Use of Thiol Compounds to Treat Neurological Disease

Abstract

The present disclosure relates, in general, to use of small diffusible thiols in the treatment of neurodegenerative diseases associated with glutamate excitotoxicity, protein aggregation and oxidative stress in the central nervous system, particularly in the brain.

1 . A method of treating a neurological disease or disorder comprising administering a small thiol compound having a molecular weight<500 daltons, a log P>0.8, and a TPSA<90 that can be oxidized by reactive-oxygen species after crossing the blood-brain barrier to a sulfinic or sulfonic acid and wherein the oxidized compound possesses GABAergic, calcium channel inhibiting, glutamatergic or other neurologic activity, wherein the small thiol compound has the structure of Formula Ia, Ib, Ic, Id, or Ie: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  and R 2  are independently selected from the group consisting of H and C 1-5 alkyl; or
 R 1  and R 2 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 3  and R 4  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 3  and R 4 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 5  and R 6  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 5  and R 6 , taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring; 
 R 7  and R 8  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 7  and R 8 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
 R 4  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
 R 4  and R 8 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 8 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 4 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 wherein a C 1-5  alkyl moiety, wherever it occurs, can optionally comprise a double bond; and 
 wherein a C 1-5  alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic or heterocyclic moiety, wherever it occurs, can optionally be substituted with from one to three substituents which are not further substituted and which are independently selected from the group consisting of —CN, thio, halo, hydroxy, C 6-10  aryl, C 1-6  alkyl, C 2-6  alkenyl, C 3-6 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, CO 2 NH 2 , CO 2 NHC 1-6 alkyl, and —CO 2 N(C 1-6 alkyl) 2 . 
 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The method of  claim 1 , further characterized by aggregation of tau protein. 
     
     
         6 . The method of  claim 1 , wherein the disease or disorder is amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, traumatic brain injury, chronic traumatic encephalopathy (CTE), Alzheimer's disease, ischemia or epilepsy. 
     
     
         7 . The method of  claim 6  wherein the disease is familial or sporadic ALS. 
     
     
         8 . A method of preventing or ameliorating brain injury caused by trauma comprising administering to a subject in need thereof a small thiol compound having a molecular weight<500 daltons, a log P>0.8, and a TPSA<90 that can be oxidized by reactive-oxygen species after crossing the blood-brain barrier to a sulfinic or sulfonic acid and where the oxidized compound possesses GABAergic, calcium channel inhibiting, glutamatergic or other neurologic activity, wherein the small thiol compound has the structure of Formula Ia, Ib, Ic, Id, or Ie: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  and R 2  are independently selected from the group consisting of H and C 1-5 alkyl; or
 R 1  and R 2 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 3  and R 4  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 3  and R 4 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 5  and R 6  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 5  and R 6 , taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring; 
 R 7  and R 8  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 7  and R 8 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
 R 4  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
 R 4  and R 8 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 8 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 4 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 wherein a C 1-5  alkyl moiety, wherever it occurs, can optionally comprise a double bond; and 
 wherein a C 1-5  alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic or heterocyclic moiety, wherever it occurs, can optionally be substituted with from one to three substituents which are not further substituted and which are independently selected from the group consisting of —CN, thio, halo, hydroxy, C 6-10  aryl, C 1-6  alkyl, C 2-6  alkenyl, C 3-6 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, CO 2 NH 2 , CO 2 NHC 1-6 alkyl, and —CO 2 N(C 1-6 alkyl) 2 . 
 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the compound reduces protein aggregation, neuronal overexcitation or oxidative stress characteristic of neurodegenerative disorders. 
     
     
         11 . A method for treating or ameliorating glutamate toxicity or slowing the degeneration of neurons in a subject comprising administering an effective amount of a small thiol compound having a molecular weight<500 daltons, a log P>0.8, and a TPSA<90 that can be oxidized by reactive-oxygen species after crossing the blood-brain barrier to a sulfinic or sulfonic acid and where the oxidized compound possesses GABAergic, calcium channel inhibiting, glutamatergic or other neurologic activity, wherein the small thiol compound has the structure of Formula Ia, Ib, Ic, Id, or Ie: 
       
         
           
           
               
               
           
         
       
       wherein 
       R 1  and R 2  are independently selected from the group consisting of H and C 1-5 alkyl; or
 R 1  and R 2 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 3  and R 4  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 3  and R 4 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 5  and R 6  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 5  and R 6 , taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring; 
 R 7  and R 8  are independently selected from the group consisting of H and C 1-5 alkyl; or 
 R 7  and R 8 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
 R 4  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
 R 4  and R 8 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 8 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 R 2  and R 4 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
 wherein a C 1-5  alkyl moiety, wherever it occurs, can optionally comprise a double bond; and 
 wherein a C 1-5  alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic or heterocyclic moiety, wherever it occurs, can optionally be substituted with from one to three substituents which are not further substituted and which are independently selected from the group consisting of —CN, thio, halo, hydroxy, C 6-10  aryl, C 1-6  alkyl, C 2-6  alkenyl, C 3-6 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, CO 2 NH 2 , CO 2 NHC 1-6 alkyl, and —CO 2 N(C 1-6 alkyl) 2 . 
 
     
     
         12 . The method of  claim 1 , wherein the administration reduces neuronal glutamate toxicity. 
     
     
         13 . (canceled) 
     
     
         14 . A method for slowing the degeneration of neurons or treating or ameliorating glutamate toxicity in a subject comprising administering an effective amount of a compound of Formula Ia, Ib, Ic, Id, or Ie that can be oxidized by reactive-oxygen species after crossing the blood-brain barrier to a sulfinic or sulfonic acid, and wherein the oxidized compound possesses GABAergic, calcium channel inhibiting, glutamatergic or other neurologic activity,
 wherein the compound of Formula Ia, Ib, Ic, Id, or Ie has the structure:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently selected from the group consisting of H and C 1-5 alkyl; or 
         R 1  and R 2 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
         R 3  and R 4  are independently selected from the group consisting of H and C 1-5 alkyl; or 
         R 3  and R 4 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
         R 5  and R 6  are independently selected from the group consisting of H and C 1-5 alkyl; or 
         R 5  and R 6 , taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring; 
         R 7  and R 8  are independently selected from the group consisting of H and C 1-5 alkyl; or 
         R 7  and R 8 , taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
         R 2  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
         R 4  and R 6 , taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring; 
         R 4  and R, taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
         R 2  and R, taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
         R 2  and R 4 , taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring; 
         wherein a C 1-5  alkyl moiety, wherever it occurs, can optionally comprise a double bond; and 
         wherein a C 1-5  alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic or heterocyclic moiety, wherever it occurs, can optionally be substituted with from one to three substituents which are not further substituted and which are independently selected from the group consisting of —CN, thio, halo, hydroxy, C 6-10  aryl, C 1-6  alkyl, C 2-6  alkenyl, C 3-6 cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, CO 2 H, CO 2 C 1-6 alkyl, C(O)C 1-6 alkyl, CO 2 NH 2 , CO 2 NHC 1-6 alkyl, and —CO 2 N(C 1-6 alkyl) 2 . 
       
     
     
         15 .- 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the administration improves one or more symptoms of diminished motor function, mobility, cognitive ability, or other symptoms of an excitotoxicity disorder. 
     
     
         30 . The method of  claim 29 , wherein one or more symptoms include diminished motor function, mobility, cognitive ability, or other symptoms of an excitotoxicity disorder. 
     
     
         31 . The method of  claim 1 , wherein the compound exhibits neuroprotective effects in a neuronal tissue-culture model of excitotoxicity, oxidative stress, glutamate overstimulation, elevated intracellular calcium, GABA receptor function, mitochondrial stress or the consequences of these phenomena. 
     
     
         32 . The method of  claim 1 , wherein the compound or its oxidized equivalent improves cell-viability, reduces calcium transport, relieves mitochondrial stress, enhances mitophagy, modulates GABA activity, glutamate activity or voltage-gated calcium channel activity in a subject. 
     
     
         33 . The method of  claim 1 , wherein the compound;
 i) reduces levels of ROS in the CNS;   ii) increases intracellular cysteine and the sum of all intracellular low-molecular weight thiols;   iii) reduces weak metal-protein interactions through binding of unchaperoned metal-ions; and/or   iv) reduces intracellular protein aggregation that is dependent on oxidation of cysteine.   
     
     
         34 . The method of  claim 1 , wherein the compound is a compound of Table A. 
     
     
         35 . The method of  claim 14 , wherein the compound is a compound of Table A. 
     
     
         36 . The method of  claim 34 , wherein the compound is selected from the group consisting of 3, 4, 5, 9, 10, 15, 16, 18, 19, 20, 21, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 83, 85, 86, 87, 88, 90, 92, 95, 96, 97, 101, 103, 105, 106, 107, 108, 109, 110, 112, 113, 116, 117, 118, 119, 120, 121, 123, 126, 127, 128, 129, 130, 131, 132, 134, 135, 137, 138, 139, 140, 142, 143, 145, 151, 158, 170, and 175. 
     
     
         37 . The method of  claim 35 , wherein the compound is selected from the group consisting of 3, 4, 5, 9, 10, 15, 16, 18, 19, 20, 21, 22, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 83, 85, 86, 87, 88, 90, 92, 95, 96, 97, 101, 103, 105, 106, 107, 108, 109, 110, 112, 113, 116, 117, 118, 119, 120, 121, 123, 126, 127, 128, 129, 130, 131, 132, 134, 135, 137, 138, 139, 140, 142, 143, 145, 151, 158, 170, and 175.