Modified carbamate-containing prodrugs and methods of synthesizing same

• US 20040152769A1
• Filed: 11/07/2003
• Published: 08/05/2004
• Est. Priority Date: 11/09/2002
• Status: Abandoned Application

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Riggs-Sauthier, Jennifer, Dyakonov, Tatyana A., Ekwuribe, Nnochiri Nkem
• Application Number:
  US10/703,647
• Publication Number:
  US 20040152769A1
• Time in Patent Office: Days
• US Class Current: 514/478
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof

Abstract

Prodrugs having a hydrolyzable carbamate moiety, compositions including the prodrugs, methods of preparing the prodrugs and methods of treatment using the prodrugs are disclosed. The prodrug has the formula DC(X)XR, where D is a biologically active agent, X is O, S or NR′, and R is a moiety that modifies various properties of the biologically active agent. The biologically active agent either includes a functional group such as an amide, thioamide, imide, thioimide, urea, thiourea, carbamate, thiocarbamate, sulfonamide, or sulfonimide group, or includes a hydroxy, amine, carboxylic acid or thiol group that is modified to include such a group. An NH group from the biologically active agent can be coupled to an activated form the C(X)XR moiety to form the prodrugs described herein. Relative to a conventional carbamate group, the presence of the additional carbonyl or sulfonyl group makes the carbamate group more susceptible to hydrolysis. The prodrugs are more stable in certain environments than the biologically active agent, and can permit the drugs to be administered orally, in those embodiments where the biologically active agent must otherwise be administered by injection or intraveneous administration.

Claims

1. A prodrug having the following formula:

2. The prodrug of claim 1, wherein the one or more improved characteristics comprises the ability of the prodrug to be orally delivered in a dosage that ultimately provides a pharmaceutically acceptable amount of the biologically active moiety, D, in systemic circulation.

3. The prodrug of claim 1, wherein the one or more improved characteristics comprises improved decreased degradation of of the biologically active agent component of the prodrug relative to unconjugated biologically active agent, D, at a pH of about 2 for less than about 2 hours.

4. The prodrug of claim 1, wherein R is a moiety that affects the solubility of D such that the prodrug is more soluble in plasma than the biologically active agent, D.

5. The prodrug of claim 1, wherein administration to a subject of an amount of the prodrug yields greater bioavailability of the biologically active agent than administration of unconjugated biologically active agent, D.

6. The prodrug of claim 1, wherein the biologically active agent component of the prodrug is more stable as a component of the prodrug than the biologically active agent from which the prodrug is derived in the presence of plasma, proteases, liver homogenate, acidic conditions, or basic conditions.

7. The prodrug of claim 1, having the formula:

8. The prodrug of claim 1, having the formula:

9. The prodrug of claim 1, wherein D is derived from a biologically active agent comprising a functional group selected from the group consisting of urea, thiourea, amide, thioamide, imide, thioimide, carbamate, thiocarbamate, sulfonamide, sulfonamide and phosphoramide.

10. The prodrug of claim 1, wherein D is derived from a biologically active agent comprising a thiol functional group that has been modified to be in the form of a thiocarbamate moiety.

11. The prodrug of claim 10, wherein the thiol-containing drug is selected from the group consisting of thiol-containing peptides and proteins, thiol-containing anti-inflammatory drugs, thiol-containing antirheumatic drugs, thiol-containing peptidomimetic inhibitors, thiol-containing angiotensin converting enzyme inhibitors, cysteine proteases, and thiol-containing antimicrobial heterocycles.

12. The prodrug of claim 10, wherein the thiol-containing drug is selected from the group consisting of glutathione, metallothiones, homo-cysteine, N-acetyl cysteine (NAC), D-penicillamine, captopril, 6-mercaptopurine, mercaprol, dimercaptopropanesulfonate, cathepsin B, cathepsin K, cathepsin L, capthepsin S, thioredoxin reductase, and thiol-containing transcription factors.

13. The prodrug of claim 1, wherein D is derived from a biologically active agent comprising a hydroxyl functional group that has been modified to be in the form of a carbamate moiety.

14. The prodrug of claim 1, wherein D is derived from a hydroxyl-containing drug selected from the group consisting of antineoplastic agents, anti-tumor agents, anti-viral and/or anti-tumor nucleosides, antibiotics and steroids.

15. The prodrug of claim 14, wherein the antitumor agents are selected from the group consisting of taxol, doxorubicin, bleomycin, vincristine (vinblastine), daunorubicin, and idarubicin.

16. The prodrug of claim 14, wherein the antiviral and/or anti-tumor nucleosides are selected from the group consisting of ddI(didanosine), ddC (zalcitabine), d4T (stavudine), FTC, lamivudine (3TC), 1592U89 (4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol), AZT (zidovudine), DAPD (D-2,6-diaminopurine dioxolane) and F-ddA.

17. The prodrug of claim 1, wherein D is derived from a biologically active agent comprising an amine functional group that has been modified to be in the form of a carbamate, thiocarbamate, urea, thiourea, amide, thioamide, sulfonamide or sulfonamide functional group.

18. The prodrug of claim 17, wherein the drug is selected from the group consisting of proteins, peptides, and compounds that bind to CNS receptors.

19. The prodrug of claim 1, wherein D is derived from a biologically active agent comprising a carboxylic acid functional group that has been modified to be in the form of an amide, thioamide, imide or thioimide moiety.

20. The prodrug of claim 1, wherein D is selected from the group consisting of phenyloin, droperidol, sulperidol, primidone, clonazepam, glipizide, glyburide, and tolbutamide.

