Therapeutic combinations as antidotes for organophosphate exposure

1:

• A therapeutic combination comprising:
• (a) (i) a compound as described in U.S. patent application publication no. US2015/0361060 A1 or WO/2014/127315 A1;
• (ii) a compound having one of the following structures or compositions having one or more compounds of the following structures, or equivalents thereof, or a stereoisomer thereof, or an analog thereof, or a pharmaceutically acceptable salt thereof, or a bioisostere thereof:
• and/or,
• (iii) a composition comprising an isolated compound consisting essentially of:
• (1) a compound having the formula:
• wherein:
• R1 is selected from the group consisting of:
• —H, -alkyl, and -aryl;
• R2 is selected from the group consisting of:
• —H, -alkyl, and -aryl;
• R3 is selected from the group consisting of:
• —(CH2)n—, and (CH2)n—CH(CH3)—, wherein n is the integer 0, 1, 2, 3, 4 or 5;
• R4 is selected from the group consisting of:
• —H, -alkyl (wherein optionally the alkyl is selected from the group consisting of:
• -methyl, -ethyl, -propyl, -butyl, -i-propyl, and -i-butyl), -cycloalkyl (wherein optionally the cycloalkyl is selected from the group consisting of:
• -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl), -aryl (wherein optionally the aryl is selected from the group consisting of:
• -phenyl, -naphthyl, -thienyl, and -indolyl), -saturated and nonsaturated heterocyclics (wherein optionally the saturated or nonsaturated heterocyclic is selected from the group consisting of:
• -aziridine, -oxirane-thiirane, -azirine, -oxirene, -thiirene, -azetidine, -oxetane, -thietane, -azete, -oxete, -thiete, -pyrrolidine, -oxolane, -thiolane, -pyrrole, -furan, -thiophene, -piperidine, -oxane, -thiane, -pyridine, -pyran, -thiopyran, -azepane, -oxepane, -thiepane, -azepine, -oxepine, -thiepine, -azocane, and -azocine), and bridged compounds (wherein optionally the bridged compound is selected from the group consisting of:
• -adamantanes, -amantadines, -biperidenes, -memantines, -methenamines, -rimantadines, -norbornanes, and -triazoles);
• (2) a compound having the formula:
• wherein
• R1 is selected from the group consisting of:
• —(CH2)n—, and (CH2)n—CH(CH3)—, wherein n is the integer 0, 1, 2, 3, 4 or 5;
• R2 is selected from the group consisting of:
• —H, -alkyl (wherein optionally the alkyl is selected from the group consisting of:
• -methyl, -ethyl, -propyl, -butyl, -i-propyl, and -i-butyl), -cycloalkyl (wherein optionally the cycloalkyl is selected from the group consisting of:
• -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl), -aryl (wherein optionally the aryl is selected from the group consisting of:
• -phenyl, -naphthyl, -thienyl, and -indolyl), -saturated and nonsaturated heterocyclics (wherein optionally the saturated or nonsaturated heterocyclic is selected from the group consisting of:
• -aziridine, -oxirane-thiirane, -azirine, -oxirene, -thiirene, -azetidine, -oxetane, -thietane, -azete, -oxete, -thiete, -pyrrolidine, -oxolane, -thiolane, -pyrrole, -furan, -thiophene, -piperidine, -oxane, -thiane, -pyridine, -pyran, -thiopyran, -azepane, -oxepane, -thiepane, -azepine, -oxepine, -thiepine, -azocane, and -azocine), and bridged compounds (wherein optionally the bridged compound is selected from the group consisting of:
• -adamantanes, -amantadines, -biperidenes, -memantines, -methenamines, -rimantadines, -norbornanes, and -triazoles);
• (3) a compound having the formula:
• wherein
• N is the integer 0, 1, 2, 3, 4, 5 or 6;
• R is selected from the group consisting of:
• —H, -alkyl (wherein optionally the alkyl is selected from the group consisting of:
• -methyl, -ethyl, -propyl, -butyl, -i-propyl, and -i-butyl), -cycloalkyl (wherein optionally the cycloalkyl is selected from the group consisting of:
• -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and -cyclooctyl), -aryl (wherein optionally the aryl is selected from the group consisting of:
• -phenyl, -naphthyl, -thienyl, and -indolyl), -saturated and nonsaturated heterocyclics (wherein optionally the saturated or nonsaturated heterocyclic is selected from the group consisting of:
• -aziridine, -oxirane-thiirane, -azirine, -oxirene, -thiirene, -azetidine, -oxetane, -thietane, -azete, -oxete, -thiete, -pyrrolidine, -oxolane, -thiolane, -pyrrole, -furan, -thiophene, -piperidine, -oxane, -thiane, -pyridine, -pyran, -thiopyran, -azepane, -oxepane, -thiepane, -azepine, -oxepine, -thiepine, -azocane, and -azocine), and bridged compounds (wherein optionally the bridged compound is selected from the group consisting of:
• -adamantanes, -amantadines, -biperidenes, -memantines, -methenamines, -rimantadines, -norbornanes, and -triazoles),
• and optionally the terminal alkyl group R is attached to an aminocarbonyl-aldoxime or a ketoaldoxime to form a bis-functional nucleophile, thereby statistically improving nucleophilic potential;
• (4) a compound having the formula:
• wherein
• R1 is selected from a group consisting of:
• —(CH2)n—, and (CH2)n—CH(CH3)—, wherein N is the integer 0, 1, 2, 3, 4 or 5;
• R2 is selected from a group consisting of a compound having a structure as set forth in the Summary:
• and any combination thereof);
• (5) a compound having the formula:
• and
• a combination thereof;
• (6) compound having a structure as set forth in Table 1 (FIG. 3) to Table 2 (FIG. 4), or equivalents thereof, or pharmaceutically acceptable salt thereof,
• wherein optionally the compound is RS2 138B, RS194B or RS191E;
• wherein optionally the compound is RS251A, RS251B, RS218A, or RS2-57B;
• or
• wherein optionally the compound is RS2-148B, RS2-140B, RS3-43D, RS3-36D, RS2-237D, RS2-234D or RS2-245C (FIG. 4A);
• (7) any combination of any of the compounds of (1) to (6);
• or
• (8) an isomer, an optical isomer or a stereoisomer;
• a racemate or a racemic mixture, an enantiomer, an individual diastereomer or a diastereomeric mixture or an analog, a crystalline product or a crystalline intermediate, a pharmaceutically acceptable salt, or a prodrug of the structure or compound, or a bioisostere of any compound or structure of (1) to (7);
• and
• (b) a brain efflux transporter inhibitor, or an inhibitor of renal tubular secretion.