Use of Thiol Compounds to Treat Neurological Disease

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
• R1 and R2 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R1 and R2, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R3 and R4 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R3 and R4, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R5 and R6 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R5 and R6, taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R7 and R8 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R7 and R8, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R2 and R6, taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring;
• R4 and R6, taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring;
• R4 and R8, taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R2 and R8, taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R2 and R4, 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 C1-5 alkyl moiety, wherever it occurs, can optionally comprise a double bond;
• and
• wherein a C1-5 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, C6-10 aryl, C1-6 alkyl, C2-6 alkenyl, C3-6cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, CO2H, CO2C1-6alkyl, C(O)C1-6alkyl, CO2NH2, CO2NHC1-6alkyl, and —CO2N(C1-6alkyl)2.

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
• R1 and R2 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R1 and R2, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R3 and R4 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R3 and R4, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R5 and R6 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R5 and R6, taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R7 and R8 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R7 and R8, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R2 and R6, taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring;
• R4 and R6, taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring;
• R4 and R8, taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R2 and R8, taken together with the atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R2 and R4, 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 C1-5 alkyl moiety, wherever it occurs, can optionally comprise a double bond;
• and
• wherein a C1-5 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, C6-10 aryl, C1-6 alkyl, C2-6 alkenyl, C3-6cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, CO2H, CO2C1-6alkyl, C(O)C1-6alkyl, CO2NH2, CO2NHC1-6alkyl, and —CO2N(C1-6alkyl)2.

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:
• R1 and R2 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R1 and R2, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R3 and R4 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R3 and R4, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R5 and R6 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R5 and R6, taken together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring;
• R7 and R8 are independently selected from the group consisting of H and C1-5alkyl;
• or
• R7 and R8, taken together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;
• R2 and R6, taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring;
• R4 and R6, taken together with the atoms to which they are attached, optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring;
• R4 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;
• R2 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;
• R2 and R4, 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 C1-5 alkyl moiety, wherever it occurs, can optionally comprise a double bond;
• and
• wherein a C1-5 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, C6-10 aryl, C1-6 alkyl, C2-6 alkenyl, C3-6cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O, N, and S, CO2H, CO2C1-6alkyl, C(O)C1-6alkyl, CO2NH2, CO2NHC1-6alkyl, and —CO2N(C1-6alkyl)2.