21. The prodrug of claim 1, wherein R is a hydrophilic moiety.

22. The prodrug of claim 21, wherein the hydrophilic moiety is a polyalkylene glycol moiety, a sugar moiety, or a polysorbate moiety.

23. The prodrug of claim 21, wherein the polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, and polybutylene glycol.

24. The prodrug of claim 21, wherein the hydrophilic moiety is a polyethylene glycol.

25. The prodrug of claim 24, wherein the polyethylene glycol comprises a monodispersed polyalkylene oxide moiety.

26. The prodrug of claim 25, wherein the monodispersed polyalkylene oxide moiety comprises from 1 to 50 alkylene oxide subunits.

27. The prodrug of claim 22, wherein R comprises a polydispersed polyalkylene oxide.

28. The prodrug of claim 27, wherein the polydispersed polyalkylene oxide is a polyethylene oxide.

29. The prodrug of claim 28, wherein the polyalkylene oxide is a straight chain, branched, graft, or fork polymer or copolymer.

30. The prodrug of claim 1, wherein R is a straight chain or branched homopolymer, random copolymer, block copolymer, graft copolymer or terpolymer selected from the group consisting of poly(oxyethylated polyols), poly(vinyl alcohol) (“

PVA”

), dextran, carbohydrate-based polymers, poly(oxazoline), difunctional poly(acryloylmorpholine) (“

PAcM”

), and poly(vinylpyrrolidone)(“

PVP”

).

31. The prodrug of claim 1, wherein R comprises a lipophilic moiety.

32. The prodrug of claim 31, wherein the lipophilic moiety is selected from the group consisting of C_1-20 alkyl, C_1-20 alkenyl, C_1-20 alkynyl, C_1-20 aryl, C_1-20 arylalkyl, C_1-20 alkylaryl, C_9-20 fatty acid, cholesteryl, lipophilic polymers, lipophilic oligomers and mixtures thereof.

33. The prodrug of claim 1, wherein R comprises an amphiphilic polymer or oligomer.

34. The prodrug of claim 33, wherein the amphiphilic polymer or oligomer comprises a polyethylene glycol oligomer or polymer moiety.

35. The prodrug of claim 33, wherein the amphiphilic polymer or oligomer comprises a lipophilic moiety selected from the group consisting of C_1-20 alkyl, C_1-20 alkenyl, C_1-20 alkynyl, C_1-20 aryl, C_1-20 arylalkyl, C_1-20 alkylaryl, C_9-20 fatty acid, cholesteryl, lipophilic polymers, lipophilic oligomers and mixtures thereof.

36. The prodrug of claim 1, wherein R comprises a salt-forming moiety.

37. The prodrug of claim 38, wherein the salt-forming moiety is selected from the group consisting of carboxylate and ammonium.

38. The prodrug of claim 1, wherein R is selected from the group consisting of a hydrophilic moiety, a lipophilic moiety, a salt forming moiety, and combinations thereof.

39. The prodrug of claim 1, wherein R is selected from the group consisting of (CH₂CH₂O)_pCH₃ where p is an integer from 0 to 9;

(CH₂)_qCH₃ where q is an integer from 1 to 9;

CH₂CH₂(OCH₂CH₂)_rOH where r is an integer from 0 to 9;

C(CH₃)₃;

CH(CH₃)₂;

C(CH₂OH)₃;

CH(CH₂OH)₂;

(CH₂CH₂O)_yC(O)(CH₂)_zCH₃ where y is an integer from 0 to 9 and z is an integer from 1 to 9; and

CH₂CH₂(OCH₂CH₂)_aC(O)(CH₂)_bCH₃ where a is an integer from 0 to 9 and b is an integer from 1 to 9.

40. The prodrug of claim 1, wherein R comprises a targeting moiety.

41. The prodrug of claim 40, wherein the targeting moiety is selected from the group consisting of ligands that bind to cell-surface receptors, folic acid or other epitopes, chemomimetic analogs, antibody fragments, antibodies, and arginine-glycine-aspartic acid (RGD).

42. The prodrug of claim 1, wherein the prodrug is more stable than the biologically active agent, D, in the presence of plasma, the presence of proteases, the presence of liver homogenate, the presence of acidic conditions, or the presence of basic conditions.

43. The prodrug of claim 42, wherein the prodrug is more stable than the biologically active agent, D, in the presence of plasma.

44. The prodrug of claim 1, wherein D consists essentially of 1,4-Dihydro-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl esterl,4-Dihydro-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester.

45. A pharmaceutical composition comprising the prodrug of claim 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient.

46. A process for synthesizing the prodrug of claim 1, comprising:

contacting a biologically active agent, D, that comprises or is modified to comprise a functional group selected from the group consisting of amide, thioamide, imide, thioimide, urea, thiourea, carbamate, thiocarbamate, sulfonamide, and sulfonamide groups, with a compound comprising a moiety, R, wherein either D or the compound comprising R is activated such that D reacts with the compound comprising R to form a hydrolyzable carbamate bond between an NH group on the amide, thioamide, imide, thioimide, urea, thiourea, carbamate, thiocarbamate, sulfonamide, or sulfonamide groups and the compound comprising R to provide a prodrug having a hydrolyzable carbamate moiety.

47. A method of treating a subject in need of treatment, said method comprising administering an effective amount of the prodrug of claim 1.

48. The method of claim 54, wherein the prodrug is orally administered.

49. The method of claim 54, wherein the prodrug is orally administered and a pharmaceutically significant portion of the prodrug survives in the GI tract and enters the bloodstream.

50. The method of claim 54, wherein the prodrug is more stable than the biologically active agent from which it is derived in the presence of plasma, proteases, liver homogenate, acidic conditions, or basic conditions.

51. A prodrug having the following formula: