Nitrate esters and their use for neurological conditions

A method for mitigating neurodegeneration in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that mitigation of neurodegeneration occurs, wherein the therapeutic compound has the formula Formula II):

• 21
• in which:
• m, n, p are integers from 0 to 10;
• R3,17 are each independently hydrogen, a nitrate group, or A;
• R1,4 are each independently hydrogen or A;
• where A is selected from:
• a substituted or unsubstituted aliphatic group (preferably a branched, or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R1 and R3 and/or between R17 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups);
• a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e.g. C=O, C=S, C=NOH), which optionally contains O, S, NR6and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• a substituted or unsubstituted aryl group;
• a heterocyclic group;
• amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino);
• hydroxy;
• alkoxy;
• a substituted or unsubstituted aryloxy;
• R2, R5, R18, R19 are optionally hydrogen, A, or X-Y;
• where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2H, PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), SR5, SSR7 or SSRs;
• Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N2H2R 3, N2HR 3R14, N3, S, SCN, SCN2H2(R 5)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, OS3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, COHM CORH CO2R1, C(O)R12, C(O)(OR13), C(O)(SR13), SR5, SSR7 or SSR5, or does not exist;
• R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents;
• or C1-C6 connections to R1-R4 in cyclic derivatives;
• or are each independently hydrogen, a nitrate group, or W;
• and
• M is H, Na+, K+, NH4+, N+HkR11(4-k) where k is 0-3, or other pharmaceutically acceptable counterion;
• and with the proviso,
• when m=n=p=1;
• R19, R2, R18, R1=H;
• R17, R3 are nitrate groups;
• that R4 is not H or C1-C3 alkyl.

A method for treating a disease state associated with neurodegeneration in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that a disease state associated with neurodegeneration is treated, wherein the therapeutic compound has the formula Formula II):

• 22
• in which:
• m, n, p are integers from 0 to 10;
• R3,17 are each independently hydrogen, a nitrate group, or A;
• R1,4 are each independently hydrogen or A;
• where A is selected from:
• a substituted or unsubstituted aliphatic group (preferably a branched, or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R1 and R3 and/or between R17 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups);
• a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e.g. C=O, C=S, C=NOH), which optionally contains O, S, NR6and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups a substituted or unsubstituted aryl group;
• a heterocyclic group;
• amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino);
• hydroxy;
• alkoxy;
• a substituted or unsubstituted aryloxy;
• R2, R5, R18, R19 are optionally hydrogen, A, or X-Y;
• where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2H, PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), SR5, SSR7 or SSRs;
• Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(RI5)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)20R9, PO2 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8,) P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(OR13), C(O)(SR13), SR5, SSR7 or SSR5, or does not exist;
• R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents;
• or C1-C6 connections to R1-R4 in cyclic derivatives;
• or are each independently hydrogen, a nitrate group, or W;
• and
• M is H, Na+, K+, NH4+, N+HkR11(4k) where k is 0-3, or other pharmaceutically acceptable counterion;
• and with the proviso,
• when m=n=p=1;
• R19, R2, R18, R1=H;
• R17, R3 are nitrate groups;
• that R4 is not H or C1-C3 alkyl.

A method for effecting neuroprotection in a subject, comprising administering to said subject an effective amount of a therapeutic compound such that neuroprotection occurs, wherein the therapeutic compound has the formula (Formula II):

• 23
• in which:
• m, n and p are integers from 0 to 10;
• R3,17 are each independently hydrogen, a nitrate group, or A;
• R1,4 are each independently hydrogen or A;
• where A is selected from:
• a substituted or unsubstituted aliphatic group (preferably a branched, or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R1 and R3 and/or between R17 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups);
• a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e.g. C=O, C=S, C=NOH), which optionally contains O, S, NR6and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• a substituted or unsubstituted aryl group;
• a heterocyclic group;
• amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino);
• hydroxy;
• alkoxy;
• a substituted or unsubstituted aryloxy;
• R2, R5, R18, R19 are optionally hydrogen, A, or X-Y;
• where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H,, N2H2R13, N2HR13R 4, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2H, PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), SR5, SSR7 or SSR5;
• Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(OR13), C(O)(SR13), SR5, SSR7 or SSR5, or does not exist;
• R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents;
• or C1-C6 connections to R1-R4 in cyclic derivatives;
• or are each independently hydrogen, a nitrate group, or W;
• and
• M is H, Na+, K+, NH4+, N+HkR11(4-k) where k is 0-3, or other pharmaceutically acceptable counterion;
• and with the proviso,
• when m=n=p=1;
• R19, R2, R18, R=H.;
• R17, R3 are nitrate groups;
• that R4 is not H or C1-C3 alkyl.

A method for effecting cognition enhancement in a subject comprising administering to said subject an effective amount of a organic nitrate, or therapeutically acceptable salt thereof, having the formula (Formula II):

• 24
• in which:
• m, n, p are integers from 0 to 10;
• R3,17 are each independently hydrogen, a nitrate group, or A;
• R14 are each independently hydrogen, or A;
• where A is selected from:
• a substituted or unsubstituted aliphatic group (preferably a branched, or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R1 and R3 and/or between R17 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups);
• a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e.g. C=0, C=S, C=NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• a substituted or unsubstituted aryl group;
• a heterocyclic group;
• amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino);
• hydroxy;
• alkoxy;
• a substituted or unsubstituted aryloxy;
• R2, R5, R18, R19 are optionally hydrogen, A, or X-Y;
• where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2H, PO2M, P(O)((O)(R3), SO, SO2, C(O)(SR13), SR5, SSR7 or SSR5;
• Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R , CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(OR13), C(O)(SR13), SR5, SSR7 or SSR5, or does not exist;
• R6, R7, R8 R9, R10, R11, R12, R13, R14, R15, R16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents;
• or C1-C6 connections to R1-R4 in cyclic derivatives;
• or are each independently hydrogen, a nitrate group, or W;
• and
• M is H, Na+, K+, NH4+, N+HkR11(4-k) where k is 0-3, or other pharmaceutically acceptable counterion;
• and with the proviso,
• when m=n=p=1;
• R19, R2, R18, R1=H;
• R17, R3 are nitrate groups;
• that R4is not H or C1-C3 alkyl.

Organic nitrates containing at least one nitrate group having the general formula (Formula III):

