MXPA06015126A - Bis(thio-hydrazide amide) salts for treatment of cancers - Google Patents

Abstract

Disclosed are bis(thio-hydrazide amide) disalts, which are represented byStructural Formula (I) Y is a covalent bond or a substituted or unsubstituted straight chained hydrocarbyl group. R1-R4 are independently-H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or R1 and R3 taken together with the carbon and nitrogen atoms to which they are bonded, and/or R2 and R4taken together with the carbon and nitrogen atoms to which they are bonded, forma non-aromatic heterocyclic ring optionally fused to an aromatic ring. Z is -Oor -S. M+ is a pharmaceutically acceptable monovalent cation and M2+is a pharmaceutically acceptable divalent cation. Also, disclosed are pharmaceutical compositions comprising a bis(thio-hydrazide amide) disalt described above. Further disclosed are methods of treating a subject with cancer. The methods comprise the step of administering an effective amount of a bis(thio-hydrazideamide) disalt described above.

Description

SALES OF BIS (TIO-HYDRAZIDA-AMIDA) FOR THE TREATMENT OF CANCERS RELATED REQUESTS This application claims the benefit of. the US Provisional Patent Application Serial No. 60 / 582,596, filed June 23, 2004, and the US Provisional Patent Application. Serial No. 60 / 681,368, filed May 16, 2005. All of the teachings of the previous applications are hereby incorporated by reference. BACKGROUND OF THE INVENTION Many drugs are currently available for use in the treatment of cancer. However, in many cases the cancer fails to respond to anticancer therapy or only slows its growth and / or its metastasis. Even when a tumor initially responds to anticancer therapy by decreasing in size or remitting, the tumor often develops resistance to the drug. For these reasons, new cancer agents and new drugs that can be used to treat multidrug-resistant cancers have been needed. Certain bis (thiohydrazide amide) compounds have been described by the present inventors as being significantly cytotoxic to cancer cells, including cancer cells that have become resistant to multiple drugs, and to increase the anticancer activity of other anticancer agents, such as taxol and Epothilone D (see, eg, US Publications No. 2004/0225016 A1, 2003/0045518 and 2003/0119914, the contents of which are hereby incorporated by reference in their entirety). COMPENDIUM OF THE INVENTION It has now been found that bis (thiohydrazide amide) disals show unexpectedly high water solubility and bioavailability. For example, disodium salts and dipotasics of Compounds (1) and (2) show a solubility in water of greater than 1,000 mg / ml, compared to a solubility of about 0.1 mg / ml for the corresponding neutral form of Compound (1) and (2) ) (see Examples 2, 10 and 15). Similar increases in solubility were observed for the disodium and dipotassium salts of Compounds (12), (13) and (14) (see Examples 12-15). Moreover, the bioavailability of the disodium salt of Compound (1) was 80%, while the bioavailability of the neutral compound was 4.8% (see Example 16). Next, a representative tautomeric structure of Compounds (1) and (2) is shown: Compound (2) Based on these results, novel bis (thiohydrazide amide) disalts, pharmaceutical compositions containing a bis (thiohydrazide amide) disal, and methods of treatment using a bis (thiohydrazide amide) disalt are described. An embodiment of the present invention is a compound represented by the following Structural Formula (I) and its tautomeric forms: 2 M + o · M2 + And it is a covalent bond or a substituted or unsubstituted straight chain hydrocarbyl group. R! - are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or Ri Y ¾ 'taken together with the carbon and nitrogen atoms to which they are attached, and / or R2 and R4, taken together with the carbon and nitrogen atoms to which they are attached, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring. Z is -O or -S. M + is a pharmaceutically acceptable monovalent cation and M2 + is a pharmaceutically acceptable divalent cation. Another embodiment of the present invention is a pharmaceutical composition consisting of a disal of bis (thiohydrazide amide) described herein and a pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions can be used in therapy, for example as anticancer agents. present invention also provides a method of treating a subject with a cancer. The method consists in administering to the subject an effective amount of a disal of bis (thiohydrazide amide) described herein. The disal of bis (thiohydrazide amide) is administered as monotherapy (ie, as the only anticancer drug administered to the subject), or is coadministered with one or more other anticancer drugs.

The present invention also provides the use of the bis (thiohydrazide amide) disals described herein in the manufacture of a medicament for the purpose of treating cancer in an individual. The present invention also provides a method of preparing a disal of bis (thiohydrazide amide). The method includes the steps of combining a neutral bis (thiohydrazide amide), an organic solvent and a base to form a solution of bis (thiohydrazide amide) and combining the solution and an organic antisolvent, thus precipitating a disal from the bis (thiohydrate-zido amide). In various embodiments, a method of preparing a bis (thiohydrazide amide) disal includes the steps of combining a neutral bis (thiohydrazide amide) and an organic solvent selected from methanol, ethanol, acetone and methyl ethyl ketone to prepare a mixture; addition of at least two equivalents of a base selected from sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide to the mixture, thus forming a solution, and combination of the solution and an organic antisolvent selected from pentane, hexa-no, cyclohexane, hept no, petroleum ether, ethyl acetate and diethyl ether to precipitate the disal of the bis (thiohydrazide amide). In various embodiments, a method of preparing a bis (thiohydrazide amide) disal includes the steps of combining a neutral bis (thiohydrazide amide), an organic solvent and a base to form a solution of bis (thiohydrazide amide), and separation of a disal of bis (thiohydrazide amide). In various embodiments, a method of preparing a bis (thiohydrazide amide) disal includes the steps of combining a neutral bis (thiohydrazide amide), an organic solvent and a base to form a solution of bis (thiohydrazide amide) and combination of the solution and methyl tert-butyl ether, thus precipitating a disal of the bis (thiohydrazide amide). In various embodiments, a method of preparing a bis (thiohydrazide amide) disal includes the steps of combining a neutral bis (thiohydrazide amide) and an organic solvent selected from methanol, ethanol, acetone and methyl ethyl ketone to prepare a mixture; addition of at least two equivalents of a base selected from sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide to the mixture, thus forming a solution, and combination of the solution and methyl tert-butyl ether to precipitate the disal of the bis (thiohydrazide amide). Since the disclosed bis (thiohydrazide amide) disks have excellent water solubility and high bioavailability, they can be used in water-based formulations suitable for intravenous and oral administration. In addition, the bis (thiohydrazide amide) disalts described are relatively non-toxic, which allows the use of the disalms described at relatively high doses with minimal side effects. The high solubility in water of the compounds, in turn, makes possible formulations at high doses. The bis (thiohydrazide amide) disals described herein can be used to treat cancers, including cancers that have become resistant to multiple drugs. Thus, the disclosed bis (thiohydrazide amide) disals can be used to treat cancers where other drug regimens have failed or become ineffective. Additionally, the bis (thiohydrazide-amide) dials described are particularly effective when used in combination with other anticancer drugs, such as taxol and a taxol analogue. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the structure of taxol (Pacli-taxel). Figure 2 is the structure of the taxotere (Twelve-taxel). Figures 3-23 are each the structure of a taxol analogue. Figure 24 is the structure of a polymer that contains an analogous group of the pending taxol of the polymeric skeleton. The polymer is a terpolymer of the three monomeric units shown. DETAILED DESCRIPTION OF THE INVENTION The bis (thiohydrazide amide) disalts of the present invention are represented by Structural Formula (I). M + is a pharmaceutically acceptable monovalent cation. M2 + is a pharmaceutically acceptable divalent cation. "Pharmaceutically acceptable" means that the cation is suitable for administration to a subject. As examples of M + or M2 +, Li +, Na +, K \ Mg2 +, Ca2 +, Zn2 + and NR4 + are included, where each R is independently hydrogen, a substituted or unsubstituted aliphatic group (eg, a hydroxyalkyl group, an aminoalkyl group or an ammonioalkyl group) or an aryl group substituted or unsubstituted, or two R groups, taken together, form a substituted or unsubstituted non-aromatic heterocyclic ring optionally fused to an aromatic ring. Preferably, the pharmaceutically acceptable cation is Li +, Na +, K +, NH3 (C2HsOH) +, N (CH3) 3 (C2HsOH) +, ar-ginin or lysine. More preferably, the pharmaceutically acceptable cation is Na * or +. Na + is even more preferred. In Structural Formula (I), Z is preferably -O. More preferably, Z is -O, x and R2 are the same and R3 and R4 are the same. In one embodiment, Y in the Structural Formula (I) is a covalent bond or a group -C (R5R6) -, - (CH2CH2) -, trans- (CH = CH) -, cis- (CH = CH) - or - (CC) -, preferably C (RSR6) -. i-4 are as described above for Structural Formula (I). Rs and R6 are each independently -H or a substituted aliphatic or aliphatic group, or Rs is -H and R6 is a substituted or unsubstituted aryl group, or Rs and R6, taken together, are a substituted or unsubstituted alkylene group C2 -C6 The pharmaceutically acceptable cation is as described above. In a preferred embodiment of the present invention, the bis (thiohydrazide amide) disal is represented by Structural Formula (II): where Ri-Rg and the pharmaceutically acceptable cation are as described above for Structural Formula (I). In a more preferred embodiment of the present invention, the bis (thiohydrazide amide) disal is represented by Structural Formula (II) wherein R x and R 2 are each a substituted or unsubstituted aryl group, preferably a substituted phenyl group or not replaced; R3 and R4 are each a substituted or unsubstituted aliphatic group, preferably an alkyl group, more preferably methyl or ethyl, and R5 and R6 are as described above, but Rs is preferably -H and R6 is preferably -H or a aliphatic or aliphatic group substituted. Alternatively, R and R2 are each a substituted or unsubstituted aryl group; R3 and R4 are each a substituted or unsubstituted aliphatic group; R5 is -H, and R6 is -H or an aliphatic or substituted aliphatic group. Preferably, Rx and R2 are each a substituted or unsubstituted aryl group, R3 and R4 are each an alkyl group and R5 is -H and Rs is -H or methyl. Even more preferably, Rx and R2 are each a substituted or unsubstituted phenyl group, R3 and R4 are each methyl or ethyl and Rs is -H and R6 is -H or methyl. Suitable substituents for an aryl group represented by Rx and R2 and an aliphatic group represented by R3, R4 and Rs for aryl and aliphatic groups are described below. In a second most preferred embodiment of the present invention, the bis (thiohydrazide amide) disal is represented by Structural Formula (II) wherein R1 and R2 are each a substituted or unsubstituted aliphatic group, preferably a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group, more preferably cyclopropyl or 1-methylcyclopropyl; R3 and R4 are as described above for Structural Formula (I), preferably both a substituted or unsubstituted alkyl group; and Rs and Rs are as described above, but Rs is preferably -H and R6 is preferably -H or a substituted aliphatic or aliphatic group, more preferably -H or methyl. Alternatively, the bis (thiohydrazide amide) salt is represented by Structural Formula (II) wherein R x and R 2 are each a substituted or unsubstituted aliphatic group; R3 and R4 are as described above for Structural Formula (I), preferably both a substituted or unsubstituted alkyl group, and Rs is -H and R6 is -H or an optionally substituted aliphatic group. Preferably, Rx and R2 are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group; R3 and R4 are both as described above for Structural Formula (I), preferably an alkyl group, and Rs is -H and Rs is -H or a substituted aliphatic or aliphatic group. More preferably, R1 and R2 are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group, R3 and R4 are both an alkyl group, and R5 is -H and R6 is -H or methyl. Even more preferably, Rx and R2 are both cyclopropyl or 1-methylcyclopropyl, R3 and R4 are both an alkyl group, preferably methyl or ethyl, and Rs is -H and Rs is -H or methyl. The following are specific examples of bis (thiohydrazide amide) disks represented by Structural Formula (II): Rx and R2 are both phenyl, R3 and R4 are both methyl, Rs is -H and R6 is ethyl; Rx and R2 are both phenyl, R3 and R4 are both phenyl and R5 and R6 are both methyl; Rx and R2 are both 2-thienyl, R3 and R4 are both phenyl and R5 and R6 are both methyl; Rx and R2 are both 4-cyanophenyl, R3 and R4 are both methyl, Rs is -H and R6 is methyl; x and R2 are both phenyl, R3 and R4 are both methyl, R5 is. -H and Rs is methyl; R1 and R2 are both phenyl, R3 and R4 are both methyl, Rs is -H and R6 is benzyl; R and R2 are both phenyl, R3 and R4 are both methyl, Rs is -H and R6 is ethyl; R2 and R2 are both phenyl, R3 and R4 are both ethyl, Rs is -H and Rs is n-butyl; Rx and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl, R5 is -H and R6 is methyl; Rx and R2 are both phenyl, R3 and R4 are both methyl, R5 is -H and R6 is iso-propyl, · Rx and R2 are both 3-nitrophenyl, R3 and R4 are both methyl, Rs is -H and Rs is methyl; R and R2 are both 4-chlorophenyl, R3 and R4 are both methyl, R5 is -H and R6 is methyl; Rx and R2 are both phenyl, R3 and R4 are both methyl, Rs is -H and R6 is 3-thienyl; Rx and R2 are both phenyl, R3 and R4 are both methyl and R5 and R6, taken together, are propylene; Rx and R2 are both 2,3-dimethoxyphenyl, R3 and R4 are both methyl, Rs is -H and R6 is methyl; Rx and R2 are both 2-chloro-5-methoxyphenyl, R3 and R4 are both methyl, Rs is -H and R6 is methyl; Ra and R2 are both 2,5-difluorophenyl, R3 and R4 are both methyl, Rs is -H and R6 is methyl; Rx and R2 are both 2,5-dichlorophenyl, R3 and R4 are both methyl, R5 is -H and R6 is methyl; x and R2 are both 2,6-dimethoxyphenyl, R3 and R4 are both methyl, Rs is -H and R6 is me- linden; Rx and R2 are both 2,5-dimethylphenyl, R3 and R4 are both methyl, Rs is -H and R6 is methyl; Rx and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both ethyl, Rs is -H and Rs is methyl; Rx and R2 are both 2, 5-diethoxyphenyl, R3 and. R4 are both methyl, Rs is -H and R6 is methyl; R2 and R2 are both cyclopropylo, R3 and R4 are both methyl and Rs and Rs are both -H; R1 and R2 are both cyclopropyl, R3 and R4 are both ethyl and Rs and R6 are both -H; and R2 are both cyclopropyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; R and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; R1 and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; Rx and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, R5 is ethyl and R6 is -H; Rx and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, R5 is n-propyl and R6 is -H; R ^ and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both methyl; R and R2 are both 1-methylcyclopropyl, R3 and R4 are both ethyl and Rs and R6 are both -H; R and R2 are both 1-methylcyclopropyl, R3 is methyl and R4 is ethyl and Rs and R6 are both -H; R and R2 are both 2-methylcyclopropyl; R3 and R4 are both methyl and Rs and Rs are both -H; R and R2 are both 2-phenylcyclopropyl; R3 and R4 are both methyl and R5 and R6 are both -H; RL and R2 are both 1-phenylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; R1 and R2 are both eyclobutyl, R3 and R4 are both methyl and Rs and R6 are both -H; R1 and R2 are both cyclopentyl, R3 and R4 are both methyl and R5 and R6 are both -H; R and R2 are both cyclohexyl; R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both cyclohexyl, R3 and R4 are both phenyl and R5 and R6 are both -H; Rx and R2 are both methyl, R3 and R4 are both methyl and Rs and R6 are both -H; R and R2 are both methyl, R3 and R4 are both t-butyl and R5 and R6 are both -H; R1 and R2 are both methyl, R3 and R4 are both phenyl and Rs and R6 are both -H; Rx and R2 are both t-butyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are ethyl, R3 and R4 they are both methyl and RS and RS are both -H; RX and R2 are both n-propyl, R3 and R4 are both methyl and RS and R6 are both -H. In these examples, the pharmaceutically acceptable cation represented by M + and M2 + is as described for Structural Formula (I), preferably Li +, Na +, K +, NH3 (C2HsOH) + or N (CH3) 3 (C2HsOH) +, more preferably Na + or K +, even more preferably Na *. For many bis (thiohydrazide amide) disalts represented by Formula (II), Y is -CH2-. As examples, those are included in which: RX and R2 are both phenyl and R3 and R4 are both o-CH3-phenyl; R1 and R2 are both o-CH3C (0) 0-phenyl and R3 and R4 are phenyl; X and R2 are both phenyl and R3 and R4 are both methyl; R and R2 are both phenyl and R3 and R4 are both ethyl; R-L and R2 are both phenyl and R3 and R4 are both n-propyl; R-L and R2 are both p-cyanophenyl and R3 and R4 are both methyl; RX and R2 are both p-nitrophenyl and R3 and R4 are both methyl; R1 and R2 are both 2,5-dimethoxyphenyl and R3 and R4 are both methyl; R1 and R2 are both phenyl and R3 and R4 are both n-butyl; R and R2 are both p-chlorophenyl and R3 and R4 are both methyl; R1 and R2 are both 3-nitrophenyl and R3 and R4 are both methyl; Rx and R2 are both 3-cyanophenyl and R3 and R4 are both methyl; R and R2 are both 3-fluorophenyl and R3 and R4 are both methyl; R- and R2 are both 2-furanyl and R3 and R4 are both phenyl; R1 and R2 are both 2-methoxyphenyl and R3 and R4 are both methyl; R1 and R2 are both 3-methoxyphenyl and R3 and R4 are both methyl; R ± and R2 are both 2,3-dimethoxyphenyl and R3 and R4 are both methyl; RX and R2 are 2-methoxy-5-chlorophenyl and R3 and R4 are both ethyl; R1 and R2 are both 2,5-difluorophenyl and R3 and R4 are both methyl; X and R2 are both 2,5-dichlorophenyl and R3 and R4 are both methyl; R1 and R2 are both 2,5-dimethylphenyl and R3 and R4 are both methyl; RX and R2 are both 2-methoxy-5-chlorophenyl and R3 and R4 are both methyl; R-L and R2 are both 3,6-dimethoxyphenyl and R 3 and R 4 are both methyl; R1 and R2 are both phenyl and R3 and R4 are both 2-ethylphenyl; RX and R2 are both 2-methyl-5-pyridyl and R3 and R4 are both methyl; or R is phenyl, R 2 is 2,5-dimethoxyphenyl and R 3 and R 4 are both methyl; RX and R2 are both methyl and R3 and R4 are both p-CF3-phenyl; RX and R2 are both methyl and R3 and R4 are both o-CH3-phenyl; RX and R2 are both - (CH2) 3COOH and R3 and R4 are both phenyl; R2 and R2 are both represented by the following structure: and R3 and R4 are both phenyl, - R and R2 are both n-butyl and R3 and R4 are both phenyl; RX and R2 are both n-pentyl and R3 and R4 are both phenyl; RX and R2 are both methyl and R3 and R4 are both 2-pyridyl; RX and R2 are both cyclohexyl and R3 and R4 are both phenyl; RX and R2 are both methyl and R3 and R4 are both 2-ethylphenyl; RX and R2 are both methyl and R3 and R4 are both 2,6-dichlorophenyl; RX-R4 are all methyl; RX and R2 are both methyl and R3 and R4 are both t-butyl; R and R2 are both ethyl and R3 and R4 are both methyl; R1 and R2 are both t-butyl and R3 and R4 are both methyl; RX and R2 are both cyclopropyl and R3 and R4 are both methyl; R1 and R2 are both cyclopropyl and R3 and R4 are both ethyl; R1 and R2 are both 1-methylcyclopropyl and R3 and R4 are both methyl; R-L and R2 are 2-methylcyclopropyl and R3 and R4 are both methyl; RX and R2 are both 1-phenylcyclopropyl and R3 and R4 are both methyl; RX and R2 are both 2-phenylcyclopropyl and R3 and R4 are both methyl; RA and R2 are both cyclobutyl and R3 and R4 are both methyl; R1 and R2 are both cyclopentyl and R3 and R4 are both methyl; R1 is cyclopropyl, R2 is phenyl and R3 and R4 are both methyl. In these examples, the pharmaceutically acceptable cation represented by M + and M2 + is as described for Structural Formula (I), preferably Li +, Na +, K +, NH3 (C2H5OH) + or N (CH3) 3 (C2Hs0H) +, more preferably Na + or K + and even more preferably Na +.

Preferred examples of the bis (thiohydrazide amide) disalts of the present invention are the following: where 2 M + and M2 + are as described above for the Structural Formula (I). Preferably, the pharmaceutically acceptable cation is 2 M +, where M + is Li +, Na *, K +, NH3 (C2HsOH) + or N (CH3) 3 (C2H5OH) +. More preferably, M + is Na + or K +. Even more preferably, M + is Wa +. In the Structural Formulas (I) - (II), R-_ and R2 are the same or different and / or R3 and R4 are the same or different. Preferably, Rx and R2 are the same and R3 and R4 are the same. The disclosed bis (thiohydrazide amide) disals can have tautomeric forms. By way of example, tautomeric forms of the compounds represented are shown below, for example, by Structural Formula (II), where Y is -CH2-: It is to be understood that, when a tautomeric form of a described compound is structurally represented, other tautomeric forms are also included. Certain compounds of the invention can be obtained as different stereoisomers (e.g., diastereomers and enantiomers). The invention includes all isomeric forms and racemic mixtures of the described compounds and methods of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures. The stereoisomers can be separated and isolated using any suitable method, such as chromatography. A "straight chain hydrocarbyl group" is an alkylene group, i.e., - (CH2) y-, with one or more (preferably · one) internal methylene groups optionally substi- with a linking group, and is a positive integer (eg, between 1 and 10), preferably between 1 and 6 and more preferably 1 or 2. A "linking group" refers to a functional group that replaces a methylene in a straight chain hydrocarbyl. Examples of suitable linking groups include a ketone (-C (O) -), alkene, alkyne, phenylene, ether (-0-), thioether (-S-) or amine (-N (Ra) -) , where R is defined later. A preferred linking group is -C (RSRS) -, where R5 and R6 have been defined above. Suitable substitutents for an alkylene group and a hydrocarbyl group are those which do not substantially interfere with the anticancer activity of the described compounds. Rs and R6 are preferred substituents for an alkylene or hydrocarbyl group represented by Y. An aliphatic group is a non-aromatic hydrocarbon of straight chain., branched or cyclic that is completely saturated or that contains one or more units of unsaturation. Typically, a straight or branched chain aliphatic group has from 1 to about 20 carbon atoms, preferably from 1 to 10, and a cyclic aliphatic group has from 3 to about 10 carbon atoms, preferably from 3 to about 8. A group aliphatic is preferably a straight or branched chain alkyl group, eg, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tere-butyl, pentyl, hexyl, pentyl or octyl, or a cycloalkyl group from 3 to 8 carbon atoms. Reference is also made to a Cx-C8 straight or branched chain alkyl group or to a C3-C8 cyclic alkyl group as a "lower alkyl" group. The t"aromatic group" can be used interchangeably with "aryl", "aryl ring", "aromatic ring", "aryl group" and "aromatic group". As aromatic groups, carbocyclic aromatic groups such as phenyl, naphthyl and anthracyl and heteroaryl groups such as imidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazole, oxazolyl and tetrazol. The term "heteroaryl group" can be used interchangeably with "heteroaryl", "heteroaryl ring", "heteroaromatic anion" and "heteroaromatic group". Heteroaryl groups are aromatic groups containing one or more heteroatoms, such as sulfur, oxygen and nitrogen, in the ring structure. Preferably, the heteroaryl groups contain from one to four heteroatoms. Aromatic groups also include fused polycyclic aromatic ring systems wherein a carbocyclic aromatic ring or a heteroaryl ring is fused with one or more other heteroaryl rings. Examples include benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazole, benzooxazole, benzimidazole, quinolinyl, isoquinolinyl and isoindolyl. The term "arylene" refers to an aryl group that is connected to the rest of the molecule by two other bonds. By way of example, the structure of a 1,4-phenylene group is shown below: The substituents for an arylene group are as described below for an aryl group. The non-aromatic heterocyclic rings are non-aromatic rings that include one or more heteroatoms, such as nitrogen, oxygen or sulfur, in the ring. The ring can be five, six, seven or eight members. Preferable- The heterocyclic groups contain from one to about four heteroatoms. As examples, te-trahydrofuranyl, tetrahydrothiophenyl, morpholino, thiomorpholin, pyrrolidinyl, piperazinyl, piperidinyl and thiazolidinyl are included. Suitable substituents on an aliphatic group (including an alguylene group), a non-aromatic heterocyclic group or a benzylic or aryl group (carbocyclic and heteroaryl) are those which do not substantially interfere with the anticancer activity of the described compounds. A substituent substantially interferes with the anticancer activity when the anticancer activity is reduced by more than about 50% in a compound with the substitute-te compared to a compound without the substituent. Examples of suitable substituents include Ra, -OH, -Br, -Cl, -I, -F, -ORa, -0-CORA, -CORa, -CN, -N02, -COOH, -S03H, - NH2, -NHRa, -N (RaRb), -C00Ra, -CHO, -C0NH2, -C0NHRa, CON (RaR), -NHC0Ra, -NRcCORa, -NHCONH2, -NHCONRaH, -NHCON (RaRb), -NR ° CONH2 , -NRcC0NRaH, -NR ° CON (RaRb), -C (= NH) -NH2, -C (= NH) -NHRa, -C (= NH) -N (RaRb), -C (= NRC) -NH2 , -C (= NRC) - HRa, -C (= NRC) -N (RaRb), -NH-C (= NH) -NH2, - HC (= NH) - HRa, -NH-C (= NH) -N (RaRb), -NH-C (= NR °) -NH2, -NH-C (= NRC) -NHRa, -NH-C (= NRC) -N (RaRb), NRdH-C (= NH) -NH2, -NRd-C (= NH) -NHRa, -NRd-C (= NH) -N (RaRb), -NRd-C (= NRC) -NH2, -NRd-C (= NRc) -NHRa, -NRd-C (= NRC) -N (RaR), -NHNH2, -NHNHRa, -NHRaRb, -S02NH2, -S02NHRa, -S02NRaR, -CH = CHRa, -CH = CRaRb, -CRc = CRaRb, -CRc = CHRa, -CRc = CRaRb, -CCRa, -SH, -SRa, -S (0) Ra and -S (0) 2Ra. Ra-Rd are each independently an alkyl group, an aromatic group or a non-aromatic heterocyclic group, or -N (RaRb), taken together, form a substituted or unsubstituted non-aromatic heterocyclic. The heterocyclic aromatic or non-aromatic alkyl group represented by Ra-Rd and the non-aromatic heterocyclic group represented by -N (RaRb) are each optionally and independently substituted with one or more groups represented by R R # is R +, -OR +, -O (haloalkyl), -SR +, -N02, -CN, -NCS, -N (R +) 2, -NHC02R +, - HC (0) R +, -NHNHC (0) R +, -NHC (O) N (R *) 2, -NHNHC (0) N (R +) 2, -NHNHC02R +, -C (0) C (0) R +, -C (O) CH2C (O) R +, -C02R \ -C (0) R +, -C (0) N (R +) 2f -OC (0) R +, -OC (O) N (R +) 2, -S (0) 2R \ S02N (R +) 27 -S (0) R +, -NHS02N (R +) 2, -NHS02R +, -C (= S) N (R +) 2 or -C (= H) -N (R +) 2. R + is -H, a C ^ C ^ alkyl group, a heterocyclic monocyclic group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -N02, amine, alkylamine or dialkylamine. Optionally, the group -N (R +) 2 is a non-aromatic heterocyclic group, provided that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 containing a secondary ring amine are optionally acylated or alkylated. Preferred substituents for a phenyl group, including phenyl groups represented by R 1 -R 47 include C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 C haloalkyl C 1 -C 4 haloalkoxy, phenyl, benzyl, pyridyl, -OH, -NH 2, -F, -Cl, -Br, -I, -N02 or -CN. Preferred substituents are a cycloalkyl group, including cycloalkyl groups represented by Ri and alkyl groups, such as a methyl or ethyl group. Another embodiment of the present invention is a pharmaceutical composition containing a disal of bis (thiohydrazide amide) described herein and. a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers can contain inert ingredients that do not inhibit the biological activity of the disclosed disalts. The pharmaceutically acceptable carriers must be biocompatible, that is, non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions when administered to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. The formulation of the compound to be administered will vary depending on the selected route of administration (e.g., solution, emulsion, capsule). Pharmaceutical carriers suitable for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing approximately 0.9% mg / ml of benzyl alcohol), phosphate buffered saline. , Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a hard gelatin or cyclodextrin coating) are known in the art (Baker et al., "Controlled Relea-se of Biological Active Agents", John Wiley and Sons, 1986). Another embodiment of the present invention is a method of treating a subject with a cancer. Eventually, the method of the invention can be used for a cancer resistant to multiple drugs as described below. The method consists of the step of administering an effective amount of a disal of bis (thiohydrazide amide) described herein. Preferably, one or more additional anti-cancer drugs are coadministered with the bis (thiohydrazide amide) disal. Examples of anticancer drugs are described below. Preferably, the co-administered anticancer drug is an agent that stabilizes microtubules, such as taxol or a taxol analogue. A "subject" is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, eg, companion animals (eg, dogs, cats and the like), farm animals (eg, cows, sheep, pigs, horses and the like) and laboratory animals (eg, rats, mice, guinea pigs and the like). As indicated above, one embodiment The present invention is directed to the treatment of subjects with cancer. "Treating subjects with a cancer" includes achieving, partially or substantially, one or more of the following: stopping the growth or spread of a cancer, reducing the extent of a cancer (eg, reducing the size of a tumor or reducing the number of affected sites), inhibition of the growth rate of a cancer and improvement or improvement of a symptom or clinical indicator associated with a cancer (such as tissue or serum components). Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to, human sarcomas and carcinomas, eg, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphosarcoma , lymphangioendotheliosarcoma, sinovioma, mesothelium, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, carcinoma sweat glands, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cistadenocarcino-ma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, Testicular tumor, lung carcinoma, cell lung carcinoma small cells, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblas-toma, acoustic neuroma, oligodendroglioma, meningioma, mela-noma, neuroblastoma and retinoblastoma; leukemias, e.g. , acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (myelocytic leukemia (granu- chronic (chronic) and chronic lymphocytic leukemia), and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavy chain disease. Other examples of leukemia include acute and / or chronic leukemias, e.g. , lymphocytic leukemia (e.g., as exemplified by the p388 (murine) cell line), large granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplified by the CEM, Jurkat and HSB-2 (acute), YAC-1 (murine) cell lines), T lymphocytic leukemia and T lymphoblastic leukemia; B-cell leukemia (e.g., as exemplified by the SB (acute) cell line) and B-lymphocytic leukemia; mixed cell leukemia, e.g., leukemia of B cells and T lymphocytic leukemia B and T; myeloid leukemias, e.g., granulocytic leukemia, myelocytic leukemia (e.g., as exemplified by cell line HL-60 (promyelocytic)) and myelogenous leukemia (e.g., as exemplified by the K562 (chronic) cell line); neutrophilic leukemia; eosinophilic leukemia; monocytic leukemia (e.g., as exemplified by the THP-1 (acute) cell line); myelomonocytic leukemia; Naegeli-type myeloid leukemia; and non-lymphocytic leukemia. Other examples of leukemia are described in Chapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed., Williams & Williams (1992), and in Section 36 of Holland Fríe Cancer Medicine, 5th Ed., Bast et al., Eds. , B.C. Decker Inc. (2000). All the teachings of the above references are incorporated herein by reference. In one embodiment, it is believed that the disclosed method is particularly effective in the treatment of a subject with non-solid tumors, such as multiple myeloma. In another embodiment, it is believed that the method described is particularly effective against leukemia T (e.g., as exemplified by the Jurkat and CEM cell lines), leukemia B (eg, as exemplified by the SB cell line), promyelocytes (eg, as exemplified by the HL-60 cell line), uterine sarcoma (eg, as exemplified by the MES-SA cell line), leukemia monocytic (eg, as exemplified by the THP-1 (acute) cell line) and lymphoma (eg, as exemplified by the cell line U937); more preferably, this embodiment of the method employs the disodium salt of Compound (1). The method described is particularly effective in the treatment of subjects whose cancer has become "multi-drug resistant". A cancer that initially responded to an anticancer drug becomes resistant to the anticancer drug when the anticancer drug is no longer effective in treating the subject with the cancer. For example, many tumors will initially respond to treatment with an anticancer drug by reducing in size or even by remission, only to develop resistance to the drug. Drug-resistant tumors are characterized by resuming their growth and / or reappearing after apparently remitting, despite the administration of higher dosages of the anticancer drug. It is said that cancers that have developed resistance to two or more anticancer drugs are "resistant to multiple drugs." For example, it is common for cancers to become resistant to three or more anticancer agents, often to five or more anticancer agents and sometimes to ten or more anticancer agents. An "effective amount" is the amount of compound with which a clinical benefit-s result is achieved when the compound is administered to a subject with a cancer. A "beneficial clinical result" includes a reduction in tumor mass, a reduction in metastasis, a reduction in the severity of symptoms associated with cancer and / or an increase in the subject's longevity compared to the absence of treatment. The precise amount of compound administered to a subject will depend on the type and severity of the disease or condition and the characteristics of the subject, such as general health, age, sex, body weight and drug tolerance. It will also depend on the degree, severity and type of cancer. The person skilled in the art will be able to determine the appropriate dosages depending on these and other factors. The effective amounts of the described compounds typically vary between about 1 mg / mm2 per day and about 10 grams / mm2 per day and preferably between 10 mg / mm2 per day and about 5 grams / mm2. When coadministered with another anticancer agent, an "effective amount" of the second anticancer agent will depend on the type of drug used. Appropriate dosages for approved anticancer agents are known and can be adjusted by the person skilled in the art according to the condition of the subject, the type of cancer being treated and the amount of disal of bis (thiohydrazide amide) that is being used. The disclosed bis (thiohydrazide amide) disalts are administered by any suitable route, including, for example, the oral one in capsules, suspensions or tablets, or parenteral administration. Parenteral administration may include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous or intraperitoneal injection. Bis (thiohydrazide amide) disals can also be administered orally (eg, via the diet), topically, by inhalation (eg, intrabronchial, intranasal or oral inhalation or intranasal drops) or rectally, depending on the type of cancer to be treated. Oral and parenteral administrations are preferred modes of administration. Eventually, bis (thiohydrazide amide) disals can be co-administered with other anticancer agents.

Waxes, such as Adriamycin, Dactinocymin, Bleomycin, Vinblastine, Cisplatin, acivicin, Aclarubicin, Acodazole Hydrochloride, Acronine, adozelesin, Aldesleukin, Altreta-Mine, Ambomycin, Ametantrone Acetate, Aminoglutethimide, Amsacrine, Anastrozole, Anthramycin, Asparginase, Asperlin, Azacitidine, Azetepa, Azotomycin, Batimastat, Benzodepa, Bi-Calutamide, Hydrochloride of bisantrene, bisnaphi-dimesylate, bizelesin, bleomycin sulfate, brequine sodium, bro-pyrimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carrubi-cin hydrochloride, carzelesin, cedefingol, chlorambucil: cirolemycin, cladribine, chrythromatin mesylate, cyclophosphamide, cytarabi-na, dacarbazine, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diazi-cuona, doxorubicin, doxorubicin hydrochloride, droloxy-phenoxime, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsami-trucine, enloplatin, empromat, epipropidine, epir hydrochloride rubicin, erbulozole, eshorubine hydrochloride, estra-mustine, sodium estramustine phosphate, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, icarubicin hydrochloride, ifosfamide, ilmofosin, interleukin II (including recombinant interleukin II, or rIL2), inter-feron alfa-2a, interferon alfa-2b, interferon alfa-nl, in-terferon alfa-n3, interferon beta-I a, interferon ganma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuproide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, ma-soprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate, sodium methotrexate, metoprine, meturedepa, mitindomide, mitocarcin, mitochromin, mitogillin, mitomalin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, walnut micinha, ormaplatin, oxisuran, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, pipo-sulfan, piroxantrone hydrochloride, plicamycin, pentamethasone, porfimer sodium, porfirinomycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazolefine, riboprine, rogletiraide, safingol, safingol hydrochloride, semustine: simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine, spiro-platin, streptonigrin, streptozocin, sulofenur, taliso-mycin, tecogallan sodium, tegafur, teloxanthrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, tiami-prine, thioguanine , thiotepa, thiazofurine, tirapazamine, citrate-toremifene, trestolone acetate, trichirin-phosphate, trimetrexate, glu trimetrexate curonato, triptoreli-na, tubulozol hydrochloride, uracil mustard, uredepa, va-preotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vi-nepidine sulfate, vinglicinato sulfate, vinleurosine sulfate , vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatine, zinostatin and zorrubicin hydrochloride. Other anticancer drugs include, but are not limited to: 20-epi-l, 25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylful eno, ade-cipenol, adozelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox , amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, an-drografolida, angiogenesis inhibitors, D antagonist, G antagonist, antarelix, anti-dorsalizing morphogenetic protein-1, antiandrogen, prostatic carcinoma, antiestrogen, antineoplaston, antisense oligonucleotides, glycinate of aphidicolin, modulators of apoptosis genes, regulators of apoptosis, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane, atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron, azatoxin, azathirosine , baccatine III derivatives, balanol, batimastat, BCR / ABL antagonists, benzoclorins, benzoyl-lestaurosporine, beta-lactam derivatives, beta-aletine, betaclamycin B, betulinic acid, bFGF inhibitor, bicalu-tamide, bisantrene, bisaziridinylpermine, bisnafide, bis-tryne A, bizelesin, breflato, biririmin, budotitan, bu-thionin sulfoximin, calcipotriol, calfostin C, camptothecin derivatives, canaripox IL-2, capecitabine, carboxamidamino-triazole, carboxyamidotriazole, CaRest M3, CARN 700, derivative inhibitor of cartilage, carzelesine, casein kinase inhibitors (ICOS), castanospermine, cecropin B, cetrorelix, clo-rinas, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin, cladribine, analogue clomiphene, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analogue, conagenin, crambescidin 816, crisnatol, cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentantraquinones, cycloplatam, cipemycin, cytarabine ocphosphate, cytolithic factor, cytostatin, dacliximab, deci-tabin, dehydrodidemnin B, deslorelin, dexamethasone, dexi- phosphamide, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorespermine, dihydro-5-azacytidine, 9-dioxamycin, diphenylspiromustine, docosanol, dolasetron , doxifluridine, droloxifene, dronabinol, duocarmycin SA, eb-selen, ecomustine, edelfosine, edrecolomab, eflornithine, ele-meno, emitefur, epirubicin, epristeride, estra-mustine analogue, estrogen agonists, estrogen antagonists, etanidazole, phosphate etoposide, exemestane, fadrozole, faza-rabina, fenretinide, filgrastim, finasteride, flavopiridol, flezelastine, fluasterone, fludarabine, hydrochloride luo-rhodunorrunicin, forfenimex, formestane, fostriecin, fote- mustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, heregulin, hexamethylenebiscetamide, hypericin, ibandronic acid, idarubicin, idoxifen, idramantone, ilmofosin, ilomastat, imidazoacrido -nas, imiquimod, immunostimulatory peptides, inhibitor of insulin-like growth factor-1 receptor, interferon agonists, interferons, interleukins, iobengua-no, iododoxorubicin, 4-ipomeanol, iroplact, irsogladine, isobengazol, isohomohalicondrine B, itasetron, j asplakinoli-da, kahalalide F, lamelarin-N triacetate, lanreotide, leinamycin, lenograstim, lenthranil sulfate, leptolestatin, letrozole, leukemia inhibitory factor, leukocyte alpha-interferon, leuprolide + estrogen + progesterone, leuprorelin, levamisole , liarozole, linear polyamine analog, lipophilic disaccharide peptide, lipophilic platinum compounds, lissoclinamide 7, lobaplatin a, lombricin, lome-trexol, lonidamine, losoxantrone, lovastatin, loxoribine, lurtotecan, lutetium texaphyrin, lyophilin, lytic peptides, maytansine, manostatin A, marimastat, masoprocol, mas-pina, inhibitors of matrilysin, inhibitors of meta - Matrix proteinase, menogaril, merbarone, meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitomycin analogues, mitonafide, fibroblast growth factor mitotoxin- saporin, mitoxantrone, mofarotene, molgramostim, monoclonal antibody, human chorionic gonadotropin, monophosphoryl lipid A + sk of the myobacterial cell wall, mopidamol, inhibitor of multi-drug resistance genes, suppressor-based therapy multiple tumor 1, mustard anticancer agent, micaperoxide B, mycobacterial cell wall extract, myriaporone, N-acetyldinaline, benzamides IT-substi tuidas, nafarelina, nagrestip, naloxona + pentazo-cin, napavine, nafterpina, nartograstim, nedaplatin, nemorrubiciña, neridrónico acid, neutral endopeptidasa, nilutamida, ni-samicina, modulators of nitric oxide, antioxidant ni-tróxido, nitrulina, 06-bencilguanina, octreotida, okicenona, oligonucleótidos, onapristona, ondansetrón, ondansetrón, ora-cina, oral cytokine inducer, ormaplatin, osaterone, oxa-liplatine, oxaunomycin, palauamine, palmitoylrizoxin, pamidronic acid, panaxitriol, panomiphene, parabactin, pazellip-tina, pegaspargase, peldesin, pentosan polysulfate sodium, pentostatin, pentrozole, perflubron, perfosfamide, perilylic alcohol, phenazinomycin, phenylacetate, fos-fatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piritrexim, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, platinum compounds, platinum-triamine complex , sodium porfimer, porphyromycin, prednisone, propylbisacridone, prostaglandin J2, protease inhibitors more, immune modulator based on protein A, protein kinase C inhibitor, protein kinase C inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine inhibitors, nucleoside phosphorylase, purpurins, pyrazoloacridine, hemoglobin conjugate and polyoxyethylene pyridoxylated, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferasta inhibitors, ras inhibitors, ras-GAP inhibitor, demethylated retelliptin, rhenium etidronate Re 186, rhizoxin, ribozymes, retinoid RII, rogletimide, rohitukine, romurtide, roquini-mex, rubiginone Bl, ruboxil, safingol, saintopine, SarC U, sarcofitol A, sargramostim, mimetics of Sdi 1, semustine, inhibitor 1 derived from senescence, oligonucleotides sensed, inhibitors of signal transduction, modulators of Signal transduction, single chain antigen binding protein, sizofirán, sobuzoxane, sodium borocaptate, sodium fe-nilacetate, solverol, pro Somatome-dine binding tenet, sonermin, sparphosic acid, spicamycin D, spiro- mustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitor, inhibitors of the division of stem cells, stimiamide, inhibitors of stromelysin, sulfinosin, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonin, glycosaminoglycan synthetic hairs, talimustine, tamoxifen methylodide, tau-romustine, tazarotene, tecogalane sodium, tegafur, telurapyri-lio, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, taliblastin, thiocoraline, thrombopoietin, thrombopoietin mimetic, thymus pharynx thymopoietin receptor agonist, thymotri-nano, thyroid stimulating hormone, tin ethylethypurpurine, tirapazamine, titanocene bichloride, topsentin, toremifene, totipotent stem cell factor, translational inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin , tropisetron, turosteride, tyrosine inhibitors k inasa, tyrphostins, UBC inhibitors, ubenimex, urogenital-derived growth inhibitory factor, urokinase receptor antagonists, vapreotyda, variolin B, vector system, erythrocyte gene therapy, velaresol, veramin, verdins, verteporfin, vinorel -bath, vinxaltin, vitaxin, vorozole, zanoterone, zeniplatine, zilascorb and zinostatin esterase. Additional preferred anticancer drugs are 5-fluorouracil and leucovo-rabies. Examples of therapeutic antibodies that can be used include, but are not limited to, HERCEPTIN® (Trastuzumab) (Genentech, CA), which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO® (abciximab) (Centocor), which is an anti-glycoprotein receptor Ilb / lIIa on platelets, for the prevention of clot formation; ZENAPAX® (daclizumab) (Roche Pharmaceuticals, Switzerland), which is a humanized immunosuppressant anti-CD25 monoclonal antibody for the prevention of acute rejection of renal allografts; PANOREX ™, which is an IgG2a anti-cell surface antigen 17-IA antibody (Glaxo Wellcome / Centocor); BEC2, which is an anti-idiotype IgG antibody (murine epitope GD3) (Im-Clone System); IMC-C225, which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN ™, which is a humanized αβ3 integrin anti-integrin antibody (Applied Molecular Evolution-Medimmune); Campath 1H / LDP-03, which is a humanized anti-CD52 IgGl antibody (Leukosite); Smart M195, which is a humanized anti-CD33 anti-body IgG (Protein Design Lab / anebo); RITUXAN ™, which is a chimeric anti-CD20 IgGl antibody (IDEC Pharm / Genentech, Roche / Zettyaku); LYMPHOCIDE ™, which is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE ™ Y-90 (Immunomedics); Lymphoscan (labeled with Tc-99m, radioimaging, Immunomedics); Nuvion (against CD3, Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primatized anti-CD80 antibody (IDEC Pharm / Mitsubhishi); ZEVALIN ™ is a radiolabeled murine anti-CD20 antibody (IDEC / Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC / Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC / Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is an anti-humanized complement factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-antibody (CAT / BASF); CDP870 is a humanized anti-TNF-a Fab fragment (Celltech); IDEC-151 is a primatized anti-CD4 IgGl antibody (IDEC Pharm / SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex / Eisai / Genmab); CD20-streptavidin (+ biotin-yttrium 90, NeoRx); CDP571 is a humanized anti-TNF-α IgG4 antibody (Celltech); LDP-02 is a humanized anti-a4p7 antibody (LeukoSite / Genentech); Ort-hoClone 0KT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA ™ is a humanized anti-CD40L IgG antibody (Biogen); ANTEGREN ™ is a humanized anti-VLA-4 IgG antibody (Elan), and CAT-152 is a human anti-TGF ~ P2 antibody (Cambridge Ab Tech). As chemotherapeutic agents that can be used in the methods and compositions of the invention, include, but are not limited to, alkylating agents, antimetabolites, natural products or hormones. Examples of alkylating agents useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include, but are not limited to, nitrogenous mustards (eg, mechloroethamine, cyclophosphamide, chlorambu-cyl, etc.), alkyl sulfonates (eg, busulfan), nitro-soureas (eg, carmustine, lomusitna, etc.) or triazenes (des-carbazine, etc.). Examples of antimetabolites useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include, but are not limited to, folic acid analogs (eg, methotrexate) or pyrimidine analogs (eg, Cytarabine), purine analogs (eg, mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of T cell malignancies in the methods and compositions of the invention include, but are not limited to, vinca alkaloids (eg, vinblastine, vincristine), epipodophyllotoxins (eg, etoposide) , antibiotics (eg, daunorubicin, doxorubicin, bleomycin), enzymes (eg, L-asparraginase) or biological response modifiers (eg, interferon alpha). Examples of alkylating agents useful for the treatment or prevention of cancer in the methods and compositions of the invention include, but are not limited to, nitrogenous mustards (eg, mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylene imine and metylmelamines (eg, hexamethylmelamine, thiotepa), alkyl sulfonates (eg, busulfan), nitroso-ureas (eg, carmusti- na, lomusin, semustine, streptozin, etc.) or triazenes (descarbazine, etc.). Examples of antimetabolites useful for the treatment or prevention of cancer in the methods and compositions of the invention include, but are not limited to, folic acid analogues (eg, methotrexate) or pyrimidine analogues (eg, fluorouracil, floxoridine). , cytarabine) and purine analogs (eg, mercaptopurine, thio-guanine, pentostatin). Examples of natural products useful for the treatment or prevention of cancer in the methods and compositions of the invention include, but are not limited to, vinca alkaloids (eg, vinblastine, vin-cristina), epipodophyllotoxins (eg, etoposide). , teniposide), antibiotics (eg, actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (eg, L-asparraginase) or biological response modifiers (eg, interferon alpha). Examples of hormones and antagonists useful for the treatment or prevention of cancer in the methods and compositions of the invention include, but are not limited to, adrenocorticosteroids (eg, prednisone), progestin (eg, hydroxyprogesterone caproate, megestrol, medroxyprogesterone acetate), estrogens (eg, diethylstilbestrol, ethinylestradiol), anti-estrogens (eg, tamoxifen), androgens (eg, testosterone propionate, fluoxymesterone), antiandrogens (eg, flu-tamide), and releasing hormone analogues of gonadotropins (eg, leuprolide). Other agents that can be used in the methods and compositions of the invention for the treatment or prevention of cancer include platinum coordination complexes (eg, cisplatin, carboblatin), an-trancenedione (eg, mitoxantrone), substituted urea ( eg, hydroxyurea), methylhydrazine derivatives (eg, procarbazine) and adrenocortical suppressors (eg, mitotane, aminoglutethimide). It is believed that disalts of bis (thiohydrazide ami- da) described herein are particularly effective when coadministered with anticancer agents that act by stopping the cells in the G2- phases due to stabilization of the microtubules. A) Yes, the described method preferably includes the co-administration of anticancer drugs that act by this mechanism. Examples of anticancer agents that act by stopping the cells in the G2-M phases due to stabilization of the microtubules include, but are not limited to, the following commercially available drugs and drugs in development: Erbulozol (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), My obulin isethionate (also known as CI-980), Vin-cristina, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorrirtins (such as Altorrirtin A and Altorrirtin C),. Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cemadotine hydrochloride (also known as LU-103793 and NSC-D) -669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as deoxiepotilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB and deoxyhepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-azaepothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Deoxiepotilone F and dEpoF), 26 -fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 ( Aventis), Vincristine Sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Acaderay of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko) , AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700 (Ajino-moto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), Vitilevuamide, Tubulisin A, Canaden-sol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261 ), H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fi-jianolida B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU ( Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapina, D-24851 (Acta Medica), A-105972 (Ab-bott), Hemiasterline, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocin (also known as NSC-698666), 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-115781 (Aventis), Eleuterobins (such as Des-methyleleuterobina, Desetileleuterobina, Isoeleterocobina A and Z-Eleuterobina), Caribaeoside, Caribaeolina, Halicondrine B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB- 245 (Aventis), A-259754 (Abbott), Diozostatin, (-) - Phenil-ahistine (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Mioseverin B, D - 43411 (Zen-taris, also known as D-81862), A-289099 (Abbott), A- 318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (yeth), D-82317 (Zentaris), D-82318 (Zen-taris), SC-12983 (NCI), sodium resverastatin phosphate , BPR-OY-007 (National Health Research Institutes) and SSR-250411 (Sanifi), and Hsp90 inhibitors, such as geldanmycin, radicicol, herbimycin A, macbecin I and II, novobiocin, 17-Allylamino-17-desme-toxigeldanamycin (17AAG), 17-Demethoxy-17- [2- (dimethylamino) ethylamino] geldanamicha (17DMAG), CNF-1010, purine-based Hsp90 inhibitors, such as PU3, PU24FC1 and PU29FC1, and radicicol oxime derivatives, such as KF25706 and KF58333. Taxol, also referred to as "Paclitaxel", is a well-known anticancer drug that acts by increasing and stabilizing the formation of microtubules. In Figure 1 the structure of taxol is shown. Many taxol analogues are known, including taxotere, whose structure is shown in Figure 2. Taxotere is also referred to as "Docetaxol". The structures of other taxol analogs are shown in Figures 3-23. These compounds have the basic skeleton of the taxane as a characteristic of common structure and have also been seen to be capable of stopping the cells in the G2-M phases due to stabilization of the microtubules. Thus, it can be seen from Figures 3-23 that a wide variety of substitutes can decorate the taxane backbone without adversely affecting biological activity. It can also be seen that none, one or both of the cyclohexane rings of a taxol analog can have a double bond at the indicated positions. For purposes of clarity, the basic skeleton of the taxane in the Structural Formula is shown below.

