USE OF BENZO-HETEROARYL SULFAMIDE DERIVATIVES AS NEUROPROTECTIVE AGENTS

Abstract

The present invention is a methods for neuroprotection, for treating an acute neurodegenerative disorder, for treating a chronic neurodegenerative disorder and/or for preventing neuron death or damage following brain, head and/or spinal cord trauma or injury comprising administering to a subject in need thereof a therapeutically effective amount of one or more novel benzo-heteroaryl sulfamide derivatives of formula (I) as herein defined.

Description

Claims

1. A method for neuroprotection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I)

2. The method of claim 1 wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano and nitro;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are each independently selected from the group consisting of hydrogen, methyl and ethyl;or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl;or a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein R1 is selected from the group consisting of hydrogen, 5-chloro, 5-fluoro, 5-bromo, 4-bromo, 7-fluoro, 5-trifluoromethyl and 5-cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each hydrogen; alternatively R3 is hydrogen and R4 is ethyl;or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 7 membered, saturated, partially unsaturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein R1 is hydrogen;X—Y is —S—CH—;A is —CH2—;R2 is hydrogen;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 membered ring structure selected from the group consisting of pyrrolidinyl and imidazolyl;or a pharmaceutically acceptable salt thereof.

8. The method of claim 2, wherein the compound of formula (I) is selected from the group consisting of

9. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide; N-[(5-fluorobenzo[b]thien-3-yl)methyl]-sulfamide; and pharmaceutically acceptable salts thereof.

10. A method for neuroprotection comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide and pharmaceutically acceptable salts thereof.

11. A method of treating an acute neurodegenerative disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)

12. The method of claim 11, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano and nitro;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are each independently selected from the group consisting of hydrogen, methyl and ethyl;or a pharmaceutically acceptable salt thereof.

13. The method of claim 2, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl;or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein R1 is selected from the group consisting of hydrogen, 5-chloro, 5-fluoro, 5-bromo, 4-bromo, 7-fluoro, 5-trifluoromethyl and 5-cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each hydrogen; alternatively R3 is hydrogen and R4 is ethyl;or a pharmaceutically acceptable salt thereof.

15. The method of claim 11, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 7 membered, saturated, partially unsaturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

17. The method of claim 16, wherein R1 is hydrogen;X—Y is —S—CH—;A is —CH2—;R2 is hydrogen;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 membered ring structure selected from the group consisting of pyrrolidinyl and imidazolyl;or a pharmaceutically acceptable salt thereof.

18. The method of claim 12, wherein the compound of formula (I) is selected from the group consisting of

19. The method of claim 11, wherein the compound of formula (I) is selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide; N-[(5-fluorobenzo[b]thien-3-yl)methyl]-sulfamide; and pharmaceutically acceptable salts thereof.

20. A method of treating an acute neurodegenerative disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide and pharmaceutically acceptable salts thereof.

21. A method of treating a chronic neurodegenerative disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)

22. The method of claim 21, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano and nitro;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are each independently selected from the group consisting of hydrogen, methyl and ethyl;or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl;or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein R1 is selected from the group consisting of hydrogen, 5-chloro, 5-fluoro, 5-bromo, 4-bromo, 7-fluoro, 5-trifluoromethyl and 5-cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each hydrogen; alternatively R3 is hydrogen and R4 is ethyl;or a pharmaceutically acceptable salt thereof.

25. The method of claim 21, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 7 membered, saturated, partially unsaturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein R1 is hydrogen;X—Y is —S—CH—;A is —CH2—;R2 is hydrogen;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 membered ring structure selected from the group consisting of pyrrolidinyl and imidazolyl;or a pharmaceutically acceptable salt thereof.

28. The method of claim 22, wherein the compound of formula (I) is selected from the group consisting of

29. The method of claim 21, wherein the compound of formula (I) is selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide; N-[(5-fluorobenzo[b]thien-3-yl)methyl]-sulfamide; and pharmaceutically acceptable salts thereof.

30. A method of treating a chronic neurodegenerative disorder comprising administering to a subject in need thereof, a therapeutically effective amount of a compound selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide and pharmaceutically acceptable salts thereof.

31. A method for preventing neuron death or damage following brain, head or spinal cord trauma or injury comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I)

32. The method of claim 31, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano and nitro;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are each independently selected from the group consisting of hydrogen, methyl and ethyl;or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each independently selected from the group consisting of hydrogen and ethyl;or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein R1 is selected from the group consisting of hydrogen, 5-chloro, 5-fluoro, 5-bromo, 4-bromo, 7-fluoro, 5-trifluoromethyl and 5-cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is hydrogen;R3 and R4 are each hydrogen; alternatively R3 is hydrogen and R4 is ethyl;or a pharmaceutically acceptable salt thereof.

35. The method of claim 31, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 7 membered, saturated, partially unsaturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

36. The method of claim 35, wherein R1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl and cyano;X—Y is selected from the group consisting of —S—CH—, —O—CH—, —O—C(CH3)—, —N(CH3)—CH— and —CH═CH—CH—;A is selected from the group consisting of —CH2— and —CH(CH3)—;R2 is selected from the group consisting of hydrogen and methyl;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated or aromatic ring structure, optionally containing one to two additional heteroatoms independently selected from the group consisting of O, N and S;or a pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein R1 is hydrogen;X—Y is —S—CH—;A is —CH2—;R2 is hydrogen;R3 and R4 are taken together with the nitrogen atom to which they are bound to form a 5 membered ring structure selected from the group consisting of pyrrolidinyl and imidazolyl;or a pharmaceutically acceptable salt thereof.

38. The method of claim 32, wherein the compound of formula (I) is selected from the group consisting of

39. The method of claim 31, wherein the compound of formula (I) is selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide; N-[(5-fluorobenzo[b]thien-3-yl)methyl]-sulfamide; and pharmaceutically acceptable salts thereof.

40. A method for preventing neuron death or damage following brain, head or spinal cord trauma or injury comprising administering to a subject in need thereof, a therapeutically effective amount of a compound selected from the group consisting of N-(benzo[b]thien-3-ylmethyl)-sulfamide and pharmaceutically acceptable salts thereof.