• 25
• in which:
• m is an integer from 1 to 10;
• n is an integer from 0 to 10;
• R3,4,17 are each independently hydrogen, a nitrate group, or A;
• where A is selected from:
• a substituted or unsubstituted aliphatic group (preferably a branched, or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R1 and R3 and/or between R17 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups);
• a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e.g. C=O, C=S, C=NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• a substituted or unsubstituted aryl group;
• a heterocyclic group;
• amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino);
• hydroxy;
• alkoxy;
• a substituted or unsubstituted aryloxy;
• R2, R5, R18, are optionally hydrogen, A, or X-Y;
• where X is F, Br, Cl, NO2, CH2, CF2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3 HM, PO3M2, P(O)(OR15) (OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2H, PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), SR5, SSR7 or SSRs;
• Y is F, Br, Cl, CH3, CF2H, CF3, OH, NH2, NHR6, NR6R7, CN, NHOH, N2H3, N2H2R 3, N2HR 3R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO2 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(OR13), C(O)(SR13), SR5, SSR7 or SSR5, or does not exist;
• R6, R7, R8 R9, R10, R11, R12, R13, R14, R15, R16 are the same or different alkyl or acyl groups containing 1-24 carbon atoms which may contain 1-4 ONO2 substituents;
• or C1-C6 connections to R1-R4 in cyclic derivatives;
• or are each independently hydrogen, a nitrate group, or W;
• and
• M is H, Na+, K+, NH4+, N+HkR11(4-k) where k is 0-3, or other pharmaceutically acceptable counterion;
• and with the proviso that,
• when m=0;
• n=1;
• R18 and R3 are the same or different and selected from H, a nitrate group, C1-C4 alkyl and chains, which may include one O, linking R18 and R3 to form pentosyl, hexosyl, cyclopentyl, or cyclohexyl rings, which rings optionally bear hydroxyl substituents;
• R17 and R4, are the same or different and selected from H, a nitrate group, C1-C4 alkyl optionally bearing 1-3 nitrate group, and acyl groups (—C(O)R5);
• R5, R6, R8, R9, R10, R12, R13, R14, R15, R16 are the same or different alkyl groups containing 1-12 carbon atoms which may contain 1-4 ONO2 substituents;
• or C1 or C2 connections to R18, R17, or R3 in cyclic derivatives;
• R7, R11 are C1-C8 alkyl or acyl;
• M is H, Na+, K+, NH4+, N+HkR11(4-k) where k is 0-3;
• X is CH2, O, NH, NMe, CN, NHOH, N2H3, N2H2R13, N2HR13R14, N3, S, SCN, SCN2H2(R15)2, SCN2H3(R15), SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SR7, SO2M, S(O)R8, S(O)2R9, S(O)OR8, S(O)2OR9, PO3 HM, PO3M2, P(O)(OR15)(OR16), P(O)(OR16)(OM), P(O)(R15)(OR8), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O), C(O)R12, C(O)(OR13), PO2M, P(O)(OR14), P(O)(R13), SO, SO2, C(O)(SR13), or SSR4;
• that Y is not CN, N2H2R13, N2HR13R14, N3, SCN, SCN2H2(R15)2, SC(O)N(R15)2, SC(O)NHR15, SO3M, SH, SO2M, PO3M2, PO3 HM, P(O)(OR15)(OR16), P(O)(OR 6)(OM), P(O)(OM)R15, CO2M, CO2H, CO2R11, C(O)R12, C(O)(SR13), SR4, SR5, or SSR5, or does not exist.

A method for preparing a compound represented by the formula Formula V):

• 26
• in which m, n=0-10;
• R4 is hydrogen, a nitrate group, or A;
• R3, R17, R18 are each independently hydrogen or A;
• and R5 is A;
• where A is selected from:
• a substituted or unsubstituted aliphatic group (preferably a branched, or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain, which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted cyclic aliphatic moiety having from 3 to 7 carbon atoms in the aliphatic ring, which optionally contains O, S, NR6 and unsaturations in the ring, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• an unsubstituted or substituted aliphatic moiety constituting a linkage of from 0 to 5 carbons, between R1 and R3 and/or between R2 and R4, which optionally contains O, S, NR6 and unsaturations in the linkage, and optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups);
• a substituted or unsubstituted aliphatic group (preferably a branched, cyclic or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain), containing carbonyl linkages (e.g. C=0, C=S, C=NOH), which optionally contains O, S, NR6 and unsaturations in the chain, optionally bearing from 1 to 4 hydroxy, nitrate, amino or aryl, or heterocyclic groups;
• a substituted or unsubstituted aryl group;
• a heterocyclic group;
• amino (including alkylamino, dialkylamino (including cyclic amino, diamino and triamino moieties), arylamino, diarylamino, and alkylarylamino);
• hydroxy;
• alkoxy;
• a substituted or unsubstituted aryloxy;
• the method comprising:
• reacting an appropriate halo-alcohol with a nitrating reagent selected from a mixture of nitric and sulfuric acid in a mixture of water and a selected organic solvent, acetyl nitrate, nitronium tetrafluoroborate, or reacting an appropriate halo-alkene with thallium nitrate in pentanes, under conditions such that an appropriate halo-organic nitrate is formed;
• reacting an appropriate halo-organic nitrate with a thiolsulfonate salt so as to produce a selected Bunte salt;
• reacting an appropriate Bunte salt, optionally with an oxidizing agent (e.g. 30% hydrogen peroxide) in the presence of an appropriate catalyst (e.g. sulfuric acid), under conditions such that the compound of Formula 5 is prepared;
• reacting an appropriate disulfide in a thiol/disulfide exchange reaction with an organic thiolate salt, under conditions such that a compound of Formula 5 is formed.