Combinatorial antitumor treatment methods and related compositions, kits, and systems

A pharmaceutical treatment system for administration to a cancer patient, the system comprising:

• a platinum-based chemotherapeutic drug in an amount sufficient to reduce the number of cancer cells in the patient;
• and
• a prodrug of 4-(phenylthio)butanoic acid (PTBA), according to Formula I:
• or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in an amount sufficient to attenuate kidney injury induced by the platinum-based chemotherapeutic drug in the patient and/or improve kidney function in the patient, wherein:
• R1 is O or NH;
• and
• R2 is one of:
• substituted or unsubstituted amine, preferably substituted or unsubstituted tertiary amine or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine,
• substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dualcycloalkyl), preferably 5-7 member heterocyclic amine or azaspiroalkyl, optionally substituted at one or more ring positions with C1-C2 alkyl, or 4-7 member substituted or unsubstituted heterocycloalkyl or hetero-dualcycloalkyl (a.k.a. azaspiroalkyl), optionally substituted at 1-4 (ring) positions and each (ring) substituent is one of branched or unbranched C1-C3 substituted or unsubstituted alkyl or cycloalkyl, more preferably substituted or unsubstituted pyrrolidine, piperidine, or piperazine, still more preferably, substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, still more preferably, 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, still more preferably, 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, or substituted or unsubstituted azaspiroheptyl, preferably 2-azaspiroheptyl or azaspiro[3.3]heptyl, still more preferably 2-azaspiro[3.3]heptyl, still more preferably 2-methyl-2-azaspiro[3.3]heptyl,
• alkanolamine, preferably ethanolamine, more preferably N-ethylethanolamine or 2-(ethylamino)ethanol,
• alkoxyalcohol, preferably alkoxy ethanol or ethoxy alcohol, more preferably 2-ethoxyethanol,
• polyol, preferably diol, more preferably propanediol, still more preferably 2,3-propanediol,
• carboxylic acid, preferably dicarboxylic acid, more preferably butanedioic acid, still more preferably, butanedioic acid,
• amide, preferably substituted amide, more preferably N-ethyl-N-amide, N-propyl-N-amide, or 2-amino-propanamide, still more preferably 2,6-diamino-N-ethyl-N-hexanamide, 2-amino-3-methyl-N-propyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-propanamide, or wherein the amide comprises:
• —R3—C(═O)NH—R4, wherein R3 is substituted alkyl, preferably substituted ethyl, more preferably amino ethyl, still more preferably 2-amino ethyl, and R4 is carboxylic acid, preferably dicarboxylic acid, more preferably pentanedioic acid, still more preferably, pentanedioic acid or pentanedioic acid, or
• —R5—NHC(═O)—R6, wherein R8 is substituted alkyl, ethyl or propyl, and R6 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane, branched or unbranched C2-C10 substituted or unsubstituted alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium, optionally substituted at 1-5 positions and each substituent is one of branched or unbranched C1-C5 substituted or unsubstituted alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), hydroxy, ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium,
• —X—R7, wherein X is C1-C3 branched or unbranched alkyl, and wherein R7 is a 4-7 member substituted or unsubstituted heterocycloalkyl or hetero-dualcycloalkyl (a.k.a. azaspiroalkyl), optionally substituted at 1-4 (ring) positions and each (ring) substituent is one of branched or unbranched C1-C3 substituted or unsubstituted alkyl or cycloalkyl, preferably substituted or unsubstituted pyrrolidine, piperidine, or piperazine, more preferably, substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, still more preferably, 4-N-piperidine or 4-N-piperazine substituted at C-1, N-4, or C-1 and N-4, still more preferably, 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, 4-N-methylpiperazine, most preferably, 4-N-methylpiperazine, preferably when X is (CH2)2, or tertiary amine or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)ethanamine, 1-(1-methyl-N,N-dimethyl)ethanamine, or 1-(N,N,N-trimethyl)ethanamine, branched or unbranched C2-C10 substituted or unsubstituted alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium, optionally substituted at 1-5 positions and each substituent is one of branched or unbranched C1-C5 substituted or unsubstituted alkyl, amine, amide, acetyl, aldehyde, alkoxy (ether), hydroxy, ester, carbonyl, carboxyl, carbamate, diol, triol, trisubstituted ammonium, —(CR8R9)Z—R10, wherein Z is an integer from 1-3, each R8 is, independently, one of H or CH3, each R9 is, independently, selected from:
• H, hydroxyl (OH), carboxyl (COOH), amino (NH2), or together with R10, forms substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dualcycloalkyl), preferably 5-7 member heterocyclic amine or azaspiroalkyl, optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably 5-6 member heterocyclic amine or 7 member azaspiroalkyl, optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine, or piperazine, still more preferably, substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, still more preferably unsubstituted 3-N-pyrrolidine or substituted 4-N-piperidine or 4-N-piperazine, substituted at C-1, N-4, or C-1 and N-4, still more preferably, 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or substituted or unsubstituted azaspiroheptyl, preferably substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, still more preferably substituted or unsubstituted 2-azaspiro[3.3]heptyl, still more preferably 2-methyl-2-azaspiro[3.3]heptyl, and each R10 is, independently, one of:
• amine, preferably tertiary amine or quaternary amine (trisubstituted ammonium or quaternary ammonium), more preferably 1-(N,N-dimethyl)amine, 1-(1-methyl-N,N-dimethyl)amine, or 1-(N,N,N-trimethyl)amine,
• optionally substituted heterocyclic amine, preferably 6 member heterocyclic amine, still more preferably 6 member heterocyclic amine, still more preferably piperazine, still more preferably, 4-N-piperazine, still more preferably 4-N-methylpiperazine or 4-N-methyl-1-piperazine,
• alkanolamine, preferably ethanolamine, N-ethanolamine or 1-aminoethanol,
• alkoxyalcohol, preferably alkoxy ethanol or ethoxy alcohol,
• polyol, preferably diol, more preferably ethanediol,
• carboxyl (COOH),
• amide, preferably substituted amide, more preferably substituted N-pentanamide, N-hexanamide, or 1-amide, more preferably 2,6-diamino-N-hexanamide, 2-amino-3-methyl-N-butanamide, or N-(1,3-dicarboyl)-2-amino-1-amide, or wherein the amide comprises:
• —C(═O)NH—R11, wherein R4 is carboxylic acid, preferably dicarboxylic acid, more preferably pentanedioic acid, still more preferably, pentanedioic acid or pentanedioic acid, or —NHC(═O)—R12, wherein R12 is substituted alkyl, preferably 1-amino-2-methylpropane or 1,5-diaminopentane, or
• —(CR13R14)Z—R15, wherein each R13 is H, each R14 is, independently, one of H, CH3, carboxyl (COOH), ethanol (CH2OH), preferably 2-ethanol, amine or alkylamine, preferably propylamine, carboxylic acid, preferably ethanoic acid or propanoic acid, Z is and integer from 1-3, and R15 is carboxyl (—COOH), amino (—NH2), or amide, preferably 1-amide, more preferably N-substituted-1-amide (or N-substituted carboxamide) (—CONH—R16, where R16 is substituted alkyl, preferably 1,3-dicarboxypropane, 1-(1-carboxy)butyric acid or butanedioic acid, 1-carboxy-2-pentanoic acid or pentanedioic acid, preferably 2-pentanedioic acid, or 2-(3-aminopropyl)ethanoic acid, or
• together with R9, forms substituted or unsubstituted heterocyclic amine or azaspiroalkyl (or hetero-dualcycloalkyl), preferably 5-7 member heterocyclic amine or azaspiroalkyl, optionally substituted at one or more ring positions with C1-C2 alkyl, more preferably 5-6 member heterocyclic amine or 7 member azaspiroalkyl, optionally substituted at one or more ring positions with C1-C2 alkyl, substituted or unsubstituted pyrrolidine, piperidine, or piperazine, still more preferably, substituted or unsubstituted 3-N-pyrrolidine, 4-N-piperidine, or 4-N-piperazine, still more preferably unsubstituted 3-N-pyrrolidine or substituted 4-N-piperidine or 4-N-piperazine, substituted at C-1, N-4, or C-1 and N-4, still more preferably, 4-N-methylpiperidine, 4-N-ethylpiperidine, 4-N-1,4-methylpiperidine, or 4-N-methyl-1-piperazine, or substituted or unsubstituted azaspiroheptyl, preferably substituted or unsubstituted 2-azaspiroheptyl or azaspiro[3.3]heptyl, still more preferably substituted or unsubstituted 2-azaspiro[3.3]heptyl, still more preferably 2-methyl-2-azaspiro[3.3]heptyl.