Quaternary Ammonium Salt Prodrugs

• US 20110178068A1
• Filed: 12/23/2010
• Published: 07/21/2011
• 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: Blumberg, Laura Cook, Remenar, Julius F., Almarsson, Orn
• Granted Patent: US 9,670,200 B2
• Time in Patent Office: Days
• US Class Current: 514/220
• 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 having the formula:

2. The method of claim 1, wherein the prodrug further comprises a biocompatible delivery system for delivering the prodrug wherein the system is capable of minimizing accelerated hydrolytic cleavage of the prodrug by minimizing exposure of the prodrug to water.

3. The method of claim 2, wherein the parent drug is present in the blood stream of the patient for a period selected from:

at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 4 days, at least one week, at least one month and at least 3 months.

4. The method of claim 1, wherein the administering step is by injection or oral delivery.

5. The method of claim 1, wherein the parent drug is amisulpride, aripiprazole, asenapine, cariprazine, citalopram, dehydroaripiprazole, escitalopram, galantamine, iloperidone, latrepirdine, lurasidone, olanzapine, paliperidone, perospirone, risperidone, and ziprasidone.

6. The method of claim 1, wherein R₃, R₄ and R₅, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycle.

7. The method of claim 6, wherein the prodrug has the formula:

8. The method of claim 1, 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.

9. The method of claim 1, wherein R₂ is hydrogen, a methyl group or an ethyl group.

10. A method for producing a prodrug compound of a tertiary amine-containing or tertiary imine-containing parent drug compound comprising the step of reacting a parent drug compound having the formula:

11. A prodrug compound prepared by the method of claim 10.

12. A prodrug compound of a tertiary amine-containing parent drug wherein said prodrug compound is represented by the formula:

13. The prodrug compound of claim 12, 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.

14. The prodrug compound of claim 12, wherein R₃, R₄ and R₅, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocycle.

15. The prodrug compound of claim 14, wherein the heterocycle is a five- or six- or seven-member heterocycle.

16. The prodrug compound of claim 15, wherein the heterocycle is a piperidine, pyrrolidine, piperazine, morpholine, azapine, diazapine, imidazole, or azetidine.

17. The prodrug compound of claim 12, wherein the parent drug is amisulpride, aripiprazole, asenapine, cariprazine, citalopram, dehydroaripiprazole, escitalopram, galantamine, iloperidone, latrepirdine, olanzapine, paliperidone, perospirone, risperidone, and ziprasidone.

18. A compound of the formula:

19. 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:

20. 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:

21. The method of claim 20, wherein R₇ and R₈ are independently selected from:

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; and

v) substituted or unsubstituted C₃-C₁₂ cycloalkyl.

22. The method of claim 20, wherein R₇ and R₈ are independently selected from:

i) hydrogen;

ii) methyl; and

iii) ethyl.

23. The method of claim 20, wherein R₉ is selected from:

i) C₃-C₂₄ secondary alkyl group; and

ii) C₄-C₂₄ tertiary alkyl group.

24. The method of claim 20, wherein R₉ is selected from branched or unbranched, substituted or unsubstituted C₅-C₂₄ alkyl.

25. The method of claim 20, wherein R₁₀ and R₁₁ are each independently selected from:

i) hydrogen;

ii) C₃-C₂₄ secondary alkyl group; and

iii) C₄-C₂₄ tertiary alkyl group.

26. The method of claim 20, wherein R₁₀ and R₁₁ are each independently selected from branched or unbranched, substituted or unsubstituted C₅-C₂₄ alkyl.

27. The method of claim 20, wherein the prodrug has the formula:

28. A prodrug compound of a tertiary amine-containing parent drug or a tertiary imine-containing parent drug wherein the prodrug compound has the formula represented by:

29. A prodrug compound of a tertiary amine-containing parent drug or a tertiary imine-containing parent drug wherein the prodrug compound has the formula represented by:

30. A prodrug compound of a tertiary amine-containing parent drug wherein the prodrug compound has the formula represented by:

31. 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:

32. A method for pH-independent sustained delivery of a tertiary amine-containing parent drug to a patient comprising administering to the patient, a prodrug compound of the parent drug having the Formula III:

33. A method for pH-independent sustained delivery of a tertiary amine-containing parent drug to a patient comprising administering to the patient, a prodrug compound and an optional biocompatible delivery system for delivering the prodrug wherein the optional delivery system is capable of minimizing accelerated hydrolytic cleavage of the prodrug wherein the prodrug has the Formula III:

34. A method of reducing the side effect of sedation or coma in the patient as compared to sedation or coma caused by administration of the parent drug of formula IV comprising administering to the patient, a prodrug compound of the parent drug having the Formula III: