Oculoselective drugs and prodrugs

• US 7,678,829 B2
• Filed: 05/24/2005
• Issued: 03/16/2010
• Est. Priority Date: 05/25/2004
• Status: Active Grant

• Current Assignee: Mati Therapeutics, Inc
• Original Assignee: QT Incorporated
• Inventors: Matier, William L., Patil, Ghanshyam
• Primary Examiner(s): OH, TAYLOR V
• Application Number:
  US11/136,625
• Publication Number:
  US 20060019955A1
• Time in Patent Office: 1,757 Days
• Field of Search: 560/155, 560/157, 514/565, 514/531, 514/461, 514/408, 549/429
• US Class Current: 514/461
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: C07C 219/14 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/08 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07D 307/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Compounds of the following formula are disclosed:

Methods of preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of treating patients by administration of the pharmaceutical compositions, are also disclosed.

Claims

1. A compound of Formula I:

2. A compound according to claim 1, wherein R¹ and R² are each independently H or W.

3. A compound according to claim 1 of Formula Ia:

4. A compound according to claim 1, wherein R⁴ is W.

5. A compound according to claim 4, wherein R¹ and R² are each H.

6. A compound according to claim 5 wherein R³ is straight chain or branched C₁-C₁₀ alkyl, R⁵ is tetrahydrofuran-3-yl, and W is:

7. A compound according to claim 6 wherein W is:

8. A compound according to claim 4 wherein R¹ and R² are each aralkyl.

9. A compound according to claim 8 wherein R⁴ is:

10. A compound according to claim 1, wherein at least one of the R⁶ substituents is other than H.

11. A compound according to claim 1, wherein each R⁶ is independently H,straight chain or branched C₁-C₅ alkyl or straight chain or branched C₂-C₆ alkoxyalkyl.

12. A compound according to claim 1, wherein each R⁶ is independently H, methyl, or CH₂OCH₃.

13. A compound according to claim 1, wherein each W is independently:

14. A compound according to claim 5, wherein each W is independently:

15. A compound according to claim 1 wherein R³ is H or straight chain or branched C₁-C₅ alkyl.

16. A compound according to claim 1 wherein R³ is methyl.

17. A compound according to claim 1, wherein R⁵ is tetrahydrofuranyl.

18. A compound according to claim 17, wherein R⁵ is tetrahydrofuran-3-yl.

19. A compound according to claim 3, wherein R⁵ is tetrahydrofuran-3-yl.

41. A compound according to claim 1, wherein R⁵ is 3-alkyltetrahydrofuran-3-yl.

43. A compound according to claim 1, of the formula:

44. A compound according to claim 43, of the formula:

45. A pharmaceutically acceptable salt of a compound according to claim 43, of formula:

[A]·

HX;

wherein A is a compound according to claim 43 and HX is an acid selected from the group consisting of hydrochloric, sulfuric, maleic, fumaric, oxalic, succinic, citric, and tartaric acids.

47. A pharmaceutical composition for treating glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, the composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 1;

or a stereoisomer or pharmaceutically acceptable salt thereof.

48. The composition according to claim 47, wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

49. The composition according to claim 47, formulated as an eye drop, eye wash, or eye ointment.

50. The composition according to claim 47, formulated for administration from a polymeric disk or wafer placed upon the surface of the eye.

51. A method of treating glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, wherein the method comprises:

administering to the eye of the patient a composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 1;

or a stereoisomer or pharmaceutically acceptable salt thereof, in a therapeutically sufficient amount to ameliorate, delay, or reduce the symptoms of glaucoma, ocular hypertension, or optic neuropathy.

52. The method according to claim 51, wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

53. The method according to claim 51, wherein the composition is administered in an eye drop, eye wash, or eye ointment.

54. The method according to claim 51, wherein the composition is administered from a polymeric disk or wafer placed upon the surface of the eye.

20. A compound of Formula II:

21. A compound according to claim 20 of formula II wherein R⁴ is H.

22. A compound according to claim 20, wherein R¹ and R² are each independently H or W.

23. A compound according to claim 20, wherein R¹, R², and R⁴ are each H.

24. A compound according to claim 20, of Formula II(a):

25. A compound according to claim 20, wherein R⁴ is W.

26. A compound according to claim 25, wherein R¹ and R² are each H.

27. A compound according to claim 26 wherein R³ is straight chain or branched C₁-C₁₀ alkyl, R⁵ is tetrahydrofuran-3-yl, and W is:

28. A compound according to claim 27 wherein W is:

29. A compound according to claim 25 wherein R¹ and R² are each aralkyl.

30. A compound according to claim 25 wherein R⁴ is:

31. A compound according to claim 20, wherein at least one of the R⁶ substituents is other than H.

32. A compound according to claim 20, wherein each R⁶ is independently H, straight chain or branched C₁-C₅ alkyl or straight chain or branched C₂-C₆ alkoxyalkyl.

33. A compound according to claim 20, wherein each R⁶ is independently H, methyl, or CH₂OCH₃.

34. A compound according to claim 20, wherein each W is independently:

35. A compound according to claim 26, wherein each W is independently:

36. A compound according to claim 20 wherein R³ is H or straight chain or branched C₁-C₅ alkyl.

37. A compound according to claim 20 wherein R³ is methyl.

38. A compound according to claim 20, wherein R⁵ is tetrahydrofuranyl.

39. A compound according to claim 38, wherein R⁵ is tetrahydrofuran-3-yl.

40. A compound according to claim 20, wherein W is:

42. A compound according to claim 20, wherein R⁵ is 3-alkyltetrahydrofuran-3-yl.

55. A pharmaceutical composition for treating glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, the composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 20 or a stereoisomer, or pharmaceutically acceptable salt thereof.

56. The composition according to claim 55, wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

57. The composition according to claim 55, formulated as an eye drop, eye wash, or eye ointment.

58. The composition according to claim 55, formulated for administration from a polymeric disk or wafer placed upon the surface of the eye.

59. A method of treating glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy associated with the eye of a patient, wherein the method comprises administering to the eye of the patient a composition comprising an ophthalmologically acceptable carrier or diluent and a compound according to claim 20, or a stereoisomer or pharmaceutically acceptable salt thereof, in a therapeutically sufficient amount to ameliorate, delay, or reduce the symptoms of glaucoma, wherein the glaucoma, ocular hypertension, or optic neuropathy.

60. The method according to claim 59, wherein the glaucoma, ocular hypertension, or optic neuropathy is classified as open-angle glaucoma.

61. The method according to claim 59, wherein the composition is administered in an eye drop, eye wash, or eye ointment.

62. The method according to claim 59, wherein the composition is administered from a polymeric disk or wafer placed upon the surface of the eye.

46. A process for producing a compound of formula IIIa: