Methods for the treatment of pain and traumatic injury using benzamides and compositions containing the same

• US 20040167226A1
• Filed: 12/15/2003
• Published: 08/26/2004
• Est. Priority Date: 12/16/2002
• Status: Abandoned Application

• Current Assignee: Renovis, Inc. (Evotec SE)
• Original Assignee: Renovis, Inc. (Evotec SE)
• Inventors: Goodman, Corey S., Serafini, Tito A.
• Application Number:
  US10/736,460
• Publication Number:
  US 20040167226A1
• Time in Patent Office: Days
• US Class Current: 514/619
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

Methods are disclosed for treating and preventing pain such as neuropathic pain, and traumatic injuries such as traumatic brain injury and acute spinal cord injury, which comprise administering effective amounts of a benzamide compound of formula I:

where n is 1 or 2, R₁ is a group selected from acetyl, alkyl, amino, acylamino (NHCOR₃), halo, nitro, and trifluoroalkyl, R₂ is saturated alkyl of 3 to 5 atoms, and R₃ is alkyl of 1 to 5 atoms. Pharmaceutical compositions, dosage forms and methods of administration are set forth.

Claims

1. A pharmaceutical composition for the treatment of pain comprising an effective pain-treating amount of a benzamide compound in a pharmaceutically acceptable carrier,

wherein the benzamide is a material of Formula I:

where n is 1 or 2, R₁ is a group selected from acetyl, alkyl, amino, acylamino (NHCOR₃), halo, nitro, and trifluoroalkyl, R₂ is saturated alkyl of 3 to 5 atoms, and R₃ is alkyl of 1 to 5.

3. The composition of either of claims 1 or 2 wherein the benzamide is selected from the group consisting of acetamidobenzamides, aminobenzamides and nitrobenzamides.

4. The composition of claim 3 wherein the benzamide is selected from the group consisting of:

N-tert-butyl-4-acetamidobenzamide (Compound A);

N-iso-propyl-4-acetamidobenzamide (Compound B);

N-tert-amyl-4-acetamidobenzamide (Compound C);

N-cyclopropylmethyl-4-acetamidobenzamide (Compound E);

N-iso-propyl-4-nitrobenzamide (Compound F);

N-tert-butyl-3-nitrobenzamide (Compound G);

N-tert-butyl-2-nitrobenzamide (Compound H);

N-n-butyl-4-nitrobenzamide (Compound J);

N-n-propyl-4-nitrobenzamide (Compound K);

N-tert-butyl-3,5-dinitrobenzamide (Compound L);

N-1-methylpropyl-4-nitrobenzamide (Compound M);

N-tert-butyl-4-aminobenzamide (Compound N);

N-tert-butyl-3-aminobenzamide (Compound P); and

N-tert-butyl 4-nitrobenzamide (Compound Q).

5. The composition of claim 4 wherein the benzamide is N-tert-butyl-4-acetamidobenzamide (Compound A).

44. A method for treating or preventing pain in a mammal comprising administering to said mammal an effective pain treating or preventing dose of a pharmaceutical composition according to any of claims 1 and 3-5.

45. A method for the prophylactic treatment of patients susceptible to outbreaks of shingles or for patients scheduled to receive chemotherapy comprising administering a therapeutically effective amount of the composition of claim 1.

47. The method of claims 44 or 46, wherein the mammal is a human.

2. A pharmaceutical composition for the treatment of traumatic injury comprising an effective traumatic injury-treating amount of a benzamide compound in a pharmaceutically acceptable carrier,

wherein the benzamide is a material of Formula I:

where n is 1 or 2, R₁ is a group selected from acetyl, alkyl, amino, acylamino (NHCOR₃), halo, nitro, and trifluoroalkyl, R₂ is saturated alkyl of 3 to 5 atoms, and R₃ is alkyl of 1 to 5.

6. The composition of claim 2 wherein the traumatic injury is selected from the group consisting of traumatic brain injury and acute spinal cord injury.

46. A method for the treatment of traumatic injury to the brain or spinal cord of a mammal comprising administering to said mammal an effective brain or spinal cord injury treating dose of a pharmaceutical composition according to any of claims 2-5.

7. A method for treating pain in a mammalian subject in need thereof, comprising delivering/administering to said subject an effective pain-treating amount of a pharmaceutical composition comprising a benzamide.

8. The method of claim 7, wherein said benzamide has a formula as set forth in I:

9. The method of claim 7, wherein said pain is acute pain.

10. The method of claim 9, wherein said pain includes post-operative pain, shock, pain resulting from inflammation, pain resulting from trauma, acute breakthrough pain associated with a chronic pain condition, and combinations thereof.

11. The method of claim 7, wherein said pain is chronic pain.

12. The method of claim 11, wherein said pain includes headache pain, back pain, sciatica, cancer pain, arthritis pain, neuropathic pain, psychogenic pain, and combinations thereof.

13. The method of claim 7, wherein said pharmaceutical composition is delivered/administered via a route selected from the group consisting of topical, oral, caudal, subcutaneous, intramuscular, intravenous, perineural, intraperitoneal, epidural intranasal, intracranial, local intracerebral, intrathecal, intraventricular, transdermal, and combinations thereof.

14. The method of claim 7, wherein said pharmaceutical composition is delivered/administered to the central nervous system of said subject.

15. The method of claim 14, wherein delivery/administration to the central nervous system is selected from the group consisting of intracranial, local intracerebral, intrathecal, and intraventricular delivery/administration.

16. The method of claim 7, wherein the pharmaceutical composition delivers an effective amount directly to the central nervous system without adversely affecting other tissues or organ systems.

17. The method of claim 13, wherein the pharmaceutical composition is administered by an infusion pump.

18. The method of claim 13, wherein the pharmaceutical composition is administered in an aerosol formulation.

19. The method of claim 13, wherein the pharmaceutical composition is administered over a period of at least several days.

20. The method of claim 13, wherein the pharmaceutical composition is administered over a period of at least four weeks.

21. The method of claim 13, wherein the pharmaceutical composition is administered over a period of at least three months.

22. The method of claim 13, wherein the pharmaceutical composition is administered on an as needed basis.

23. The method of claim 13, wherein the pharmaceutical composition is administered as a sustained release formulation or in a formulation that is capable of crossing the blood brain barrier.

24. The method of claim 7, wherein the pain is associated with a condition selected from the group consisting of diabetic neuropathy, herpes zoster, fibromyalgia AIDS, syphilis, neuritis, temporomandibular disorder, back pain, myofacial pain, acute spinal cord injury, traumatic brain injury, cancer pain, visceral pain, intraneural inflammation, optic neuropathy, neuropathy secondary to nerve trauma, post herpetic neuralgia, reflex sympathetic dystrophy, and ankylosing spondylitis.

25. A method for producing local anesthesia or analgesia in a mammal, the method comprising administering to a mammal the pharmaceutical composition of claim 7.

26. The method of claim 25, wherein the local anesthesia or analgesia is effective for treatment of conditions associated with increased sensory functions, said conditions selected from the group consisting of hyperesthesia, hyperalgesia, dyesthesia, allodynia, tinnitus and ganglionic dysfunction.

27. The method of claim 26, wherein the local anesthesia or analgesia is administered topically to a skin region having or manifesting neuropathic pain.

28. The method of claim 27, wherein said treatment of neuropathic pain in a skin region of a mammal comprises the application to said skin region a transdermal patch containing said pharmaceutical composition.

29. A method for treating a patient suffering from a traumatic injury comprising administering to said patient an effective amount of a pharmaceutical composition comprising a benzamide compound of the formula I:

30. The method of claim 29, wherein said traumatic injury is an injury to the central nervous system.

31. The method of claims 8 or 29 wherein R₁ is amino, acylamino (NHCOR₃), or nitro.

32. The method of claim 31 wherein R₂ is t-Bu.

33. The method of claim 32 wherein n is 1.

34. The method of claims 8 or 29 wherein n is 1, R₁ is 4-amino, 4-acylamino (NHCOR₃), or 4-nitro and R₂ is t-Bu.

35. The method of claims 8 or 29 wherein said composition is administered orally.

36. The method of claims 8 or 29 wherein said composition is administered parenterally.

37. The method of claim 36, wherein said parenteral administration is selected from the group consisting of topical, caudal, subcutaneous, intramuscular, intravenous, perineural, intraperitoneal, epidural, intranasal, intracranial, local intracerebral, intrathecal, intraventricular, transdermal, and combinations thereof.

38. The method of claim 37, wherein said administration is by infusion pump.

39. The method of claims 8 or 29 wherein said composition is administered rectally.

40. The method of claim 29, wherein said traumatic injury is selected from the group consisting of traumatic brain injury and spinal cord injury.

41. The method of claim 40, wherein the spinal cord injury is an acute or chronic spinal cord injury.

42. The method of claims 8 or 29, wherein said benzamide is selected from the group consisting of:

N-tert-butyl-4-acetamidobenzamide (Compound A);

N-iso-propyl-4-acetamidobenzamide (Compound B);

N-tert-amyl-4-acetamidobenzamide (Compound C);

N-methylcyclopropyl-4-acetamidobenzamide (Compound E);

N-iso-propyl-4-nitrobenzamide (Compound F);

N-tert-butyl-3-nitrobenzamide (Compound G);

N-tert-butyl-2-nitrobenzamide (Compound H);

N-n-butyl-4-nitrobenzamide (Compound J);

N-n-propyl-4-nitrobenzamide (Compound K);

N-tert-butyl-3,5-dinitrobenzamide (Compound L);

N−

1-methylpropyl-4-nitrobenzamide (Compound M);

N-tert-butyl-4-aminobenzamide (Compound N);

N-tert-butyl-3-aminobenzamide (Compound P); and

N-tert-butyl 4-nitrobenzamide (Compound Q).

43. The method of claim 42 wherein said benzamide is N-tert-butyl-4-acetamidobenzamide (Compound A).