(SAW) : The double bonds of the cyclohexane rings in the taxane skeleton represented by the Structural Formula (VI) have been omitted. The basic skeleton of the taxane can include zero or a double bond in one or both of the cyclohexane rings., as indicated in Figures 3-23 and in the following Structural Formulas (VII) and (VIII). A number of atoms of the Structural Formula (VI) have also been omitted to indicate sites in which structural variation among the taxol analogs commonly occurs. For example, the substitution on the backbone of the taxane simply with an oxygen atom indicates that a hydroxyl, acyl, alkoxy and oxygen-bearing substituent is commonly present at the site. These and other substitutions on the taxane skeleton can be made without losing the ability to increase and stabilize microtubule formation. Thus, the term "taxol analog" is defined herein as meaning a compound having the basic skeleton of taxol and promoting the formation of microtubules. The taxol analogues can be formulated as a colloidal composition of nanoparticles to improve the infusion time and to eliminate the need to administer the drug with Cremophor, which causes hypersensitivity reactions in some patients. An example of a taxol analog formulated as a colloidal composition of nanoparticles is ABI-007, which is a colloidal composition of paclitaxel nanoparticles that is stable. with protein that is reconstituted in saline. Typically, the taxol analogs used herein are represented by Structural Formula (VII) or (VIII): (HIV) 10 is a lower alkyl group, a substituted lower alkylene group, a phenyl group, a substituted phenyl group, -SR19, -NHR19 or -0R19. R1X is a lower alkyl group, a substituted lower alkyi group, an aryl group or a substituted aryl group. R12 is -H, -OH, lower alkyl, lower alkyl substituted rior, lower alkoxy, substituted lower alkoxy, -0-C (O) - (lower alkyl), -0-C (0) - (substituted lower alkyl), -0-CH2-0- (lower alkyl) or - S-CH2-0- (lower alkyl). R13 is -H, -CH3 or, taken together with R14, -CH2-. R14 is -H, -OH, lower alkoxy, -0-C (O) - (lower alkyl), substituted lower alkoxy, -0-C (O) - (substituted lower alkyl), -0-CH2-0-P (O) (0H) 2, -0-CH2-0- (lower alkyl), -0-CH2-S- (lower alkyl) or, taken together with R20, a double bond. R1S is -H, lower acyl, lower alkyl, substituted lower alkyl, alkoxymethyl, alctiomethyl, OC (O) -O (lower alkyl), -OC (O) -O (substituted lower alkyl), -OC (O) -NH (lower alkyl) or -OC (O) -NH (substituted lower alkyl). R16 is phenyl or substituted phenyl. R 17 is -H, lower acyl, substituted lower acyl, lower alkyl, substituted lower alkyl, (lower alkoxy) methyl or (lower alkyl) thiometyl. R18 is -H, -CH3 or, taken together with R17 and the carbon atoms to which R17 and R18 are attached, a five or six membered non-aromatic heterocyclic ring. R19 is a lower alkyl group, a substituted lower alkyl group, a phenyl group or a substituted phenyl group. R20 is -H or a halogen. R21 is -H, lower alkyl, substituted lower alkyl, lower acyl or substituted lower acyl. Preferably, the variables in the Structural Formulas (VII) and (VIII) are defined as follows: R10 is phenyl, tert-butoxy, -S-CH2-CH- (CH3) 2, -S-CH (CH3) 3, - S- (CH2) 3CH3, -0-CH (CH3) 3, -NH-CH (CH3) 3, -CH = C (CH3) 2 or para-chlorophenyl; R1X is phenyl, (CH3) 2CHCH2-, 2-furanyl, cyclopro-pyl or para-toluyl; R12 is -H, -OH, CH3C0- or - (CH2) 2-iV- morpholino; R13 is methyl, or R13 and R14, taken together, are -CH2-; R14 is -H, -CH2SCH3 or -CH2-0-P (0) (0H) 2; R1S is CH3CO-; R16 is phenyl; R17 is -H, or R17 and R18, taken together, are -0-C0-0-; R18 is -H; R20 is -H or -F; and R21 is -H, -C (0) -CHBr- (CH2) 13-CH3 or -C (O) - (CH2) 14 -CH3, -C (O) -CH2-CH (OH) -COOH, - C (O) -CH2-0-C (O) -CH2CH (NH2) -C0NH2, -C (O) -CH2-0-CH2CH2OCH3 or C (O) -0-C (O) -CH2CH3. A taxol analog can also bind to, or be aware of, a pharmaceutically acceptable polymer, such as a polyacrylamide. An example of such a polymer is shown in Figure 24. The term "taxol analog", as used herein, includes such polymers. The bis (thiohydrazide amide) disals described herein can be prepared by a method of the invention. The method of preparing the bis (thiohydrazide amide) disalts described includes the steps of combining a neutral bis (thiohydrazide amide), an organic solvent and a base to form a solution of bis (thiohydrazide amide) and combining the solution and a organic antisolvent, thereby precipitating a disal of the bis (thiohydrazide amide) (eg, compounds represented by the Structural Formulas (I) - (V)). The neutral forms of the bis (thiohydrazide amide) disals described can be prepared according to methods described in US Publications. N ° 2003/0045518 and 2003/0119914, both entitled TAXOL SYNTHESIS OF POTENTIALS, and also according to methods described in the US Publication. N ° 2004/0225016 Al, entitled TREATMENT FOR CANCERS. All the teachings of these publications are incorporated here for reference. Typically, at least about two molar equivalents of the base are employed per molar equivalent of neutral bis (thiohydrazide amide); more typically, from about 2 to about 5 equivalents, or preferably from about 2.0 to about 2.5 equiv- worthy Suitable bases can be strong enough to react with a bis (thiohydrazide amide) and produce a disal. In various embodiments, the base may be an amine (eg, triethylamine, diphenylamine, butylamine or the like), an ammonium hydroxide (eg, tetramethyl ammonium hydroxide, tetrabutylammonium hydroxide or the like), a metal hydroxide alkali (lithium hydroxide, sodium hydroxide, potassium hydroxide or the like), an alkali metal C 1 -C 8 alkoxide or an alkali metal amide (eg, sodium amide, lithium diisopropylamide or the like). In some embodiments, the base is sodium hydroxide, potassium hydroxide, sodium C1-C6 alkoxide, alkoxide of potassium, sodium amide or potassium amide, or preferably sodium hydroxide, sodium methoxide or sodium ethoxide. In various embodiments, the base may be an alkali metal hydride (e.g., sodium hydride, potassium hydride or the like), a divalent metal base (e.g., magnesium oxide), a alkali (e.g., butyl lithium) or an alkali metal aryl (e.g., phenyllithium). More typically, the base is lithium hydride, sodium hydride, potassium hydride, butyl lithium, butyl sodium, butyl potassium, phenyl-lithium, phenylsodium or phenyl-potassium. As used herein, an alkali metal includes lithium, sodium, potassium, cesium and rubidium. The organic solvent can be any organic solvent that is stable when the base is added to a mixture of the bis (thiohydrazide amide) and the organic solvent. Typically, the organic solvent is sufficiently polar to dissolve the bis (thiohydrazide amide) salt formed by the method to form a solution. In various embodiments, the organic solvent is miscible in water. The organic solvent can generally be selected from an aliphatic alcohol Cx-C4 (e.g., methanol, ethanol, 1-propanol, 2- propanol or the like), an aliphatic ketone Cx-C4 (eg, acetone, methyl ethyl ketone, 2-butanone or the like), a C2-C4 aliphatic ether (eg, diethyl ether, dipropyl ether, diisopropyl ether or the like), a C2-C4 cycloaliphatic ether (eg tetrahydrofuran, dioxane or the like), dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, a glycol (eg, ethylene glycol, propylene glycol, tetramethylene glycol or the like), an alkyl glycol ether (eg , ethylene glycol dimethyl ether or the like) and acetonitrile. More typically, the organic solvent may be selected from methanol, propanol (e.g., 1-propanol, 2-propanol), butanol (e.g., 1-butanol, tert-butyl alcohol or the like), acetone, tetrahydrofuran, and methyl ethyl ketone. Preferably, the organic solvent can be selected from methanol, ethanol, acetone and methyl ethyl ketone. As used herein, the organic antisolvent is a solvent which, when added to the solution created by combining the base, the bis (thiohydrazide amide) and the organic solvent, causes the precipitation of the bis (thiohydrazide amide) disal from the solution. Typically, the organic antisolvent can be selected from a C5-cyano (? · 9 · / pentane, petroleum ether, hexane, heptane, octane, isooctane or similar) alkane, C5-C10 cycloalkane (eg, cyclohexa-no, cyclopentane or similar), a C3-C10 alkyl ester (eg, ethyl acetate, propyl acetate, methyl butyrate or the like), a C3-C10 alkyl ether (eg, methyl ethyl ether, diethyl ether, methyl propyl ether or the like) ), benzene, toluene and xylene. More typically, the organic antisolvent can be selected from diethyl ether, dipropyl ether (eg, propyl as 1-propyl or 2-propyl), methyl propyl ether, ethyl propyl ether, methyl tert-butyl ether, methyl acetate, ethyl acetate , propyl acetate, pentane, hexane, cyclohexane, heptane and petroleum ether. In some embodiments, the organic antisolvent may be a C3-C10 alkane or C5-C10 cycloalkane. In various preferred embodiments, the organic antisolvent may be heptane, or the organic antisolvent may be diethyl ether or ethyl acetateIn various preferred embodiments, the organic antisolvent may be methyl tert-butyl ether. In various embodiments, the neutral bis (thiohydrazide-amide) may be substantially insoluble in the organic solvent, thereby forming a mixture, whereby, by combining the base with the mixture, a solution of bis (thiohydrazide amide) is formed. Typically, the bis (thiohydrazide amide) solution can be transparent. In general, between about 0.25 and about 2.5 moles of the neutral bis (thiohydrazide amide) are combined per liter of organic solvent, or typically between about 0.75 and about 1.5 moles of the neutral bis (thiohydrazide amide) per liter of organic solvent. Preferably, about 1 mole of the neutral bis (thiohydrazide amide) is combined per liter of organic solvent. As used agui, a "solution of bis (thiohydrazide amide), when formed from the organic solvent, the neutral bis (thiohydrazide amide) and the base, may include one or more species such as bis (thiohydrazide amide) neutral, the monosal of bis (thiohi-drazide amide), the disal of bis (thiohydrazide amide) or the like .. In preferred embodiments, the organic solvent is ethanol.Preferably, the base is aqueous sodium hydroxide of about 2 molar to about 5 molar. molar, or more preferably from about 2 to about 2, 5 molar. In preferred embodiments, the organic solvent is acetone. Preferably, the base is ethanolic sodium ethoxide of about 2 molar to about 5 molar, or more preferably from about 2 to about 2.5 molar. The bis (thiohydrazide amide) disalts prepared by the present invention are the disalts described above, including those represented by the Structural Formulas (I) - (V). The neutral bis (thiohydrazide amides) employed in the described method for preparing the disks represented by the Structural Formulas (I) - (II) can be represented by the following Structural Formulas (I ') - (II'), where the variables have the same values and preferred values as in the Structural Formulas (I) - (II), respectively: Thus, as used herein, a neutral bis (thiohydrazide amide) has at least two hydrogens (eg, the hydrogens bonded to the nitrogen atoms in the Structural Formulas (? ') And (II') which can react with the bases described herein to form a disal In Structural Formula (I), M + is a pharmaceutically acceptable monovalent cation M2 + is a pharmaceutically acceptable di-valent cation as described above In various preferred embodiments, the organic solvent may be acetone; the base can be ethanolic sodium ethoxide, the organic solvent can be ethanol, the base can be aqueous sodium hydroxide, the antisolvent can be heptane, the neutral bis (thiohydrazide amide) can be: and / or the neutral bis (thiohydrazide amide) can be: The present invention is illustrated by the following examples, which are not intended to be limiting in any way. EXAMPLES Example 1. 2- (N '-Methyl-N' -thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) sodium ethanolate: Compound (3) To a stirred clear solution of N-ma-lonylbis (β '-thiobenzoyl-N' -methylhydrazide) (2 g) in THF (25 ml), sodium amide (0.2 g) was added. The resulting mixture was stirred at room temperature for 4 hours. The precipitated product was collected by filtration and washed with THF and ether. The resulting solids were dried in vacuo (0.1 mmHg) for 12 hours. A light yellow solid weighing 1.53 g was obtained.

