TREATMENT OF ORGANOPHOSPHATE EXPOSURE WITH TETRAHYDROINDOLONE ARYLPIPERAZINE COMPOUNDS

1 . A method of treating the effects of exposure to an organophosphate compound, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound having the following formula (Formula I):

where:

(a) A 2 and A 3 are C or N;

(b) R 3 is hydrogen, alkyl, aralky, heteroaralkyl, alkenyl, aralkenyl, heteroaralkenyl, aryl, heteroaryl, or does not exist when A 3 is N;

(c) R 6 is hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl; and

(d) R 6′ is hydrogen unless R 6 is alkyl, in which case R 6′ is hydrogen or the same alkyl as R 6 .

(e) L is a linker; and

(f) B is a moiety having a formula selected from the group consisting of:

(i) Formula II:

where:

(1) R2 is hydrogen, alkyl, hydroxy, halo, alkoxy, cyano, methylthio;

(2) R3 is hydrogen, alkyl, hydroxy, halo, alkoxy, trifluoromethyl, nitro, amino, aminocarbonyl, aminosulfonyl; and

(3) R2 and R3 can be taken together to form a 5 or 6 member aromatic or non-aromatic ring, which can contain from 0 to 3 heteroatoms selected from the group of N, O, or S of which the N may be further substituted if in a non-aromatic ring;

(ii) Formula III:

where:

(1) A 1 is N, O, or S, and when it is N, it can be further substituted with Z, which in alkyl, aralkyl, heteroaralky, or heteroalkyl.

(2) A2 is C or N; and

(3) R is selected from the group consisting of hydrogen, alkyl, NH 2 , NHQ 1 , NQ 1 Q 2 , OH, OQ 1 , SQ 1 , halo, nitro, cyano, and trifluoromethyl, and wherein Q 1 and Q 2 are selected from the group consisting of alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, alkanoyl, aroyl, aralkanoyl, heteroaralkanoyl, heteroaroyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and heteroaralkylsulfonyl; and

(iii) Formula IV:

where the 6-member heterocyclic ring of Formula IV is selected from the group consisting of a 2-pyridyl moiety, a 4-pyridyl moiety, a 2-pyrimidyl moiety,

a 4-pyrimidyl moiety, a 2-pyrazinyl moiety, and a 2-triazinyl moiety; or a salt or ester thereof.

2 . The method of claim 1 , wherein the linker is selected from the group consisting of:

(a) a straight chain alkyl group having the formula —(CH 2 ) m —, wherein m is an integer from 1 to 6; and

(b) an alkyl substituted hydrocarbyl moiety having the following formula:

where:

(i) n is 0, 1 or 2;

(ii) R7 and R8 are hydrogen, methyl or ethyl;

(iii) R9 and R9′ are both hydrogen, methyl or ethyl;

(iv) if n is 1 and R7 or R8 is methyl or ethyl, then R9 and R9′ are hydrogen;

(v) if n is 1 and R7 and R8 are hydrogen, then R9 and R9′ are methyl or ethyl; and

(vi) if n is 2, then R9 and R9′ are hydrogen and one or both of R7 and R8 are methyl or ethyl.

3 . The method of claim 1 , wherein:

(a) A 2 and A 3 are C;

(b) R 6 is hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl; and

(c) R 6 and R 3 are hydrogen.

4 . The method of claim 3 , wherein R 6 is hydrogen.

5 . The method of claim 1 , wherein B is:

and R 2 and R 3 are the same or independently hydrogen, alkyl, hydroxy, halo, alkoxy, trifluoromethyl, nitro, amino, aminocarbonyl, or aminosulfonyl.

6 . The method of claim 1 , wherein B is a moiety selected from the group consisting of a m-trifluoromethylphenylpiperazinyl moiety, a m-chlorophenylpiperazinyl moiety, a o-methoxyphenylpiperazinyl moiety, a 1-naphthylpiperazinyl moiety, a 2-pyrimidylpiperazinyl moiety, a 3-indazolylpiperazinyl moiety a 2,3-dichlorophenylpiperazinyl moiety, and a 2,3-dimethylphenylpiperazinyl moiety.

7 . The method of claim 1 , wherein R is selected from the group consisting of a halo group, an alkyl group, a cyano group, a trifluoromethyl group, an alkoxy group, an amino group, an alkylamino group, and a dialkyamino group.

8 . The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of:

1-{2-[4-(3-Trifluoromethylphenyl)piperazine-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one;

1-{3-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(3-Chlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one;

1-{3-[4-(2-Methoxyphenyl)piperazine-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{2-[4-(2-Pyrimidyl)piperazine-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one;

1-{3-[4-(2-Pyrimidyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(2-Pyrimidyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{2-[4-(1-Naphthyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one;

1-{3-[4-(1-Naphthyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(1-Naphthyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{2-[4-(3-Indazolyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one;

1-{3-[4-(3-Indazolyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(3-Indazolyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{3-[4-(2,3-Dichlorophenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one;

1-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one;

1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]butyl}-1,5,6,7-tetrahydroindol-4-one;

1-{3-[4-(2,3-Dimethylphenyl)piperazin-1-yl]propyl}-1,5,6,7-tetrahydroindol-4-one; and

1-{2-[4-(2,3-Dimethylphenyl)piperazin-1-yl]ethyl}-1,5,6,7-tetrahydroindol-4-one.

9 . The method of claim 1 , wherein the composition comprises a pharmaceutically acceptable excipient in combination with the compound of Formula I.

10 . The method of claim 1 , wherein the composition is administered by an administrative route selected from the group consisting of intravenous, oral, topical, intraperitoneal, intravesical, transdermal, nasal, rectal, vaginal, intramuscular, intradermal, subcutaneous and intrathecal.

11 . The method of claim 1 , wherein the therapeutically effective amount of the compound of Formula I is in the range of 0.0001 mg/kg to 60 mg/kg.

12 . The method of claim 1 , wherein the therapeutically effective amount of the compound of Formula I is administered to the subject following exposure of the subject to the organophosphate compound.

13 . The method of claim 1 , wherein the therapeutically effective amount of the compound of Formula I is administered to the subject prior to exposure of the subject to the organophosphate compound.