Combination therapy including metal channel activators

JP2025529311APending Publication Date: 2025-09-04BIOHAVEN THERAPEUTICS LTD
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Patent Information

Application Number
JP2025513654
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2022-09-06
Filing Date
2023-09-06
Publication Date
2025-09-04

AI Technical Summary

Benefits of technology

を提供するために、経口投与グルタミン酸調節因子よりも大きいCmaxを有し得る。グルタミン酸調節因子の舌下製剤は、治療上有益な効果、及び場合によってはより迅速な治療効果を提供するために、経口投与グルタミン酸調節因子よりも早い又は小さいTmaxを有し得る。代替的に、グルタミン酸調節因子の舌下製剤は、1ミリグラムの薬剤当たり経口投与グルタミン酸調節因子よりも大きいAUCを有し得る。加えて、グルタミン酸調節因子が金属チャネル活性化剤をより効果的にし得るため、固有の副作用の軽減を伴って、より少ない量の金属チャネル活性化剤が同じ結果を達成するために必要とされ得る。

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Abstract

Pharmaceutical compositions are provided that include a metal channel activator and a glutamate modulator. Also provided are methods for treating depressive disorders, including administering the pharmaceutical compositions. Also provided are methods for treating neurological or neurodegenerative disorders, including administering the pharmaceutical compositions. Also provided are methods for treating pain disorders, including administering the pharmaceutical compositions.
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Claims

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

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

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

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

9. the metal channel activator 【Chemical 1】 The pharmaceutical composition according to any one of claims 1 to 8, which is a pharmaceutically acceptable salt thereof.

10. the metal channel activator 【Chemistry 2】 The pharmaceutical composition according to any one of claims 1 to 8, which is a pharmaceutically acceptable salt thereof.

11. 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 of 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 of any one of claims 1 to 12, wherein the glutamate modulator is riluzole or a pharmaceutically acceptable salt thereof.

14. 14. The pharmaceutical composition of claim 13, wherein the riluzole or a pharmaceutically acceptable salt thereof is in the form of a prodrug.

15. The prodrug of riluzole has the following structure: 【Chemistry 3】 wherein R ２３ But H, CH ３ , C.H. ２ CH ３ , C.H. ２ CH ２ CH ３ , C.H. ２ CCH, CH(CH ３ ) ２ , C.H. ２ CH (CH ３ ) ２ , CH(CH ３ ) CH ２ CH ３ , C.H. ２ OH, CH ２ OCH ２ Ph, CH ２ CH ２ OCH ２ Ph,CH(OH)CH ３ , C.H. ２ Ph, CH ２ (cyclohexyl), CH ２ (4-OH-Ph), (CH ２ ) ４ NH ２ , (CH ２ ) ３ NHC (NH ２ ) NH, CH ２ (3-indole), CH ２ (5-imidazole), CH ２ CO ２ H, CH ２ CH ２ CO ２ H, CH ２ CONH ２ , and C.H. ２ CH ２ CONH ２ 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is selected from the group consisting of:

16. The prodrug of riluzole has the following structure: 【Chemistry 4】 16. The pharmaceutical composition of claim 14 or 15, comprising:

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

18. 18. The method of claim 17, wherein the depressive disorder is major depressive disorder (MDD), severe 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 response, 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. Neurological or neurodegenerative disorders include amyotrophic lateral sclerosis, bipolar disorder, treatment-resistant depression and major depression, generalized anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive impairment, dementia, agitation, apathy, psychosis, post-traumatic stress disorder, irritability, disinhibition, learning disabilities, 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, alopecia, 20. The method of claim 19, wherein the condition is Zheimer'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's 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. 22. The method of claim 21, wherein the pain disorder is acute pain, chronic pain, neuropathic pain, nociceptive pain, or radicular pain.

23. 22. The method of claim 21, wherein the pain disorder is migraine, inflammatory pain, persistent pain, cancer pain, and post-surgical pain.

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

25. 1. A kit for treating a patient suffering from a disorder for which a glutamate modulator is clinically relevant, comprising: (a) a glutamate modulator according to any one of claims 200-463; and (b) instructions for administering said glutamate modulator together with a metal channel activator according to one of the methods of claims 17-23.

26. A pharmaceutical composition comprising a glutamate modulator according to any one of formulas 200-202, wherein said metal channel activator is a compound according to one of formulas 1-5.

27. 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. 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 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. 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 4.

30. 27. 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. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemistry 5】 glutamate modulators, 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; A metal channel activator according to: 【Chemistry 6】 wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl; and A is C ２～８ alkyl, and X is H, F, CF ３ , optionally substituted phenyl, or optionally substituted pyridinyl; Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, said chemical elements being independently C, H, O, N, S, F, Cl, or Br; R １ F, Cl, Br, CN, OCH ３ , CHF ２ , C.F. ３ , C １～４ -CO ２ -Alkyl, C １～４ Alkyl, —CH ２ CO ２ H, —CH ２ CO ２ CH ２ CH ３ , or -CH ２ CON (CH ３ ) ２ , or C １～５ hydroxyalkyl, and R ２ , R ３ , and R ４ are independently H, F, Cl, Br, I, or a substituent consisting of 2 to 5 chemical elements having a molecular weight of 15 Da to 200 Da, wherein said chemical elements are independently C, H, O, N, S, F, Cl, or Br, including pharmaceutically acceptable salts thereof.

32. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemistry 7】 glutamate modulators, 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; A metal channel activator according to any of the following: 【Chemistry 8】 and a metal channel activator, including a pharmaceutically acceptable salt thereof.

33. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemistry 9】 a glutamate modulator, including a pharmaceutically acceptable salt thereof; A metal channel activator according to: 【Chemistry 10】 wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl; and A is C ２～８ alkyl, and X is H, F, CF ３ , optionally substituted phenyl, or optionally substituted pyridinyl; Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, said chemical elements being independently C, H, O, N, S, F, Cl, or Br; R １ F, Cl, Br, CN, OCH ３ , CHF ２ , C.F. ３ , C １～４ -CO ２ -Alkyl, C １～４ Alkyl, —CH ２ CO ２ H, —CH ２ CO ２ CH ２ CH ３ , or -CH ２ CON (CH ３ ) ２ , or C １～５ hydroxyalkyl, and R ２ , R ３ , and R ４ are independently H, F, Cl, Br, I, or a substituent consisting of 2 to 5 chemical elements having a molecular weight of 15 Da to 200 Da, wherein said chemical elements are independently C, H, O, N, S, F, Cl, or Br, including pharmaceutically acceptable salts thereof.

34. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemistry 11】 a glutamate modulator, including a pharmaceutically acceptable salt thereof; A metal channel activator according to any of the following: 【Chemistry 12】 and a metal channel activator, including a pharmaceutically acceptable salt thereof.

