Prodrugs of NH-acidic compounds

• US 8,686,009 B2
• Filed: 06/24/2010
• Issued: 04/01/2014
• Est. Priority Date: 06/25/2009
• 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, rn, Zeidan, Tarek A.
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US12/823,102
• Publication Number:
  US 20110003828A1
• Time in Patent Office: 1,377 Days
• Field of Search: 548/183, 514/369
• US Class Current: 514/369
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/00 Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 239/553 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
• CPC Class Codes: C07D 239/56 One oxygen atom and one sulfur atom
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals

Abstract

The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by 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 conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.

Claims

1. A compound of Formula XVII, XVIII or XIX:

2. A compound having the formula:

11. A compound of claim 2, wherein R₁ is —

C(R_A)(R_B)—

OC(O)OR₂₀;

wherein R₂₀ is C₇-C₂₄ alkyl, C₇-C₂₄ alkenyl or C₇-C₂₄ alkynyl, or a pharmaceutically acceptable salt thereof.

12. A compound of claim 2, wherein R₁ is —

C(R_A)(R_B)—

OC(O)R₂₀;

wherein R₂₀ is C₇-C₂₄ alkyl, C₇-C₂₄ alkenyl or C₇-C₂₄ alkynyl, or a pharmaceutically acceptable salt thereof.

3. A compound having the formula XXIV, XXV or XXVI, or a pharmaceutically acceptable salt thereof:

4. A compound of claim 3, wherein R₁ is selected from table 1 or a pharmaceutically acceptable salt thereof;

13. A compound of claim 3, wherein R₁ is —

C(R_A)(R_B)—

OC(O)OR₂₀;

wherein R₂₀ is C₇-C₂₄ alkyl, C₇-C₂₄ alkenyl or C₇-C₂₄ alkynyl, or a pharmaceutically acceptable salt thereof.

14. A compound of claim 3, wherein R₁ is —

C(R_A)(R_B)—

OC(O)R₂₀;

wherein R₂₀ is C₇-C₂₄ alkyl, C₇-C₂₄ alkenyl or C₇-C₂₄ alkynyl, or a pharmaceutically acceptable salt thereof.

16. A compound of claim 3, wherein R₁ is selected from Table 2 or a pharmaceutically acceptable salt thereof:

17. A compound of claim 3, wherein R₁ is selected from Table 3 or a pharmaceutically acceptable salt thereof:

18. A compound of claim 3, wherein R₁ is selected from Table 4 or a pharmaceutically acceptable salt thereof:

5. A compound having the formula XXVII, XXVIII or XXIX:

7. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R₁ is selected from table 1:

8. A compound of claim 5, wherein R₁ is selected from table 2 or a pharmaceutically acceptable salt thereof:

9. A compound of claim 5, wherein R₁ is selected from table 3 or a pharmaceutically acceptable salt thereof:

10. A compound of claim 5, wherein R₁ is selected from table 4 or a pharmaceutically acceptable salt thereof:

6. A compound selected from Table G or a pharmaceutically acceptable salt thereof:

15. A compound of Formula XVII, XVIII or XIX: