Combination therapy comprising metal channel activators

By combining metal channel activators with glutamate modulators, combined therapy is formed, and the existing treatment is not effective, achieving significant therapeutic effects on depression disorders, pain disorders, and neurodegenerative or neurodegenerative disorders.

CN120500475APending Publication Date: 2025-08-15BIOHAVEN THERAPEUTICS LTD
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Patent Information

Application Number
CN202380076847.5
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Priority Date
2022-09-06
Filing Date
2023-09-06
Publication Date
2025-08-15

AI Technical Summary

Technical Problem

Existing metal channel activators have limited therapeutic effects in the treatment of neurodegenerative and neurodegenerative disorders, especially inadequate treatment of depression, pain disorders and related neurodegenerative or neurodegenerative disorders.

Method used

Combining metal channel activators with glutamate modulators is formed to form a combination therapy to target different molecular targets and enhance the therapeutic effect.

Benefits of technology

Through combined therapy, the treatment effect on depression, pain disorders, and neurodegenerative or neurodegenerative conditions has been significantly improved, providing better treatment results.

✦ Generated by Eureka AI based on patent content.

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Abstract

A pharmaceutical composition comprising a metal channel activator and a glutamic acid modulator is provided. Also provided is a method of treating depressive disorder comprising administering the pharmaceutical composition. Also provided is a method of treating a neurological or neurodegenerative disorder comprising administering the pharmaceutical composition. Also provided is a method of treating a pain disorder comprising administering the pharmaceutical composition.
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Claims

1. A pharmaceutical composition comprising a metal channel activator and a glutamate modulator.

2. The pharmaceutical composition according to claim 1, wherein the metal channel activator is a potassium channel activator.

3. The pharmaceutical composition according to claim 2, wherein the potassium channel activator is a Kv7 channel activator.

4. The pharmaceutical composition of claim 3, wherein the Kv7 channel activator is a Kv7.1 channel activator, a Kv7.2 channel activator, a Kv7.3 channel activator, a Kv7.4 channel activator, a Kv7.5 channel activator, or any combination thereof.

5. The pharmaceutical composition according to claim 3 or 4, wherein the Kv7 channel activator is a Kv7.2 / 7.3 channel activator.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the metal channel activator is selected from one or more compounds according to any one or more of Formulas 1 to 171.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the glutamate modulator is selected from one or more compounds according to any one or more of Formulas 200 to 463.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein the glutamate modulator is selected from one or more compounds according to any one or more of Formulas 200 to 463, and wherein the metal channel activator is selected from one or more disclosed compounds according to any one or more of Formulas 1 to 171.

9. according to the pharmaceutical composition described in any one of claims 1 to 8, wherein the metal channel activator is or a pharmaceutically acceptable salt thereof.

10. according to the pharmaceutical composition described in any one of claims 1 to 8, wherein said metal channel activator is or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the glutamate modulator is riluzole, memantine, n-acetylcysteine, amantadine, topiramate, pregabalin, lamotrigine, ketamine, s-ketamine, AZD8108, AZD6765 (lanicemine), BHV-4157 (troriluzole), dextromethorphan, AV-101, CERC-301, GLY-13, and pharmaceutically acceptable salts, prodrugs, or analogs thereof.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the glutamate modulator or a pharmaceutically acceptable salt thereof is in the form of a prodrug.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the glutamate modulator is riluzole or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 13 , wherein the riluzole or a pharmaceutically acceptable salt thereof is in the form of a prodrug.

15. The pharmaceutical composition according to claim 14, wherein the prodrug of riluzole has the following structure: where R 23 Selected from the group consisting of: H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CH2OCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2 and CH2CH2CONH2.

16. The pharmaceutical composition according to claim 14 or 15, wherein the prodrug of riluzole has the following structure:

17. A method for treating a depressive disorder, comprising administering the pharmaceutical composition according to any one of claims 1 to 16.

18. The method of claim 17, wherein the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof.

19. A method of treating a neurological or neurodegenerative disorder comprising administering a pharmaceutical composition according to any one of claims 1 to 16.

20. The method of claim 19, wherein the neurological or neurodegenerative disorder is amyotrophic lateral sclerosis, bipolar disorder, treatment-resistant and major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychosis, post-traumatic stress disorder, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorder, Rett syndrome, eating disorders, conduct disorders, neurodegenerative disorders, pain disorders, post-traumatic stress disorder (PTSD), supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, disease), mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, spinocerebellar ataxia (SCA), cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's disease, Huntington's disease, or any combination thereof.

21. A method of treating a pain disorder comprising administering a pharmaceutical composition according to any one of claims 1 to 16.

22. The method of claim 21, wherein the pain disorder is acute pain, chronic pain, neuropathic pain, nociceptive pain, radicular pain.

23. The method of claim 21, wherein the pain disorder is migraine, inflammatory pain, persistent pain, cancer pain, and postoperative pain.

24. A kit for treating a patient suffering from a condition clinically relevant to a metal channel activator, the kit comprising: (a) a metal channel activator according to any one of Formulas 1 to 171; as well as (b) instructions for administering the metal channel activator in combination with a glutamate modulator by one of the methods of claims 17 to 23.

25. A kit for treating a patient suffering from a condition clinically relevant to a glutamate modulator, the kit comprising: (a) a glutamate modulator according to any one of claims 200 to 463; as well as (b) instructions for administering the glutamate modulator together with the metal channel activator by one of the methods of claims 17 to 23.

26. A pharmaceutical composition comprising a glutamate modulator according to one of Formulas 200 to 202, and the metal channel activator is a compound according to one of Formulas 1 to 5.

27. The pharmaceutical composition of claim 26, wherein the glutamate modulator is a compound according to Formula 200, and the metal channel activator is a compound according to Formula 2.

28. The pharmaceutical composition of claim 26, wherein the glutamate modulator is a compound according to Formula 200, and the metal channel activator is a compound according to any one of Formula 2-1, Formula 2-2, Formula 2-3, Formula 2-4, Formula 2-5, Formula 2-6, Formula 2-7, Formula 2-8, Formula 2-9, or Formula 2-10.

29. The pharmaceutical composition of claim 26, wherein the glutamate modulator is a compound according to Formula 200, and the metal channel activator is a compound according to Formula 4.

30. The pharmaceutical composition of claim 26, wherein the glutamate modulator is a compound according to Formula 201 and the metal channel activator is a compound according to Formula 5.

31. A pharmaceutical composition comprising: a glutamate modulator according to: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and Metal channel activators according to: wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridyl, isopropyl or tert-butyl; A is C 2-8 alkyl; X is H, F, CF3, optionally substituted phenyl or optionally substituted pyridyl; Y is H, F, Cl, Br, I or a moiety having a molecular weight of 15 to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or Br; R 1 It is F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl, -CH2CO2H, -CH2CO2CH2CH3 or -CH2CON(CH3)2 or C 1-5 hydroxyalkyl; and R 2 、R 3 and R 4 It is independently H, F, Cl, Br, I or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or Br, including pharmaceutically acceptable salts thereof.

32. A pharmaceutical composition comprising: a glutamate modulator according to: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and A metal channel activator according to any of the following: Including pharmaceutically acceptable salts thereof.

33. A pharmaceutical composition comprising: a glutamate modulator according to: including pharmaceutically acceptable salts thereof; and Metal channel activators according to: wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridyl, isopropyl or tert-butyl; A is C 2-8 alkyl; X is H, F, CF3, optionally substituted phenyl or optionally substituted pyridyl; Y is H, F, Cl, Br, I or a moiety having a molecular weight of 15 to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or Br; R 1 It is F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl, -CH2CO2H, -CH2CO2CH2CH3 or -CH2CON(CH3)2 or C 1-5 hydroxyalkyl; and R 2 、R 3 and R 4 It is independently H, F, Cl, Br, I or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or Br, including pharmaceutically acceptable salts thereof.

34. A pharmaceutical composition comprising: a glutamate modulator according to: including pharmaceutically acceptable salts thereof; and A metal channel activator according to any of the following: Including pharmaceutically acceptable salts thereof.

35. according to the pharmaceutical composition described in any one of claims 31 to 34, wherein said metal channel activator is compound or a pharmaceutically acceptable salt thereof.

36. according to the pharmaceutical composition described in any one of claims 31 to 34, wherein the metal channel activator is compound or a pharmaceutically acceptable salt thereof.

37. according to the pharmaceutical composition described in any one of claims 31 to 34, wherein the metal channel activator is compound or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition according to any one of claims 31 to 34, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

39. The pharmaceutical composition according to any one of claims 31 to 34, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition according to any one of claims 31 to 34, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

41. according to the pharmaceutical composition described in any one of claims 31 to 34, wherein the metal channel activator is compound or a pharmaceutically acceptable salt thereof.

42. according to the pharmaceutical composition described in any one of claims 31 to 34, wherein the metal channel activator is compound or a pharmaceutically acceptable salt thereof.

43. according to the pharmaceutical composition described in any one of claims 31 to 34, wherein the metal channel activator is compound or a pharmaceutically acceptable salt thereof.

44. according to the pharmaceutical composition described in any one of claims 31 to 34, wherein the metal channel activator is compound or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition comprising: a glutamate modulator according to: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and Metal channel activators according to: wherein R1 is selected from the group consisting of: H, halogen, CN, CH2CN, CF3, C1-C6 alkyl, OCH3, (C═O)OCH3, O(C═O)CH3, OCF3, (CH2) m C3-C6 cycloalkyl, phenyl and pyridyl; R2 is selected from the group consisting of: H, F, OCH3, CH3 and CF3; R3 and R4 are independently varied and are selected from the group consisting of: H, F, Cl, CF3, OCF3, OC1-C3 alkyl or C1-C3 alkyl; and R5 is selected from the group consisting of: C1-C6 alkyl, (CHR6) w C3-C6 cycloalkyl, (CHR6) w CH2C3-C6 cycloalkyl, CH2(CHR6) w C3-C6 cycloalkyl, CR6═CH-C3-C6 cycloalkyl, CH═CR6-C3-C6 cycloalkyl, (CHR6) w C5-C6 cycloalkenyl, CH2(CHR6) w C5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6) w Ar, CH2(CHR6) w Ar, (CHR6) w CH2Ar and CH2-C(CH3)3; wherein w=0-3; Ar is phenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, thienyl or pyridyl; and R6 is C1-C3 alkyl; R' is selected from the group consisting of H, CH3, CH2CH3 or halogen; wherein all alkyl, cycloalkyl, aryl and heteroaryl groups in R1, R2, R3, R4, R5, R6 and Ar are optionally substituted with one or two substituents independently selected from the group consisting of C1-C3 alkyl, halogen, OCH3, OCH2CH3, CN and CF3, including pharmaceutically acceptable salts thereof.

46. A pharmaceutical composition comprising: a glutamate modulator according to: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and Metal channel activators according to: Including pharmaceutically acceptable salts thereof.

47. A pharmaceutical composition comprising: a glutamate modulator according to: including pharmaceutically acceptable salts thereof; and Metal channel activators according to: wherein R1 is selected from the group consisting of: H, halogen, CN, CH2CN, CF3, C1-C6 alkyl, OCH3, (C═O)OCH3, O(C═O)CH3, OCF3, (CH2) m C3-C6 cycloalkyl, phenyl and pyridyl; R2 is selected from the group consisting of: H, F, OCH3, CH3 and CF3; R3 and R4 are independently varied and are selected from the group consisting of: H, F, Cl, CF3, OCF3, OC1-C3 alkyl or C1-C3 alkyl; and R5 is selected from the group consisting of: C1-C6 alkyl, (CHR6) w C3-C6 cycloalkyl, (CHR6) w CH2C3-C6 cycloalkyl, CH2(CHR6) w C3-C6 cycloalkyl, CR6═CH-C3-C6 cycloalkyl, CH═CR6-C3-C6 cycloalkyl, (CHR6) w C5-C6 cycloalkenyl, CH2(CHR6) w C5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6) w Ar, CH2(CHR6) w Ar, (CHR6) w CH2Ar and CH2-C(CH3)3; wherein w=0-3; Ar is phenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, thienyl or pyridyl; and R6 is C1-C3 alkyl; R' is selected from the group consisting of H, CH3, CH2CH3 or halogen; wherein all alkyl, cycloalkyl, aryl and heteroaryl groups in R1, R2, R3, R4, R5, R6 and Ar are optionally substituted with one or two substituents independently selected from the group consisting of C1-C3 alkyl, halogen, OCH3, OCH2CH3, CN and CF3, including pharmaceutically acceptable salts thereof.

48. A pharmaceutical composition comprising: a glutamate modulator according to: including pharmaceutically acceptable salts thereof; and Metal channel activators according to: Including pharmaceutically acceptable salts thereof.

49. The pharmaceutical composition of any one of claims 26 to 48, wherein the weight ratio of the metal channel activator to the glutamate modulator ranges from about 1:30 to about 1:

1.

50. The pharmaceutical composition of claim 49, wherein the weight ratio of the metal channel activator to the glutamate modulator is about 1:

4.

51. A method of treating a depressive disorder, the method comprising administering a pharmaceutical composition according to any one of claims 26 to 48.

52. The method of claim 51, wherein the depressive disorder is major depressive disorder (MDD), disruptive mood dysregulation disorder, persistent depressive disorder, bipolar spectrum disorder, postpartum depression, premenstrual dysphoric disorder (PMDD), seasonal affective disorder (SAD), atypical depression, treatment-resistant depression (TRD), depression associated with agitation or anxiety, adjustment disorder with depressed mood, prolonged depressive reaction, or a combination thereof.

53. A method of treating a neurological or neurodegenerative disorder comprising administering a pharmaceutical composition according to any one of claims 26 to 48.

54. The method of claim 53, wherein the neurological or neurodegenerative disorder is amyotrophic lateral sclerosis, bipolar disorder, treatment-resistant and major depressive disorder, generalized anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, dementia, agitation, apathy, psychosis, post-traumatic stress disorder, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorder, Rett syndrome, eating disorders, conduct disorders, neurodegenerative disorders, pain disorders, post-traumatic stress disorder (PTSD), supranuclear anesthesia, paralysis, frontotemporal dementia, frontotemporal lobar degeneration, delirium, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, drug addiction, tinnitus, mental retardation, obsessive-compulsive disorder, spinal muscular atrophy, radiation therapy, multiple sclerosis, chronic cerebellar ataxia, spinocerebellar ataxia (SCA), cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, schizophrenia, fragile X syndrome, Parkinson's disease, Huntington's disease, or any combination thereof.

55. A method of treating a pain disorder comprising administering a pharmaceutical composition according to any one of claims 26 to 48.

56. The method of claim 55, wherein the pain disorder is acute pain, chronic pain, neuropathic pain, nociceptive pain, radicular pain.

57. The method of claim 56, wherein the pain disorder is migraine, inflammatory pain, persistent pain, cancer pain, and postoperative pain.

58. A kit for treating a patient suffering from a condition clinically relevant to a metal channel activator, the kit comprising: (a) the metal channel activator; as well as (b) instructions for administering the metal channel activator in combination with a glutamate modulator by one of the methods of claims 51 to 57.

59. A kit for treating a patient suffering from a condition clinically relevant to a glutamate modulator, the kit comprising: (a) the glutamate modulator; as well as (b) instructions for administering the glutamate modulator together with the metal channel activator by one of the methods of claims 51 to 57.

60. A method of treating a depressive disorder, the method comprising administering one or more metal channel activators according to Formulas 1 to 171; and One or more glutamate modulators according to formulas 200 to 463.

61. A method of treating a neurological or neurodegenerative disorder, the method comprising administering one or more metal channel activators according to Formulas 1 to 171; and One or more glutamate modulators according to formulas 200 to 463.

62. A method of treating pain or a pain disorder, the method comprising administering one or more metal channel activators according to Formulas 1 to 171; and One or more glutamate modulators according to formulas 200 to 463.

63. The method according to any one of claims 60 to 62, wherein: The glutamate modulator is a compound according to: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound according to: wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridyl, isopropyl or tert-butyl; A is C 2-8 alkyl; X is H, F, CF3, optionally substituted phenyl or optionally substituted pyridyl; Y is H, F, Cl, Br, I or a moiety having a molecular weight of 15 to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or Br; R 1 It is F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl, -CH2CO2H, -CH2CO2CH2CH3 or -CH2CON(CH3)2 or C 1-5 hydroxyalkyl; and R 2 、R 3 and R 4 are independently H, F, Cl, Br, I or a substituent having a molecular weight of 15 to 200 Da and consisting of 2 to 5 chemical elements, wherein The chemical elements are independently C, H, O, N, S, F, Cl or Br, including pharmaceutically acceptable salts thereof.

64. The method of any one of claims 60 to 62, wherein the glutamate modulator is a compound according to: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound selected from the following: Including pharmaceutically acceptable salts thereof.

65. The method of any one of claims 60 to 62, wherein the glutamate modulator is a compound according to: including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound according to: wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridyl, isopropyl or tert-butyl; A is C 2-8 alkyl; X is H, F, CF3, optionally substituted phenyl or optionally substituted pyridyl; Y is H, F, Cl, Br, I or a moiety having a molecular weight of 15 to 300 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl or Br; R 1 It is F, Cl, Br, CN, OCH3, CHF2, CF3, C 1-4 -CO2-alkyl, C 1-4 Alkyl, -CH2CO2H, -CH2CO2CH2CH3 or -CH2CON(CH3)2 or C 1-5 hydroxyalkyl; and R 2 、R 3 and R 4 are independently H, F, Cl, Br, I or a substituent having a molecular weight of 15 to 200 Da and consisting of 2 to 5 chemical elements, wherein The chemical elements are independently C, H, O, N, S, F, Cl or Br, including pharmaceutically acceptable salts thereof.

66. The method of any one of claims 60 to 62, wherein the glutamate modulator is a compound according to: including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound selected from the following: Including pharmaceutically acceptable salts thereof.

67. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

68. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

69. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

70. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

71. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

72. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

73. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

74. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

75. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

76. The method of any one of claims 60 to 66, wherein the metal channel activator is a compound or a pharmaceutically acceptable salt thereof.

77. The method of any one of claims 60 to 62, wherein: Glutamate modulators are compounds based on: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound according to: wherein R1 is selected from the group consisting of: H, halogen, CN, CH2CN, CF3, C1-C6 alkyl, OCH3, (C═O)OCH3, O(C═O)CH3, OCF3, (CH2) m C3-C6 cycloalkyl, phenyl and pyridyl; R2 is selected from the group consisting of: H, F, OCH3, CH3 and CF3; R3 and R4 are independently varied and are selected from the group consisting of: H, F, Cl, CF3, OCF3, OC1-C3 alkyl or C1-C3 alkyl; and R5 is selected from the group consisting of: C1-C6 alkyl, (CHR6) w C3-C6 cycloalkyl, (CHR6) w CH2C3-C6 cycloalkyl, CH2(CHR6) w C3-C6 cycloalkyl, CR6═CH-C3-C6 cycloalkyl, CH═CR6-C3-C6 cycloalkyl, (CHR6) w C5-C6 cycloalkenyl, CH2(CHR6) w C5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6) w Ar, CH2(CHR6) w Ar, (CHR6) w CH2Ar and CH2-C(CH3)3; wherein w=0-3; Ar is phenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, thienyl or pyridyl; and R6 is C1-C3 alkyl; R' is selected from the group consisting of H, CH3, CH2CH3 or halogen; wherein all alkyl, cycloalkyl, aryl and heteroaryl groups in R1, R2, R3, R4, R5, R6 and Ar are optionally substituted with one or two substituents independently selected from the group consisting of C1-C3 alkyl, halogen, OCH3, OCH2CH3, CN and CF3, including pharmaceutically acceptable salts thereof.

78. The method of any one of claims 60 to 62, wherein the glutamate modulator is a compound according to: wherein R23 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH2CCH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2OH, CHOCH2Ph, CH2CH2OCH2Ph, CH(OH)CH3, CH2Ph, CH2(cyclohexyl), CH2(4-OH-Ph), (CH2)4NH2, (CH2)3NHC(NH2)NH, CH2(3-indole), CH2(5-imidazole), CH2CO2H, CH2CH2CO2H, CH2CONH2, and CH2CH2CONH2, including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound according to: Including pharmaceutically acceptable salts thereof.

79. The method of any one of claims 60 to 62, wherein the glutamate modulator is a compound according to: including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound according to: wherein R1 is selected from the group consisting of: H, halogen, CN, CH2CN, CF3, C1-C6 alkyl, OCH3, (C═O)OCH3, O(C═O)CH3, OCF3, (CH2) m C3-C6 cycloalkyl, phenyl and pyridyl; R2 is selected from the group consisting of: H, F, OCH3, CH3 and CF3; R3 and R4 are independently varied and are selected from the group consisting of: H, F, Cl, CF3, OCF3, OC1-C3 alkyl or C1-C3 alkyl; and R5 is selected from the group consisting of: C1-C6 alkyl, (CHR6) w C3-C6 cycloalkyl, (CHR6) w CH2C3-C6 cycloalkyl, CH2(CHR6) w C3-C6 cycloalkyl, CR6═CH-C3-C6 cycloalkyl, CH═CR6-C3-C6 cycloalkyl, (CHR6) w C5-C6 cycloalkenyl, CH2(CHR6) w C5-C6 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ar, (CHR6) w Ar, CH2(CHR6) w Ar, (CHR6) w CH2Ar and CH2-C(CH3)3; wherein w=0-3; Ar is phenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, thienyl or pyridyl; and R6 is C1-C3 alkyl; R' is selected from the group consisting of H, CH3, CH2CH3 or halogen; wherein all alkyl, cycloalkyl, aryl and heteroaryl groups in R1, R2, R3, R4, R5, R6 and Ar are optionally substituted with one or two substituents independently selected from the group consisting of C1-C3 alkyl, halogen, OCH3, OCH2CH3, CN and CF3, including pharmaceutically acceptable salts thereof.

80. The method of any one of claims 60 to 62, wherein the glutamate modulator is a compound according to: including pharmaceutically acceptable salts thereof; and The metal channel activator is a compound according to: Including pharmaceutically acceptable salts thereof.

81. The method of any one of claims 60 to 80, wherein the metal channel activator and the glutamate modulator are administered in a weight ratio ranging from about 1:30 to 1:

1.

82. The method of claim 81, wherein the weight ratio of the metal channel activator to the glutamate modulator is about 1:4.

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