35. The metal channel activator is 【Chemistry 13】 or a pharmaceutically acceptable salt thereof.

36. The metal channel activator is 【Chemistry 14】 or a pharmaceutically acceptable salt thereof.

37. The metal channel activator is 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

38. The metal channel activator is 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

39. The metal channel activator is 【Chemistry 17】 or a pharmaceutically acceptable salt thereof.

40. The metal channel activator is 【Chemistry 18】 or a pharmaceutically acceptable salt thereof.

41. The metal channel activator is 【Chemistry 19】 or a pharmaceutically acceptable salt thereof.

42. The metal channel activator is 【Chemistry 20】 or a pharmaceutically acceptable salt thereof.

43. The metal channel activator is 【Chemical formula 21】 or a pharmaceutically acceptable salt thereof.

44. The metal channel activator is 【Chemical 22】 or a pharmaceutically acceptable salt thereof.

45. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemical 23】 glutamate modulators, 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; 1. A metal channel activator according to: 【Chemistry 24】 In the formula, R １ H, halogen, CN, CH ２ C.N., C.F. ３ , C １ ~C ６ Alkyl, OCH ３ , (C=O)OCH ３ , O(C=O)CH ３ , OCF ３ , (CH ２ ) ｍ C ３ ~C ６ is selected from the group consisting of cycloalkyl, phenyl, and pyridyl; R ２ But H, F, OCH ３ , C.H. ３ , and CF ３ and R ３ and R ４ changes independently, H, F, Cl, CF ３ , OCF ３ , O.C. １ ~C ３ Alkyl, or C １ ~C ３ alkyl; R ５ But C １ ~C ６ Alkyl, (CHR ６ ) ｗ C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ CH ２ C ３ ~C ６ Cycloalkyl, CH ２ (CHR ６ ) ｗ C ３ ~C ６ Cycloalkyl, CR ６ =CH-C ３ ~C ６ Cycloalkyl, CH═CR ６ -C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, CH ２ (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, Ar, (CHR ６ ) ｗ Ar, CH ２ (CHR ６ ) ｗ Ar, (CHR ６ ) ｗ CH ２ Ar, and CH ２ -C(CH ３ ) ３ wherein w=0-3, Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl, and R ６ But C １ ~C ３ alkyl, and R' is H, CH ３ , C.H. ２ CH ３ or halogen, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ and all alkyl, cycloalkyl, aryl, and heteroaryl groups in Ar are independently selected from C １ ~C ３ Alkyl, halogen, OCH ３ , OCH ２ CH ３ , CN, and CF ３ and a metal channel activator, including a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents selected from the group consisting of:

46. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemistry 25】 glutamate modulators, 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; A metal channel activator according to: 【Chemical 26】 and a metal channel activator, including a pharmaceutically acceptable salt thereof.

47. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemical 27】 a glutamate modulator, including a pharmaceutically acceptable salt thereof; A metal channel activator according to: [Chemical Formula 28] In the formula, R １ H, halogen, CN, CH ２ C.N., C.F. ３ , C １ ~C ６ Alkyl, OCH ３ , (C=O)OCH ３ , O(C=O)CH ３ , OCF ３ , (CH ２ ) ｍ C ３ ~C ６ is selected from the group consisting of cycloalkyl, phenyl, and pyridyl; R ２ But H, F, OCH ３ , C.H. ３ , and CF ３ and R ３ and R ４ changes independently, H, F, Cl, CF ３ , OCF ３ , O.C. １ ~C ３ Alkyl, or C １ ~C ３ alkyl; R ５ But C １ ~C ６ Alkyl, (CHR ６ ) ｗ C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ CH ２ C ３ ~C ６ Cycloalkyl, CH ２ (CHR ６ ) ｗ C ３ ~C ６ Cycloalkyl, CR ６ =CH-C ３ ~C ６ Cycloalkyl, CH═CR ６ -C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, CH ２ (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, Ar, (CHR ６ ) ｗ Ar, CH ２ (CHR ６ ) ｗ Ar, (CHR ６ ) ｗ CH ２ Ar, and CH ２ -C(CH ３ ) ３ wherein w=0-3, Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl, and R ６ But C １ ~C ３ alkyl, and R' is H, CH ３ , C.H. ２ CH ３ or halogen, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ and all alkyl, cycloalkyl, aryl, and heteroaryl groups in Ar are independently selected from C １ ~C ３ Alkyl, halogen, OCH ３ , OCH ２ CH ３ , CN, and CF ３ and a metal channel activator, including a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents selected from the group consisting of:

48. 1. A pharmaceutical composition comprising a glutamate modulator according to: 【Chemical 29】 a glutamate modulator, including a pharmaceutically acceptable salt thereof; A metal channel activator according to: 【Chemistry 30】 and a metal channel activator, including a pharmaceutically acceptable salt thereof.

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

1.

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

4.

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

52. 52. The method of claim 51, wherein the depressive disorder is major depressive disorder (MDD), severe 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 response, 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. Neurological or neurodegenerative disorders include amyotrophic lateral sclerosis, bipolar disorder, treatment-resistant depression and major depression, generalized anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive impairment, dementia, agitation, apathy, psychosis, post-traumatic stress disorder, irritability, disinhibition, learning disabilities, 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, alopecia, 54. The method of claim 53, wherein the condition is Zheimer'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's 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. 56. The method of claim 55, wherein the pain disorder is acute pain, chronic pain, neuropathic pain, nociceptive pain, or radicular pain.

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

58. 1. A kit for treating a patient suffering from a disorder for which a metal channel activator is clinically relevant, comprising: (a) the metal channel activator; (b) instructions for administering the metal channel activator in combination with a glutamate modulator according to one of the methods of claims 51-57.

59. 1. A kit for treating a patient suffering from a disorder for which a glutamate modulator is clinically relevant, comprising: (a) the glutamate regulatory factor; (b) instructions for administering the glutamate modulator together with a metal channel activator according to one of the methods of claims 51-57.

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

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

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

63. The glutamate modulator is a compound according to 【Chemical 31】 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; The metal channel activator is a compound according to 【Chemical 32】 wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl; and A is C ２～８ alkyl, and X is H, F, CF ３ , optionally substituted phenyl, or optionally substituted pyridinyl; Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, said chemical elements being independently C, H, O, N, S, F, Cl, or Br; R １ F, Cl, Br, CN, OCH ３ , CHF ２ , C.F. ３ , C １～４ -CO ２ -Alkyl, C １～４ Alkyl, —CH ２ CO ２ H, —CH ２ CO ２ CH ２ CH ３ , or -CH ２ CON (CH ３ ) ２ , or C １～５ hydroxyalkyl, and R ２ , R ３ , and R ４ is independently H, F, Cl, Br, I, or a substituent consisting of 2 to 5 chemical elements having a molecular weight of 15 Da to 200 Da, wherein said chemical elements are independently C, H, O, N, S, F, Cl, or Br, including pharmaceutically acceptable salts thereof.

64. The glutamate modulator is a compound according to 【Chemical 33】 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; The metal channel activator is a compound selected from the following: 【Chemical 34】 63. The method of any one of claims 60 to 62, wherein the compound is:

65. The glutamate modulator is a compound according to 【Chemistry 35】 a compound, including pharmaceutically acceptable salts thereof, The metal channel activator is a compound according to 【Chemical 36】 wherein D is optionally substituted cyclobutyl, optionally substituted phenyl, optionally substituted isoxazolyl, optionally substituted pyridinyl, isopropyl, or t-butyl; and A is C ２～８ alkyl, and X is H, F, CF ３ , optionally substituted phenyl, or optionally substituted pyridinyl; Y is H, F, Cl, Br, I, or a moiety having a molecular weight of 15 Da to 300 Da and consisting of 2 to 5 chemical elements, said chemical elements being independently C, H, O, N, S, F, Cl, or Br; R １ F, Cl, Br, CN, OCH ３ , CHF ２ , C.F. ３ , C １～４ -CO ２ -Alkyl, C １～４ Alkyl, —CH ２ CO ２ H, —CH ２ CO ２ CH ２ CH ３ , or -CH ２ CON (CH ３ ) ２ , or C １～５ hydroxyalkyl, and R ２ , R ３ , and R ４ is independently H, F, Cl, Br, I, or a substituent consisting of 2 to 5 chemical elements having a molecular weight of 15 Da to 200 Da, wherein said chemical elements are independently C, H, O, N, S, F, Cl, or Br, including pharmaceutically acceptable salts thereof.

66. The glutamate modulator is a compound according to 【Chemical 37】 a compound, including pharmaceutically acceptable salts thereof, The metal channel activator is a compound selected from the following: 【Chemical Formula 38】 63. The method of any one of claims 60 to 62, wherein the compound is:

