Use of Benzo-Heteroaryl Sulfamide Derivatives for the Treatment of Disease Modification / Epileptogenesis

Abstract

The present invention is a method for treating, preventing, reversing, arresting or inhibiting the occurrence, development and maturation of seizures or seizure-related disorders. More specifically, the present invention is directed to methods for the use of benzo-heteroaryl sulfamide derivatives of formula (I) as described herein to therapeutically or prophylactically treat, prevent, reverse, arrest or inhibit epileptogenesis and epilepsy.

Description

Claims

1. A method for treating epileptogenesis, comprising administering to a patient in need of treatment with an anti-epileptogenic drug (an AEGD) a therapeutically effective amount of a compound of 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 N-(benzo[b]thien-3-yl methyl)-sulfamide;N-[(5-chlorobenzo[b]thien-3-yl)methyl]-sulfamide;N-(3-benzofuranylmethyl)-sulfamide;N-[(5-fluorobenzo[b]thien-3-yl)methyl]-sulfamide;N-(1-benzo[b]thien-3-ylethyl)-sulfamide;N-(1-naphthalenylmethyl)-sulfamide;N-[(2-methyl-3-benzofuranyl )methyl]-sulfamide;N-[(5-bromobenzo[b]thien-3-yl)methyl]-sulfamide;N-[(4-bromobenzo[b]thien-3-yl)methyl]-sulfamide;N-[(7-fluorobenzo[b]thien-3-yl)methyl]-sulfamide;N-[(1-methyl-1H-indol-3-yl)methyl]-sulfamide;N-[(4-trifluoromethylbenzo[b]thien-3-yl)methyl]-sulfamide;N-[(4-cyanobenzo[b]thien-3-yl)methyl]-sulfamide;N-[(benzo[b]thien-3-yl)methyl]-sulfamoylpyrrolidine;N-[(benzo[b]thien-3-yl)methyl]-N′-ethylsulfamide;imidazole-1-sulfonic acid [(benzo[b]thien-3-yl)methyl]-amide;and pharmaceutically acceptable salts thereof.

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. The method for claim 1, wherein the predisposing factor(s) rendering the patient in need of treatment with an anti-epileptogenic drug (an AEGD) are selected from the group consisting of: injury or trauma of any kind to the CNS; neurosurgical procedures, activities that risk CNS injury, e.g., combat activities, auto or horse racing and contact sports including boxing; spinal cord trauma; infections of the CNS; anoxia; stroke (CVAs); history of Transient Ischemic Attacks (TIA's); carotid stenosis; history of athererosclerotic vessel disease; history of pulmonary emboli; peripheral vascular disease; autoimmune diseases affecting the CNS, e.g., lupus; birth injures, e.g., perinatal asphyxia; cardiac arrest; therapeutic or diagnostic vascular surgical procedures, e.g., carotid endarterectomy or cerebral angiography; hypotension; injury to the CNS from emboli, hyper or hypo perfusion; hypoxia; known genetic predisposition to disorders known to respond to AEGDs; space occupying lesions of the CNS; brain tumors, e.g., glioblastomas; bleeding or hemorrhage in or surrounding the CNS, e.g., intracerebral bleeds or subdural hematomas; brain edema; febrile convulsions; hyperthermia; exposure to toxic or poisonous agents; drug intoxication or withdrawal, e.g. cocaine, methamphetamine or alcohol; family history of; seizure disorders or an epilepsy related seizure like neurological disorder or seizure related disorder, history of status epilepticus; current treatment with medications that lower seizure threshold, e.g., lithium carbonate, thorazine or clozapine; evidence from surrogate markers or biomarkers that the patient is in need of treatment with an anti-epileptogenic drug, e.g. MRI scan showing hippocampal sclerosis, elevated serum levels of neuronal degradation products, elevated levels of ciliary neurotrophic factor (CNTF) or an EEG suggestive of a seizure disorder or an epilepsy related seizure like neurological disorder or an analogous seizure related disorder.

11. The method of claim 1, wherein the predisposing factor(s) rendering the patient in need of treatment with an anti-epileptogenic drug (an AEGD) are selected from the group consisting of: closed or penetrating head trauma; neurosurgical procedures, carotid stenosis, stroke or other cerebral-vascular accident (CVA); status epilepticus and space occupying lesions of the CNS.

12. The method of claim 1, wherein the said predisposing factor(s) are closed head trauma or penetrating head trauma or a neurosurgical procedure.

13. The method of claim 1, wherein the said predisposing factor(s) are; stroke, other cerebral-vascular accident (CVA), presence of carotid stenosis or Transient Ischemic Attack's.

14. The method of claim 1, wherein the said predisposing factor is status epilepticus.

15. A method of treating epileptogenesis, comprising administering to a patient in need of treatment with an anti-epileptogenic drug (an AEGD) a therapeutically effective amount of a compound selected from the group consisting N-(benzo[b]thien-3-ylmethyl)-sulfamide and pharmaceutically acceptable salts thereof.

16. The method for claim 15, wherein the predisposing factor(s) rendering the patient in need of treatment with an anti-epileptogenic drug (an AEGD) are selected from the group consisting of: injury or trauma of any kind to the CNS; neurosurgical procedures, activities that risk CNS injury, e.g., combat activities, auto or horse racing and contact sports including boxing; spinal cord trauma; infections of the CNS; anoxia; stroke (CVAs); history of Transient Ischemic Attacks (TIA's); carotid stenosis; history of athererosclerotic vessel disease; history of pulmonary emboli; peripheral vascular disease; autoimmune diseases affecting the CNS, e.g., lupus; birth injures, e.g., perinatal asphyxia; cardiac arrest; therapeutic or diagnostic vascular surgical procedures, e.g., carotid endarterectomy or cerebral angiography; hypotension; injury to the CNS from emboli, hyper or hypo perfusion; hypoxia; known genetic predisposition to disorders known to respond to AEGDs; space occupying lesions of the CNS; brain tumors, e.g., glioblastomas; bleeding or hemorrhage in or surrounding the CNS, e.g., intracerebral bleeds or subdural hematomas; brain edema; febrile convulsions; hyperthermia; exposure to toxic or poisonous agents; drug intoxication or withdrawal, e.g. cocaine, methamphetamine or alcohol; family history of; seizure disorders or an epilepsy related seizure like neurological disorder or seizure related disorder, history of status epilepticus; current treatment with medications that lower seizure threshold, e.g., lithium carbonate, thorazine or clozapine; evidence from surrogate markers or biomarkers that the patient is in need of treatment with an anti-epileptogenic drug, e.g. MRI scan showing hippocampal sclerosis, elevated serum levels of neuronal degradation products, elevated levels of ciliary neurotrophic factor (CNTF) or an EEG suggestive of a seizure disorder or an epilepsy related seizure like neurological disorder or an analogous seizure related disorder.

17. The method of claim 15, wherein the predisposing factor(s) rendering the patient in need of treatment with an anti-epileptogenic drug (an AEGD) are selected from the group consisting of: closed or penetrating head trauma; neurosurgical procedures, carotid stenosis, stroke or other cerebral-vascular accident (CVA); status epilepticus and space occupying lesions of the CNS.

18. The method of claim 15, wherein the said predisposing factor(s) are closed head trauma or penetrating head trauma or a neurosurgical procedure.

19. The method of claim 15, wherein the said predisposing factor(s) are; stroke, other cerebral-vascular accident (CVA), presence of carotid stenosis or Transient Ischemic Attack's.

20. The method of claim 15, wherein the said predisposing factor is status epilepticus.

21. The method, as in claim 1, wherein said patient has not developed epilepsy at the time of said administration.

22. The method, as in claim 1, wherein said patient is at risk for developing epilepsy at the time of said administration.

23. The method, as in claim 15, wherein said patient has not developed epilepsy at the time of said administration.

24. The method, as in claim 15, wherein said patient is at risk for developing epilepsy at the time of said administration.