound at a reference pH as compared to the parent drug. The physical, chemical and solubility properties of these derivatives can be further modulated by the choice of counterion X⁻. In one embodiment, the present invention provides a prodrug compound of Formula I:

where R₁-R₅ are defined in the written description of the invention. The prodrug compounds of the invention can be used to treat any condition for which the tertiary amine-containing parent drug or tertiary imine-containing parent drug is useful as a treatment.

Claims

1. A method for sustained delivery of a tertiary amine-containing parent drug to a patient comprising administering a prodrug compound of the parent drug having the formula:

2. The method of claim 1, wherein R₇ and R₈ are independently:

i) hydrogen;

ii) branched or unbranched, substituted or unsubstituted C₁-C₆ alkyl;

iii) branched or unbranched, substituted or unsubstituted C₂-C₆ alkenyl;

iv) branched or unbranched, substituted or unsubstituted C₂-C₆ alkynyl;

or

v) substituted or unsubstituted C₃-C₁₂ cycloalkyl.

3. The method of claim 1, wherein R₇ and R₈ are independently:

i) hydrogen;

ii) methyl;

or

iii) ethyl.

4. The method of claim 1, wherein R₉ is:

i) C₈-C₂₄ secondary alkyl group;

or

ii) C₈-C₂₄ tertiary alkyl group.

5. The method of claim 1, wherein R₉ is selected from branched, substituted or unsubstituted C₉-C₂₄ alkyl.

17. The method of claim 1, wherein the optional biocompatible delivery system is polymeric matrix delivery system.

6. A method for sustained delivery of a tertiary amine-containing parent drug to a patient comprising administering a prodrug compound of the parent drug having the formula:

7. A method of reducing a side effect of sedation or coma in a patient as compared to sedation or coma caused by administration of the parent drug of formula IV:

8. A method for sustained delivery of a tertiary amine-containing parent drug to a patient comprising administering a prodrug compound of the parent drug having the formula:

9. The method of claim 8, wherein R₇ and R₈ are independently:

i) hydrogen;

ii) branched or unbranched, substituted or unsubstituted C₁-C₆ alkyl;

iii) branched or unbranched, substituted or unsubstituted C₂-C₆ alkenyl;

iv) branched or unbranched, substituted or unsubstituted C₂-C₆ alkynyl;

or

v) substituted or unsubstituted C₃-C₁₂ cycloalkyl.

10. The method of claim 8, wherein R₇ and R₈ are independently:

i) hydrogen;

ii) methyl;

or

iii) ethyl.

11. The method of claim 8, wherein R₉ is:

i) C₇-C₂₄ secondary alkyl group;

or

ii) C₇-C₂₄ tertiary alkyl group.

12. The method of claim 8, wherein R₇ and R₈ are both hydrogen.

13. The method of claim 12, wherein Y is selected from the group consisting of:

14. The method of claim 8, wherein the administering step is by injection or oral delivery.

15. The method of claim 8, wherein the parent drug is amisulpride, aripiprazole, asenapine, cariprazine, citalopram, dehydroaripiprazole, escitalopram, galantamine, iloperidone, latrepirdine, lurasidone, olanzapine, paliperidone, perospirone, risperidone, or ziprasidone.

16. The method of claim 8, wherein the prodrug has lower aqueous solubility at a reference pH as compared to the aqueous solubility of the parent drug at the same reference pH wherein the reference pH is a pH at which the parent drug is fully protonated.