^ -NMR (DMSO-ds) d (ppm): 2.2-2.7 (m, 2H), 3.1-3.7 (m, 6H), 7.1-7.5 (m, 10H ). Elemental analysis calculated for C19H19N4Na02S2 · 0.55H20: C 52.75%, H 4.66%, N 12.98%; found: C 52.42%, H 4.41%, N 13.07%. Example 2. 2 - (? '- Methyl-N' -thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) ethoxide disodium: Compound (1) Method A: To a stirred clear NaOH solution (0.358 g, 8.95 mmol) in H20 (10 mL), N-malonylbis ('-thiobenzoyl-N' -methyl idrazide) (1.79 g, 4, 48 mmol) at room temperature. The resulting solution was filtered and then the filtrate was cooled with a dry ice / PrOH bath, followed by lyophilization, to obtain Compound 1 as a solid. ^ "H-NMR (DMSO-d6) d (ppm): 2.15 (s, 2H), 3.45 (s, 6H), 7.0-7.2 (m, 6H), 7.2- 7.4 (m, 4H) Elemental analysis calculated for C19H18N4Na202S2 · 0.7H20 (457.22): C 49.91, H 4.29, N 12.26, found: C 49.95, H 4.17 N 12.05 Method B: To a stirred solution of N-malonylbis (β '-thiobenzoyl-N' -methylhydrazide) (0.92 g) in THF (15 ml), a solution of NaOH (0.184 g) was added. ) in MeOH (15 mL) After 15 minutes of stirring at room temperature, the resulting solution was concentrated and precipitated with ether, to obtain 1 g of a light orange powder after filtration. according to those obtained from Method A.

Example 3. Lithium 2- (α'-methyl-N '-thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) ethanolate: Compound (4) To a solution of N-malonylbis (N '-thiobenzoyl-N' -methylhydrazide) (8 g, 20 mmol) in THF (90 ml), lithium di-sopropylamide was added. (LDA) (20 mmol, 2M in hepta-no / THF / ethylbenzene) at 0 ° C and the mixture was stirred for 2 hours. The precipitate was collected, washed with EtOAc and dried, to give a lithium monosal of N-malo-nilbis (N '-thiobenzoyl-N' -methylhydrazide) (6.5 g). ¾-NMR (DMSO-d6) d (ppm): 7.71-7.32 (m, 10H), 3, 72-2, 73 (m, 9H). Example 4. 2- (N '-Methyl-N' -thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) dilithic ethanolate: Compound (5) Compound 5 was prepared according to the method described in Example 3, except for using 2 equivalents of LDA instead of one equivalent. "" "H-NMR (DMSO-ds) 5 (ppm): 7.61-7.12 (m, 10H), 3.82-2.29 (m, 8H) Example 5. 2- (? ' Etethyl amine-N'-thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) ethanolate ethanolate: Compound (6) The monoethanolamine compound was prepared in a similar manner to that of Example 3 using one equivalent of Ethanolamine instead of LDA. 1 H-RM (DMSO-d 6) d (ppm): 7.72-7.33 (m, 10H), 3.80-2.63 (m, 13H). EXAMPLE 6 Diethanolamine 2- (α'-Methyl-N '-thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) ethanolate: Compound (7) The diethanolamine compound was prepared in a similar manner to that of Example 3 using two equivalents of ethanolamine in place of an equivalent of LDA. "-H-NMR (DMS0-d6) d (ppm): 7.69-7.31 (m, 10H), 3, 78-2, 64 (m, 16H). Example 7. Magnesium-2 - ('' -Methyl-N '-thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) ethanolate: Compound (8) The pH of an MgO suspension (440 mg, 1.1 mmol, 15 ml) in water was adjusted to 2-3 to form a clear solution. To this solution was added 2 - (N '-methyl-N' -thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) ethanolate dilithic (1 mmol) and the mixture was stirred for 3 hours. The formed precipitate was collected and washed with water and then dried to obtain the magnesium salt (2.1 g). ¾-NMR (DMSO-d6) d (ppm): 7.68-7.32 (m, 10H), 3.98-2.49 (m, 8H). Example 8. 2- (N '-Methyl-N'-thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) calcium ethanolate: Compound (9) The calcium compound was prepared in a similar manner to that of Example 7 using Ca (OH) 2 instead of MgO. XH-NMR (DMSO-d6) d (ppm): 7.67-7.34 (m, 10H), 3, 91-2, 55 (m, 8H). Example 9. 2- ('-Methyl-N' -thiobenzoylhydrazinocarbonyl) -1- (Methylthiobenzoylhydrazono) monopotassium ethanolate: Compound (10) N-malonylbis (β '-thiobenzoyl-N' -methylhydrazide) (micronized), 5.006 g (12.5 mmol), was suspended in 70 ml of absolute ethanol. 12.4 ml (1 equivalent) of a 1.008 N solution of potassium hydroxide in methanol was added to this suspension with stirring. The resulting solution was filtered through a glass acrodisk (Gelman) and concentrated to approximately 5 ml. To this concentrated solution was added 5 ml of ethyl acetate, followed by anhydrous ether, until the resulting solution became turbid. This solution was left for crystallization overnight. A hardened precipitate was broken with a spatula, filtered, washed twice with anhydrous ether and dried under vacuum at 50 ° C to obtain a monopotassium salt as light yellow solids (4.05 g, 70%). ^ • H-RM (DMSO-d6) (a mixture of tautomers) d (ppm): 7.4-7.25, 7.22 (m, 10H), 3.60, 3.45 and 3.19 ( singlets, 6H), 2.78, 2.39 and 1.96 (singlets, 3H). IR (Br): 1686s, 1572, 1478 was "1. Analysis calculated for C19H19K2N402S2 + H20: C, 49.98; H, 4.64; K, 8.56; N, 12.27. Found: C, 49 , 99; H, 4.51; K, 8.67; N, 11.91.

Example 10. 2- (β '-Methyl-N' -thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) dipotassium ethanolate: Compound (2) Method A: N-malonylbis (N '-thioben-zoyl-' -methylhydrazide) (micronized, 5.006 g, 12.5 mmol) was treated with 24.95 ml (2 equivalents) of a 1.002 N solution of hydroxy-dodecyl. potassium in water (volumetric standard solution, Al-drich). All the material was dissolved, except for a few particles, and 6 ml of Milli-Q water was added to obtain a solution in which some small particles remained. The solution was then filtered through a glass acrodisk (Gelman), the filter was rinsed with 2 ml of Milli-Q water and the combined solution was diluted to 50 ml with Milli-Q water and lyophilized to produce a compound of title as yellow foams (6.17 g). ^ -H-NMR (DMSO-d6) d (ppm): 7.34-7.31 (m, 4H), 7.11-7.09 (m, 6H), 3.51 (m, 6H), 2.11 (s, 2H). IR (KBr): 1561, cm "x.Analysis calculated for C19H18K2N402S2 + H20: C, 46.13; H, 4.07; K, 15.81; N, 11.33. Found: C, 46.08; H, 4.21; K, 16.05; N, 11.32. • Method B: Alternatively, N-malonylbis (N'-thiobenzoyl-N 'methylhydrazide) (micronized, 5.006 g, 12.5 mmol) was dissolved in anhydrous THF (62 ml). 25.1 ml (2 equivalents) of a 1.008N solution of potassium hydroxide in methanol (volumetric standard solution, Aldrich) was added to this solution. The solvent was removed from the resulting solution under reduced pressure, to leave about 5 ml of an oily residue, which was triturated with anhydrous ether until a light yellow solid was obtained. The solid was filtered, washed twice with anhydrous ether and dried under vacuum at 50 ° C, to obtain have the dipotassium salt as a powder (4.3 g, 73%). The MN data were identical to those obtained before in Method A. Example 11. 2- (N '-Methyl-N' -thiobenzoylhydrazinocarbonyl) -1- (methylthiobenzoylhydrazono) choline ethanolate: Compound (11). drop to a stirred solution of N-malonylbis (N '-thiobenzoyl-N' methylhydrazide) (2 g, 5 mmol) in 65 ml of anhydrous THF 1.32 ml of a solution of choline hydroxide (45% solution in MeOH ) in 10 ml of anhydrous THF. At first, a clear solution was formed, followed by precipitation of a fine solid. The solution was left for 1 hour to complete the precipitation. The precipitate was filtered, washed twice with ether: HF (2: 1, v / v) and then once with anhydrous ether and dried under vacuum at 50 ° C to obtain the title salt as a yellow powder. clear (2.14 g, 85%). • '"H-NMR (DMSO-ds) (a mixture of tautomers) d (ppm): 7.4-7.35, 7.24-7.19 (m, 10H), 3.83-3.80 (m, 2H), 3.40-3.37 (m, 2H), 3.60, 3.45 and 3.19 (singles, 6H), 3.10 (m, 9H), 2.64, 2 , 32 and 2.06 (singlets, 3H), IR (KBr): 1686s, 1586s, 1482s cm "1. Example 12. 2- (I t -Methyl-N'-thio-l-methylcyclopropylhydrazi-nocarbonyl) -1- (methylthio-l-methylcyclopropylhydrazono) disodium ethanolate: Compound (12) To a stirred transparent NaOH solution (24.7 mg, 0.62 mmol) in H20 (5 mL), N-malonylbis (N '-thio-l-methylcyclopropyl-N' -methylhydrazide) (110 mg, 0.31 mmol) at room temperature. The resulting solution was filtered and then the filtrate was cooled with a dry ice / PrOH bath, followed by lyophilization, to obtain Compound (12) as a solid . ^ -NMR (DMSO-d6) d (ppm): 0.38 (t, 4H, J = 5), 0.83 (t, 4H, J = 5), 1.18 (S, 6H), 2, 62 (s, 2H), 3.38 (s, 6H). Use 13. 2- (N '-Methyl-N' -thiocyclopropylhydrazinocarbo-nyl) -1- (methylthiocyclopropylhydrazono) disodium ethanolate: Compound (13) The disodium compound was prepared by a method similar to that used for Example 12. "" "H-RMM (DMSO-d6) d (ppm): 0.45 (m, 4H), 0.85 (m, 4H), 2.61 (s, 2H), 2.70 (m, 1H), 3.41 (s, 6H), Example 14. 2- (α '-Methyl-N' -thio-l-methylcyclopropylhydrazi-nocarbonyl) - 1- (Methylthio-l-methylcyclopropylhydrazono) dipotassium eta-nolate: Compound (14) The dipotassium compound was prepared by a method similar to that used for Example 12, except for the use of KOH instead of NaOH. "" "H-NMR (DMS0-d6) d (ppm): 0.39 (m, 4H), 0.82 (m, 4H), 1.18 (s, 6H), 2.60 (s, 2H ), 3.38 (s, 6H) Example 15. The bis (thiohydrazide amide) disalts have a significantly higher solubility than the corresponding monosales and neutral forms A compound was weighed and water was added to the compound in such a way that the concentration The mixture was then stirred well and sonicated (approximately 5-10 minutes at about 50 ° C.) If the added amounts were solubilized of the compound completely, more quantities of the compound were added to the solution and the mixture was stirred well and sonicated until a suspension was obtained. The suspension was then filtered through a 0.2 μt filter ?. The filtered solution was diluted with DMSO. The mixture was then analyzed by HPLC to determine the concentration of the compound. The HPLC system consisted of the HP Model 1100 (Agilent, Wilmington, DE) equipped with a model 1100 quaternary pump, a model 1100 autotomator and a Model 1100 Diode Disposition Detector for UV detection at 280 nm. HPLC analysis was carried out using a mobile phase gradient consisting of acetonitrile-water containing 0.1% formic acid. The mobile phases were degassed and filtered through a solvent filtration apparatus and pumped at a constant rate of 1.0 ml / min. The separation was made on an XTerra MS C18 analytical column, 4.6 mm d.i. x 150 mm (Waters Corp., Milford, MA, USA) equipped with a precolumn filter (XTerra MS C18, 3.9 mm x 20 mm). The column was maintained at 40 ° C. The acquisition of data and the adjustment of instruments were controlled using the HP Chemstation program (version 8.03). The solubility data for the compound studied are shown below in Table 1.

Table 1. Solubility data As can be seen from Table 1, the bis (thiohydrazide amide) disalts, for example Compounds 1, 2, 5, 7, 12, 13 and 14, have a significantly higher water solubility than the corresponding neutral or minimal compounds. nosalinos. In particular, Compounds 1 and 2 showed a solubility in water significantly greater than the corresponding neutral form. Similarly, the dials compounds, Compounds 1, 2, 5 and 7, showed a much higher water solubility than the corresponding monosaline compounds, Compounds 3, 4, 6 and 10.

Example 16. Bis (thiohydrazide amide) disals have a significantly higher bioavailability than the corresponding monosales and neutral forms. A) Procedure for pharmacokinetic study in dogs Male Beagle dogs were acclimated for at least one week before use, fed to them with laboratory feed and water ad libitum and they were housed in rooms with controlled temperature and humidity. The compounds were prepared as a solution for intravenous injection or a capsule for oral administration. Three dogs were used for the study. The compounds were injected intravenously through the cephalic vein or by oral probing. The dose was adjusted based on the animals' body weight. Blood samples were collected at intervals of 5, 10 and 30 minutes and 1, 2, 4, 6, 8 and 24 h (example) after administration of the compound and plasma samples were prepared after centrifugation (5,000 rpm. , 8 minutes) of whole blood samples. The compound was measured in the plasma by liquid chromatography with a tandem mass spectrophotometer (LC / MS / MS) after extracting 50 μ? of these samples by precipitation of proteins with acetonitrile. The concentration of the compound was determined by the standard curve (concentration vs. peak area) prepared with the same controlled plasma extraction procedure. The area under the curve ("AUC") was calculated using the modified trapezoidal method. The AUC portion from the last measurable plasma concentration to infinity was estimated by C / k, where k was expressed by the regression of minimum squares of the time points of the log-linear concentration and C represents the last measurable plasma concentration. Bioavailability was calculated by AUCpo / AUCiv.

B) Bioanalytical method of Compounds (1) and (3) in plasma by LC / MS / MS Compounds (1) and (3) and their internal standard of heparinized plasma were extracted by precipitation of proteins with acetonitrile. Chromatography was performed on an XTerra column (Waters, particle size: 5 μp ?, 100 mm × 3.0 mm d.i.) using a mixture of acetonitrile, water and formic acid. The analysis was carried out in a Sciex API 365 tandem mass spectrometer with a turbo ion spray interface. Negative ions were measured using the multiple reaction monitoring mode (MRM) with m / z 399.0-165.1. The operating time was 9 minutes per sample and Compounds (1) and (3) were quantified by a peak area ratio using a linear weighted square-weighted regression graph l / X2. Table 2 below shows the bioavailability data for each compound studied. As can be seen in Table 2, the disaline compound, Compound (1), showed a much greater bioavailability than the corresponding neutral compound or monosaline compound, Compound (3). Table 2. Bioavailability data Example 17. Process method for preparing disodium salts I. General method Approximately 50 mmol of the form is suspended neutral of a compound of the invention in 50 ml of acetone. Approximately 2.04 equivalents of NaOH in ethanol are dissolved to form 38 ml of a 21% solution. The NaOH solution is added to the suspension of the compound while maintaining the temperature at about 0 ° C. The mixture is stirred for about 20 minutes to obtain a clear solution and then about 1 is added., 2 ml of water. The solution is allowed to come to room temperature and about 400 ml of heptane are added. The solution is allowed to stir for approximately 12 hours and the resulting precipitate is collected by filtration. The precipitate is added to about 60 ml of acetone and stirred for 2 hours at room temperature, then collected by filtration and dried in vacuo for 1 hour at about 50 ° C to obtain the pure disodium salt of the compound. II. Preparation of 2- (β '-methyl-N' -thiobenzoyl-drazinocarbonyl) -1- (methylthiobenzoylhydrazono) disodium ethanolate: Compound (1) Compound (1) was prepared by the above general method. The analytical data were the following: XH NMR (DMSO-d6) (ppm) 7.38-7.02 (m, 10H), 3.51 (s, 6H), 2, 13 (s, 2H). Elemental analysis: Calculated for C19H20N4Na202S2: C 49.34, H 4.36, N 12.11, S 13.87; found C 49.28, H 4.18, N 11.91, S 13.63. Examples 18-20: Preparation of a disodium bis (thiohi-drazide amidide) solution A sample of a bis (thiohydrazide amide) (Compound 1, 15 grams) was combined with 40 ml of absolute ethanol to form a mixture in the form of suspension. Aqueous sodium hydroxide (3.0 grams of NaOH in 3.0 ml of H20) was added to the mixture with stirring at room temperature and the mixture was cooled to not exceed 35 degrees C.

The vessel was added with aqueous sodium hydroxide with 1 ml of water and 5 ml of ethanol and the rinsings were added to the mixture. After. addition, the mixture was stirred for 110 minutes. The resulting yellow solution of sodium bis (thiohydrazide amide) was separated into three equal portions for the following examples. Example 18: 63% yield of disodium salt of bis- (thiohydrazide amide) A one-third portion of the above yellow solution of disodium bis (thiohydrazide amide) was combined with 17 ml of methyl tert-butyl ether and stirred for 60 minutes (precipitation occurred in less than 30 minutes). The resulting suspension was filtered and washed with 10 ml of a 1: 1 mixture of ethyl acetate: methyl tert-butyl ether, followed by 5 ml of ethyl acetate. The residual solvent was removed in vacuo to obtain 3.51 grams (63%) of the disodium salt of Compound (1) as a light yellow solid. A yellow contaminant was visible. Example 19: 87% yield of disodium salt of pure bis- (thiohydrazide amide) A one-third portion of the above yellow solution of disodium bis (thiohydrazide amide) was combined with 17 ml of methyl tert-butyl ether and stirred for 60 minutes (precipitation occurred in less than 30 minutes). An additional 17 ml of methyl tert-butyl ether was added to the resulting slurry and stirred for a further 14 hours.-The resulting suspension was filtered, washed with 10 ml of a 1: 1 mixture of ethyl acetate: methyl tert-butyl ether. butyl ether, followed by 10 ml of ethyl acetate. The residual solvent was removed in vacuo to obtain 4.84 grams (87%) of the disodium salt of Compound (1) as a light yellow solid. No yellow contaminant was visible. Example 20: 96% yield of disodium salt of pure bis- (thiohydrazide amide) A one-third portion of the above yellow solution of disodium bis (thiohydrazide amide) was combined with 17 ml of methyl tert-butyl ether and stirred for 60 minutes (precipitation occurred in less than 30 minutes). An additional 34 ml of methyl tert-butyl ether was added to the resulting slurry, and stirred for a further 14 hours. The resulting suspension was filtered, washed with 10 ml of a 1: 1 mixture of ethyl acetate: methyl tert-butyl ether, followed by 10 ml of ethyl acetate. The residual solvent was removed in vacuo to obtain 5.35 grams (96%) of the disodium salt of Compound (1) as a light yellow solid. No yellow contaminant was visible. While this invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (17)