67. The metal channel activator is 【Chemical Formula 39】 or a pharmaceutically acceptable salt thereof.

68. The metal channel activator is 【Chemistry 40】 or a pharmaceutically acceptable salt thereof.

69. The metal channel activator is 【Chemistry 41】 or a pharmaceutically acceptable salt thereof.

70. The metal channel activator is 【Chemistry 42】 or a pharmaceutically acceptable salt thereof.

71. The metal channel activator is 【Chemistry 43】 or a pharmaceutically acceptable salt thereof.

72. The metal channel activator is 【Chemical 44】 or a pharmaceutically acceptable salt thereof.

73. The metal channel activator is 【Chemistry 45】 or a pharmaceutically acceptable salt thereof.

74. The metal channel activator is 【Chemistry 46】 or a pharmaceutically acceptable salt thereof.

75. The metal channel activator is 【Chemistry 47】 or a pharmaceutically acceptable salt thereof.

76. The metal channel activator is 【Chemistry 48】 or a pharmaceutically acceptable salt thereof.

77. The glutamate modulator is a compound according to 【Chemistry 49】 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; The metal channel activator is a compound according to 【Chemistry 50】 In the formula, R １ H, halogen, CN, CH ２ C.N., C.F. ３ , C １ ~C ６ Alkyl, OCH ３ , (C=O)OCH ３ , O(C=O)CH ３ , OCF ３ , (CH ２ ) ｍ C ３ ~C ６ is selected from the group consisting of cycloalkyl, phenyl, and pyridyl; R ２ But H, F, OCH ３ , C.H. ３ , and CF ３ and R ３ and R ４ changes independently, H, F, Cl, CF ３ , OCF ３ , O.C. １ ~C ３ Alkyl, or C １ ~C ３ alkyl; R ５ But C １ ~C ６ Alkyl, (CHR ６ ) ｗ C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ CH ２ C ３ ~C ６ Cycloalkyl, CH ２ (CHR ６ ) ｗ C ３ ~C ６ Cycloalkyl, CR ６ =CH-C ３ ~C ６ Cycloalkyl, CH═CR ６ -C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, CH ２ (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, Ar, (CHR ６ ) ｗ Ar, CH ２ (CHR ６ ) ｗ Ar, (CHR ６ ) ｗ CH ２ Ar, and CH ２ -C(CH ３ ) ３ wherein w=0-3, Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl, and R ６ But C １ ~C ３ alkyl, and R' is H, CH ３ , C.H. ２ CH ３ or halogen, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ and all alkyl, cycloalkyl, aryl, and heteroaryl groups in Ar are independently selected from C １ ~C ３ Alkyl, halogen, OCH ３ , OCH ２ CH ３ , CN, and CF ３ 63. The method of any one of claims 60 to 62, wherein the compound is, including pharmaceutically acceptable salts thereof, optionally substituted with one or two substituents selected from the group consisting of:

78. The glutamate modulator is a compound according to 【Chemistry 51】 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; The metal channel activator is a compound according to 【Chemistry 52】 63. The method of any one of claims 60 to 62, which is a compound, including pharmaceutically acceptable salts thereof.

79. The glutamate modulator is a compound according to 【Chemistry 53】 a compound, including pharmaceutically acceptable salts thereof, The metal channel activator is a compound according to 【Chemical 54】 In the formula, R １ H, halogen, CN, CH ２ C.N., C.F. ３ , C １ ~C ６ Alkyl, OCH ３ , (C=O)OCH ３ , O(C=O)CH ３ , OCF ３ , (CH ２ ) ｍ C ３ ~C ６ is selected from the group consisting of cycloalkyl, phenyl, and pyridyl; R ２ But H, F, OCH ３ , C.H. ３ , and CF ３ and R ３ and R ４ changes independently, H, F, Cl, CF ３ , OCF ３ , O.C. １ ~C ３ Alkyl, or C １ ~C ３ alkyl; R ５ But C １ ~C ６ Alkyl, (CHR ６ ) ｗ C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ CH ２ C ３ ~C ６ Cycloalkyl, CH ２ (CHR ６ ) ｗ C ３ ~C ６ Cycloalkyl, CR ６ =CH-C ３ ~C ６ Cycloalkyl, CH═CR ６ -C ３ ~C ６ cycloalkyl, (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, CH ２ (CHR ６ ) ｗ C ５ ~C ６ Cycloalkenyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, Ar, (CHR ６ ) ｗ Ar, CH ２ (CHR ６ ) ｗ Ar, (CHR ６ ) ｗ CH ２ Ar, and CH ２ -C(CH ３ ) ３ wherein w=0-3, Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl, and R ６ But C １ ~C ３ alkyl, and R' is H, CH ３ , C.H. ２ CH ３ or halogen, and R １ , R ２ , R ３ , R ４ , R ５ , R ６ and all alkyl, cycloalkyl, aryl, and heteroaryl groups in Ar are independently selected from C １ ~C ３ Alkyl, halogen, OCH ３ , OCH ２ CH ３ , CN, and CF ３ 63. The method of any one of claims 60 to 62, wherein the compound is, including pharmaceutically acceptable salts thereof, optionally substituted with one or two substituents selected from the group consisting of:

80. The glutamate modulator is a compound according to 【Chemistry 55】 a compound, including pharmaceutically acceptable salts thereof, The metal channel activator is a compound according to 【Chemical 56】 63. The method of any one of claims 60 to 62, which is a compound, including pharmaceutically acceptable salts thereof.

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

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