Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives

• US 8,592,427 B2
• Filed: 06/24/2011
• Issued: 11/26/2013
• Est. Priority Date: 06/24/2010
• 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, rn, Zeidan, Tarek A.
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US13/168,497
• Publication Number:
  US 20110319422A1
• Time in Patent Office: 886 Days
• Field of Search: 514/253.07, 544/363
• US Class Current: 514/253.07
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• 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 215/227 only one oxygen atom which is attached in position 2

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 having the formula:

2. A compound of claim 1 having the formula:

3. A compound of claim 2, wherein R₅ is selected from:

4. A compound of claim 2, wherein Cyl is selected from:

5. A compound of claim 2 having the formula:

6. A compound of claim 2 having the formula:

7. A compound of claim 6 having the formula:

8. A compound of claim 7 having the formula:

9. A compound of claim 8 having the formula:

12. A compound of claim 6 selected from Table XI-XII:

10. A compound having the formula:

11. A compound having the formula:

13. A compound selected from Tables A, B, C, or D;

14. A compound selected from Table VI-VII;

15. A compound having the Formula XXXVIII or XXXIX:

16. A compound having the formula:

17. A compound having the Formula XLII, XLIII or XLIV:

18. A compound selected from Table III:

19. A compound of Formula IV or V;

20. The compound of claim 19, wherein R₂₀ is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aliphatic and substituted aliphatic.

21. The compound of claim 19, wherein R₁ is selected from —

C(O)O—

CH₂—

OC(O)R₂₁ or —

C(O)NH—

CH₂—

OC(O)R₂₁ or —

C(O)O—

CH₂—

OC(O)N(R₂₁)₂.

22. The compound of claim 19, wherein R₁ is selected from —

C(O)O—

CH(CH₃)—

OC(O)R₂₁ or —

C(O)NH—

CH(CH₃)—

OC(O)R₂₁ or —

C(O)O—

CH(CH₃)—

OC(O)N(R₂₁)₂.

23. The compound of claim 19, wherein R₁ is selected from from —

C(O)O—

CH(C₆H₅)—

OC(O)R₂₁ or —

C(O)NH—

CH(C₆H₅)—

OC(O)R₂₁ or —

C(O)O—

CH(C₆H₅)—

OC(O)N(R₂₁)₂.