R-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine and other dermal anesthetics

• US 20060079558A1
• Filed: 09/27/2005
• Published: 04/13/2006
• Est. Priority Date: 09/27/2004
• Status: Abandoned Application

• Current Assignee: Bridge Pharma, Inc.
• Original Assignee: Bridge Pharma, Inc.
• Inventors: Chen, Jan L., Aberg, Gunnar
• Application Number:
  US11/235,869
• Publication Number:
  US 20060079558A1
• Time in Patent Office: Days
• US Class Current: 514/318
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention relates to the R-isomers of anesthetic compounds, the methods of treatment therewith, the compounds being useful for inducing local anesthesia, analgesia and sleep.

Claims

1. A substantially pure R-isomer of a compound having the formula:

or pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH₂)_n group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula

in which R₃ and R₄ may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R₁ represents a hydrogen, or a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position, wherein the compound is useful for inducing anesthesia and analgesia in a patient in need thereof.

2. The compound of claim 1, wherein the compound comprises more than 95% or more R-isomer.

3. The compound of claim 1, wherein the compound comprises more than 97% or more R-isomer.

4. The compound of claim 1, wherein the compound comprises more than 99% or more R-isomer.

5. The compound of claim 1, wherein the compound is R-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (R-LAC-34).

6. The compound of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of the monohydrochloride, dihydrochloride, mesylate, lactate, acetate, and sulfamate.

7. A pharmaceutical formulation for providing anesthesia and analgesia in a patient in need thereof, comprising:

a therapeutically effective amount of substantially pure R-isomer of a compound of formula;

or pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH₂)_n group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula

in which R₃ and R₄ may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R₁ represents a hydrogen, or a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position, and a pharmaceutically acceptable excipient.

8. The formulation of claim 7, wherein the compound is R-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (R-LAC-34).

9. The formulation of claim 7, wherein the compound comprises 95% or more R-isomer.

10. The formulation of claim 9, wherein the therapeutically effective amount is an amount effective for inducing anesthesia in a patient in need thereof upon administration.

11. The formulation of claim 9, wherein the therapeutically effective amount is an amount effective for providing analgesia or alleviating pain in a patient in need thereof upon administration.

12. The formulation of claim 9, wherein the formulation is suitable for oral, sublingual, parenteral, topical, transdermal, ocular, intranasal, aural, intrarespiratory, rectal, vaginal, and urethral administration.

13. The formulation of claim 12, wherein the formulation is suitable for parenteral administration and the parenteral administration is selected from the group consisting of intravenous, intra-arterial, intracardiac, intraspinal, intraosseous, intra-articular, intrasynovial, subcutaneous, intradermal, and intramuscular injection, implantation, infiltration or infusion.

14. The formulation of claim 13, wherein the formulation is suitable for intradermal administration.

15. The formulation of claim 13, wherein the excipient, suitable for parenteral administration, is an aqueous vehicle, a non-aqueous vehicle, an antimicrobial agent, an isotonic agent, a surfactant, a buffer, an antioxidant, a suspending agent, a dispersing agent, an emulsifying agent, a sequestering agent, a chelating agent and any combinations or mixtures thereof.

16. The formulation of claim 13, wherein the aqueous vehicle selected from the group consisting of Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose, Lactated Ringers Injection and any combinations or mixtures thereof.

17. The formulation of claim 13, wherein the excipient comprises about 20% PEG 300, about 10 mM histidine and about 5% sucrose in water for injection.

18. The formulation of claim 13, wherein the compound is present in the formulation from about 0.001% to about 25%, by weight.

19. The formulation of claim 13, wherein the compound is present in the formulation from about 0.05% to about 10% by weight.

20. The formulation of claim 13, wherein the compound is present in the formulation from about 0.1% to about 5% by weight.

21. The formulation of claim 14, wherein the compound is present in the formulation from about 0.1% to about 10% by weight.

22. The formulation of claim 13, wherein the compound is a free base.

23. The formulation of claim 13, wherein the compound is a pharmaceutically acceptable salt selected from the group consisting of the monohydrochloride, dihydrochloride, mesylate, lactate, acetate, and sulfamate

24. The formulation of claim 23, wherein the formulation further comprises at least one additional active agent.

25. The formulation of claim 24, wherein the additional active agent is selected from the group consisting of a vasoconstrictor, an analgesic, a glucocorticosteroid, an antihistamine, a local anesthetic, a capsaicinoid, a spreading or diffusing agent and a viscoelastic agent.

26. The formulation of claim 11, wherein the formulation is suitable for topical administration.

27. The formulation of claim 26, wherein the topical administration is selected from epicutaneous, transdermal, conjunctival, intraocular, intranasal, aural, mucosal, rectal, vaginal, and urethral administration.

28. The formulation of claim 26, wherein the topical formulation is a cream, ointment, emollient, paste, gel, solution, suspension, liposome, aerosol, spray and patch.

29. The formulation of claim 27, wherein the excipient, suitable for topical administration, is a penetration enhancer, an antioxidant, a stabilizer, a carrier, an aqueous vehicle, a non-aqueous vehicle, a water insoluble cellulose, a hydrocarbon, and emulsifier, a gelling agent, an antimicrobial agent, a preservative, a buffer, a surfactant and any combinations or mixtures thereof.

30. The formulation of claim 26, wherein the compound is present in the formulation from about 0.001% to about 25%, by weight.

31. The formulation of claim 26, wherein the compound is present in the formulation from about 0.01% to about 10% by weight.

32. The formulation of claim 26, wherein the compound is present in the formulation from about 0.1% to about 5% by weight.

33. The formulation of claim 26, wherein the compound is a free base.

34. The formulation of claim 26, wherein the compound is a pharmaceutically acceptable salt selected from the group consisting of the monohydrochloride, dihydrochloride, mesylate, lactate, acetate, and sulfamate.

35. The formulation of claim 26, wherein the formulation further comprises at least one additional active agent.

36. The formulation of claim 35, wherein the additional active agent is selected from the group consisting of a vasoconstrictor, an analgesic, a glucocorticosteroid, an antihistamine, a local anesthetic, a capsaicinoid, a spreading or diffusing agent and a viscoelastic agent.

37. A method of inducing anesthesia in a patient in need thereof, comprising:

administering to a discrete site in a patient in need thereof an anesthetic inducing amount of a substantially pure R-isomer of a compound of formula;

or pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH₂)_n group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula

in which R₃ and R₄ may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R₁ represents a hydrogen, or a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position,

wherein administration of the compound to the discrete site provides an onset of action faster than that of lidocaine administration to the discrete site.

38. The method of claim 37, wherein the compound is R-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (R-LAC-34).

39. The method of claim 37, wherein the compound provides anesthesia in about 1 second to about 5 minutes upon administration to the discrete site.

40. The method of claim 37, wherein the anesthesia is selected from the group consisting of topical anesthesia, dermal anesthesia, ocular anesthesia, intravenous regional anesthesia, infiltration anesthesia, field block anesthesia, spinal anesthesia, and nerve block anesthesia.

41. The method of claim 37, wherein the site is a pre-surgical site, surgical site or open wound.

42. The method of claim 37, wherein administration of the compound provides anesthesia for about 5 minutes to about 48 hours.

43. The method of claim 42, wherein administration of the compound provides anesthesia for about 24 hours to about 26 weeks.

44. The method of claim 37, wherein the compound is co-administered with at least one additional active agent.

45. The method of claim 44, wherein the additional active agent is selected from the group consisting of a vasoconstrictor, an analgesic, a glucocorticosteroid, an antihistamine, a local anesthetic, phenol, a capsaicinoid, a spreading or diffusing agent and a viscoelastic agent.

46. The method of claim 37, wherein the compound is more than 95% pure R-isomer.

47. The method of claim 37, wherein the compound is more than 97% pure R-isomer.

48. The method of claim 37, wherein the compound is more than 99% pure R-isomer.

49. A method of providing analgesia or alleviating pain in a patient in need thereof, comprising:

administering to a discrete site in a patient in need thereof an anesthetic inducing amount of a substantially pure R-isomer of a compound of formula;

or pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH₂)_n group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula

in which R₃ and R₄ may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R₁ containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position, wherein administration of the compound to the discrete site provides an onset of action faster than that of lidocaine administration to the discrete site.

50. The method of claim 49, wherein the compound is R-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (R-LAC-34).

51. The method of claim 49, wherein the compound provides analgesia in about 1 second to about 5 minutes upon administration to the discrete site.

52. The method of claim 49, wherein the compound attenuates or relieves nociceptive pain, neuropathic pain, pain from nerve injury, pain from neuralgia, pain from myalgias, pain associated with painful trigger points, pain from tumors in soft tissues, pain associated with neurotransmitter-dysregulation syndromes and pain associated with orthopedic disorders such as conditions of the foot, knee, hip, spine, shoulders, elbow, hand, head and neck.

53. The method of claim 49, wherein the site is a surgical site or open wound.

54. The method of claim 49, wherein administration of the compound provides analgesia for about 5 minutes to about 48 hours.

55. The method of claim 49, wherein administration of the compound provides analgesia for about 24 hours to about 26 weeks.

56. The method of claim 49, wherein the compound is co-administered with at least one additional active agent.

57. The method of claim 56 wherein the additional active agent is selected from the group consisting of a vasoconstrictor, an analgesic, a glucocorticosteroid, an antihistamine, a local anesthetic, phenol, a capsaicinoid, a spreading or diffusing agent and a viscoelastic agent.

58. The method of claim 49, wherein the compound comprises more than 95% R-isomer.

59. The method of claim 49, wherein the compound comprises more than 97% R-isomer.

60. The method of claim 49, wherein the compound comprises more than 99% R-isomer.

61. The method of claim 52, wherein the pain is associated with a condition selected from the group consisting of tendonitis, bursitis, osteoarthritis, and rheumatoid arthritis.

62. The method of claim 52, wherein the pain is associated with an orthopedic disorder of the foot selected from the group consisting of heel spurs, corns, bunions, Morton'"'"'s neuroma, hammertoes, ankle sprain, fractures of the ankle or metatarsals or sesamoid bone or toes, plantar fascitis and injuries to the achilles tendon.

63. The method of claim 52, wherein the pain is associated with an orthopedic disorder of the hand selected from the group consisting of arthritis, carpal tunnel syndrome, and ganglion cysts.

64. The method of claim 52, wherein the pain is associated with a disorder selected from the group consisting of lateral epicondylitis, medial epicondylitis, rotator cuff tendonitis, DeQuervian'"'"'s tenosynovitis, and trigger finger/trigger thumb.

65. The method of claim 52, wherein the pain is associated with a disorder selected from the group consisting of Paget'"'"'s disease, scoliosis, contusions, sprains, strains, lower back pain, and heel spur.

66. The method of claim 52, wherein the pain is associated with a bone fracture.

67. The method of claim 52, wherein the pain is associated an injury selected from the group consisting of a tear of the anterior cruciate ligament, a tear of the posterior cruciate ligament, a tear of the medial collateral ligament, a tear of the lateral collateral ligament;

a meniscal cartilage tear;

a cartilage defect of the knee; and

combinations of any of the foregoing.

68. The method of claim 52, wherein the pain is associated with an orthopedic disorder of the shoulder selected from the group consisting of bursitis, dislocation, separation, impingement and tear of the rotator cuff, tendonitis, adhesive capsulitis, shoulder fracture, and combinations of any of the foregoing.

69. A method of improving sleep in a patient in need thereof, comprising:

administering to a discrete site in a patient in need thereof an anesthetic inducing amount of a substantially pure R-isomer of a compound of formula;

or pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH₂)_n group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula

in which R₃ and R₄ may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R₃ may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R₁ represents a hydrogen, or a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position, wherein administration of the compound to the discrete site provides an onset of action faster than that of lidocaine administration to the discrete site, and wherein administration of the compound alleviates pain experienced by the patient and provides for improved sleep resulting from the alleviation of pain.

70. A process for preparing R-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (R-LAC-34) comprising:

a) sequentially converting;

i) an N-protected D-pipecolic acid to a corresponding diazomethyl ketone;

ii) the diazomethyl ketone to a methyl ester;

iii) the methyl ester to a primary alcohol; and

iv) the primary alcohol to an R-alkyl halide;

b) reacting the R-alkyl halide with 2-(phenylamino)indane; and

c) removing an N-protecting group to obtain R-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (R-LAC-34).

71. The process of claim 70, wherein the N-protecting group is removed and a second protecting group is introduced prior to the reacting step b).

72. The process of claim 70, wherein the N-protecting group is removed prior to step b).

73. The process of claim 70, wherein the N-protecting group is a benzyl or benzyloxycarbonyl.

74. The process of claim 73, wherein the benzyloxycarbonyl is removed by acid hydrolysis.

75. The process of claim 73, wherein the benzyl group is removed by hydrogenolysis.

76. A method of preparing an R-isomer of a compound of formula 1:

comprising;

a) by reacting a compound of formula 2

with an R-enantiomer of a compound of formula 3,

wherein R₁ represents a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms or a substituted or unsubstituted phenyl and X is a halogen (bromo, chloro, fluoro, iodo) or a reactive esterified hydroxyl group, to form a compound of formula 1; and

b) hydrogenating a compound of formula 1 , wherein R₁ is a residue removable by means of hydrogenolysis to give a compound of formula 1, wherein R₁ is hydrogen; and

c) hydrolyzing a compound of formula 1, wherein R₁ is a residue removable by means of hydrolysis, to form a compound of formula 1, wherein R₁ is hydrogen; and

d) transforming free bases obtained into their salts or transforming salts into their free bases.