1. CLAIMS 1. A compound represented by the following structural formula: where: Y is a covalent bond or a substituted or unsubstituted straight chain hydrocarbyl group; Rx-R4 are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or RL and R3, taken together with the carbon and nitrogen atoms to which they are attached, and / or R2 and R4, taken together with the carbon and nitrogen atoms to which they are attached, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring; Z is -O or -S, and M + is a pharmaceutically acceptable monovalent cation and M2 + is a pharmaceutically acceptable divalent cation.
2. 2. The compound of Claim 1, wherein the pharmaceutically acceptable cation is Na + or K +.
3. 3. The compound of Claim 2, wherein the pharmaceutically acceptable cation is Na *.
4. 4. The compound of Claim 3, wherein Z is O, Rx and R2 are the same and R3 and R4 are the same.
5. 5. The compound of Claim 4, wherein:? is a covalent bond or a group -C (R5R6) -, - (CH2CH2) -, trans- (CH = CH) -, ci - (CH = CH) - or - (CC) - and Rs and R6 are each independently -H or an aliphatic or substituted aliphatic group, or Rs is -H and R6 is a substituted or unsubstituted aryl group, or Rs and R6, taken-together, are a substituted or unsubstituted C2-C6 alkylene group.
6. 6. The compound of Claim 5, wherein: Y is -C (R5R6) -, R-L and R2 are each a substituted or unsubstituted aryl group and R3 and R4 are each a substituted or unsubstituted aliphatic group.
7. 7. The compound of Claim 6, wherein Rs is -H and R6 is -H or an aliphatic or substituted aliphatic group.
8. 8. The compound of Claim 7, wherein R3 and R4 are each an alkyl group and R6 is -H or methyl.
9. 9. The compound of Claim 8, wherein Rx and R2 are each a substituted or unsubstituted phenyl group and R3 and R4 are each methyl or ethyl.
10. 10. The compound of Claim 9, wherein the phenyl group represented by R1 and the phenyl group represented by R2 are optionally substituted with one or more groups selected from: -Ra, -OH, -Br, -Cl, -I, - F, -0Ra, -0-C0Ra, -C0Ra, -CN, -NCS, -N02, -COOH, -S03H, -NH2, -NHRa, -N (RaRb), -COORa, -CHO, -C0NH2, -C0NHR3, -CON (RaRb), -NHCORa, -NRcC0Ra, -NHC0NH2, -NHCONRaH, -NHC0N (RaRb), -NRcC0NH2, -NRcC0NRaH, -NRcCON (RaRb), -C (= NH) -NH2, -C (= NH) -NHRa, -C (= H) -N (RaRb), -C (= NRC) -NH2, C (= NRC) -NHRa, -C (= NRC) -N (RaRb), -NH -C (= NH) -NH2, -NH-C (= NH) -NHRa, -NH-C (= NH) -N (RaR), -NH-C (= NRC) -NH2, -NH-C ( = NRC) -NHRa, -NH-C (= NRC) -N (RaR), NRdH-C (= NH) -NH2, -NRd-C (= NH) -NHRa, -NRd-C (= NH) - N (RaRb), -NRd-C (= NRC) -NH2, -NRd-C (= NRC) -NHR, -NRd-C (= NRC) -N (RaRb), -NHNH2, -NHNHRa, -NHRaRb, -S02NH2, -S02NHRa, -S02NRaRb, - CH = CHRa, -CH = CRaRb, -CRc = CRaRb, -CRc = CHRa, -CRc = CRaRb, -CCRa, -SH, -SRa, -S (0) R and -S (0) 2Ra, where Ra- Rd are each independently an alkyl group, an aromatic group or a non-aromatic heterocyclic group, or -N (RaRb), taken together, form a substituted or unsubstituted non-aromatic heterocyclic, where the heterocyclic aromatic or non-aromatic alkyl group represented by R-Rd and the non-aromatic heterocyclic group represented by -N (RaRb) are each optionally and independently substituted with one or more groups represented by R *; R # is R +, -0R +, -O (haloalkyl), -SR +, -N02, -CN, -NCS, -N (R +) 2, - HC02R +, - HC (0) R +, -NH HC (0) R + , -NHC (O) N (R +) 2, - H HC (0) N (R +) 2, -NH HC02R +, -C (0) C (0) R +, -C (O) CH2C (O) R +, -C02R +, -C (0) R +, -C (0) N (R +) 2, -OC (0) R +, -OC (O) N (R +) 2, ~ S (0) 2R +, S02N (R +) 2, -S (0) R +, -NHS02N (R +) 2, - HS02R +, -C (= S) N (R +) 2 or -C (= NH) - N (R +) 2; R + is -H, an alkyl group 0 to -4, a heterocyclic monocyclic group, a non-aromatic heterocyclic group or a phenyl group optionally substituted by alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -N02, amine, alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, provided that the non-aromatic heterocyclic groups represented by R * and -N (R +) 2 containing a secondary ring amine are optionally acylated or alkylated.
11. 11. The compound of Claim 10, wherein the phenyl groups represented by R and R2 are optionally substituted with alkyl 02-04 / C ^ -C ^ alkoxy, C1-C1 haloalkyl, C ^ C haloalkoxy, phenyl, benzyl, pyridyl. , -OH, -NH2, -F, -Cl, -Br, -I, -N02 or -CN.
12. 12. The compound of Claim 5, wherein Y is -CR5R6-, Rx and R2 are both a substituted or unsubstituted aliphatic group, Rs is -H and R5 is -H or an optionally substituted aliphatic group.
13. 13. The compound of Claim 12, wherein Rx and R2 are both a C3-C8 cycloalkyl group optionally substituted with at least one alkyl group.
14. 14. The compound of Claim 13, wherein R3 and R4 are both an alkyl group and R6 is -H or methyl.
15. 15. The compound of Claim 14, wherein Rx and R2 are both cyclopropyl or 1-methylcyclopropylo.
16. 16. A compound represented by the following structural formula: where: RL and R2 are both phenyl, R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both phenyl, R3 and R4 are both ethyl and Rs and R6 are both -H; Ri Y ¾ are both 4-cyanophenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Rx and R2 are both 4-methoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri and ¾ are both phenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Ri and ¾ are both phenyl, R3 and R4 are both ethyl, Rs is methyl and R6 is -H; Rx and R2 are both 4-cyanophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; Ri and ¾ are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri and ¾ are both 2,5-dimethoxyphenyl, R3 and R4 are both meticulous lo, Rs is methyl and R6 is -H; Rx and R2 are both 3-cyanophenyl, R3 and R4 are both methyl and Rs and R6 are both -H; R1 and R2 are both 3-fluorophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both 4-chlorophenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Rx and R2 are both 2-dimethoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 3-methoxyphenyl, R3 and R4 are both methyl and Rs and Rs are both -H; R1 and R2 are both 2,3-dimethoxyphenyl, R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both 2,3-dimethoxyphenyl, R3 and R4 are both methylo, R5 is methyl and R6 is -H; x and R2 are both 2, 5-difluorophenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 2,5-difluorophenyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; Rx and R2 are both 2, 5-dichlorophenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 2,5-dimethylphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both phenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; ¾ and 2 are both heavenpropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both heavenpropyl, R3 and R4 are both ethyl and R5 and R6 are both -H; Rx and R2 are both skypropyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; R-L and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri and ¾ are both 1-methylcyclopropyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; R and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, R5 is ethyl and R6 is -H; Rj_ and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, Rs is n-propyl and R6 is -H; R and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both methyl; Rx and R2 are both 1-methylcyclopropyl, R3 and R4 are both ethyl and R5 and R6 are both -H; R-L and R2 are both 1-methylcyclopropyl, R3 is methyl, R4 is ethyl and R5 and R6 are both -H; Rx and R2 are both 2-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; R-L and R2 are both 2-phenylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 1-phenylcyclopropyl, R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both cyclobutyl, R3 and R4 are both methyl and Rs and R6 are both -H; R and R2 are both cyclopentyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri and R2 are both cyclohexyl, R3 and R4 are both methyl and R5 and R6 are both -H; R and R2 are both cyclohexyl, R3 and R4 are both phenyl, Rs and R6 are both -H; R-L and R2 are both methyl, R3 and R4 are both methyl and Rs and R6 are both -H; R2 and R2 are both methyl, R3 and R4 are both t-butyl and Rs and R6 are both -H; Rx and R2 are both methyl, R3 and R4 are both phenyl and Rs and R6 they are both -H; Rx and R2 are both t-butyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are ethyl, R3 and R4 are both methyl and Rs and Rs are both -H; or Rx and R2 are both zz-propyl, R3 and R4 are both methyl and Rs and R6 are both -H.
17. 17. A compound represented by the following structural formula: 18. A compound represented by a structural formula selected from: A consistent pharmaceutical composition a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: where: Y is a covalent bond or a substituted or unsubstituted straight chain hydrocarbyl group; R3.-R4 are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or Rx and R3, taken together with the carbon and nitrogen atoms to which they are attached , and / or R2 and R4, taken together with the carbon and nitrogen atoms to which they are attached, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring; Z is -O or -S, and M + is a pharmaceutically acceptable monovalent cation and M2 + is a pharmaceutically acceptable divalent cation. 20. The pharmaceutical composition of Claim 19, wherein the pharmaceutically acceptable cation is Na + or 21. The pharmaceutical composition of Claim 20, wherein the pharmaceutically acceptable cation is Na +. 22. The pharmaceutical composition of Claim 21, wherein Z is O, Rx and R2 are the same and R3 and R4 are the same. 23. The pharmaceutical composition of the Claim 22, where: Y is a covalent bond or a group -C (RSR6) -, - (CH2CH2) -, trans- (CH = CH) -, cis- (CH = CH) - or - (CC) - and Rs and Rs are each independently -H or a substituted aliphatic or aliphatic group, or Rs is -H and Rs is a substituted or unsubstituted aryl group, or Rs and Rs, taken together, are a substituted or unsubstituted alkylene group C2 -C6 24. The pharmaceutical composition of Claim 23, wherein: Y is -C (RSR6) -, RL and R2 are each a substituted or unsubstituted aryl group and R3 and R4 are each a substituted aliphatic group or not replaced. 25. The pharmaceutical composition of Claim 24, wherein Rs is -H and R6 is -H or a substituted aliphatic or aliphatic group. 26. The pharmaceutical composition of Claim 25, wherein R3 and R4 are each an alkyl group and R6 is-H or methyl. 27. The pharmaceutical composition of Claim 26, wherein R and R2 are each a substituted or unsubstituted phenyl group and R3 and R4 are each methyl or ethyl. 28. The pharmaceutical composition of Claim 27, wherein the phenyl group represented by Rx and the phenyl group represented by R2 are optionally substituted with one or more groups selected from: -Ra, -OH, -Br, -Cl, -I, -F, -0Ra, -0-CORA, -C0Ra, -CN, -N02, -COOH, -S03H, -NH2, -NHRa, -N (RaRb), -COORa, -CHO, -C0NH2, -C0NHR, -CON (RRb), -NHC0Ra, -NRcC0Ra, -NHCONH2, NHCONRaH, -NHCON (RaRb), -NRcC0NH2, -NRcC0NRaH, -NRcCON (RaRb), -C (= NH) -NH2, -C (= NH) -NHRa, -C (= NH) -N (RaRb), -C (= NRC) -NH2, C (= NRC) -NHRa, -C (= NRC) -N (RaRb), -NH-C (= NH) -NH2, -MH-C (= NH) -NHRa, -NH-C (= NH) -N (RaRb), -NH-C (= NRC) -NH2, -NH-C (= NRC) -NHR, -NH-C (= NRC) -N (RaRb), NRdH-C (= NH) -NH2, -NRd-C (= NH) -NHRa, -NRd-C (= NH) -N (RaRb), -NRd-C (= NRC) -NH2, -NRd-C (= NRC) - HRa, -NRd-C (= NRC) -N (RaRb), -NHNH2, -NHNHRa, - HRRb, -S02NH2, -S02NHRa, -S02NRaRb, -CH = CHRa, -CH = CRaRb, - CRc = CRaRb, -CRc = CHRa, -CRc = CRaRb, -CCRa, -SH, -SRa, -S (0) Ra and -S (0) 2Ra, where Ra-Rd are each independently an alkyl group, a an aromatic group or a non-aromatic heterocyclic group, or -N (RaRb), taken together, form a non-substituted or unsubstituted non-aromatic heterocyclic, with the aromatic or non-aromatic alkyl heterocyclic group represented by Ra-Rd and the group non-aromatic heterocyclic represented by -N (RaRb) are each optionally and independently substituted with one or more groups represented by R *; R # is R +, -0R +, -O (haloalkyl), -SR +, -N02, -CN, -NCS, -N (R +) 2, -NHC02R +, -NHC (0) R +, - H HC (0) R + , -NHC (O) N (R +) 2, -NHNHC (0) N (R +) 2, -NHNHC02R +, -C (0) C (0) R +, -C (0) CH2C (0) R +, -C02R + , -C (0) R +, -C (0) N (R +) 2, -0C (0) R +, -0C (O) N (R +) 2, -S (0) 2R +, S02N (R +) 2, -S (0) R +, -NHS02N (R +) 2, -NHS02R +, -C (= S) N (R +) 2 or -C (= NH) -N (R +) 2; R + is -H, a C ^ -C ^ alkyl group, a monocyclic hetearyroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -N02, amine , alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, provided that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 containing a secondary ring amine are optionally acylated or alkylated. 29. The pharmaceutical composition of Claim 28, wherein the phenyl groups represented by Rj and R2 are optionally substituted with C ^ -C ^ alkyl, C ^ -C4 alkoxy, C, -C4 haloalkyl, C ^ -C ^ haloalkoxy. , phenyl, benzyl, pyridyl, -OH, -NH2, -F, -Cl, -Br, -I, -N02 or -CN. 30. The pharmaceutical composition of Claim 23, wherein Y is -CRSR6-, R and R2 are both a substituted or unsubstituted aliphatic group, Rs is -H and R6 is -H or an optionally substituted aliphatic group. 31. The pharmaceutical composition of Claim 30, wherein Rx and R2 are both a C3-C8 cycloalguyl group optionally substituted with at least one alkyl group. 32. The pharmaceutical composition of Claim 31, wherein R3 and R4 are both an alkyl group and R6 is -H or methyl. 33. The pharmaceutical composition of Claim 32, wherein Rx and R2 are both cyclopropyl or 1-methylcyclopropyl. 34. A pharmaceutical composition consisting of a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: where: Rx and R2 are both phenyl, R3 and R4 are both methyl and R5 and Rs are both -H; Ri and ¾ are both phenyl, R3 and R4 are both ethyl and R5 and R6 are both -H; Rx and R2 are both 4-cyanophenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Rx and R2 are both 4-methoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; R2 and R2 are both phenyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; R1 and R2 are both phenyl, R3 and R4 are both ethyl, RS is methyl and R6 is -H; R1 and R2 are both 4-cyanophenyl, R3 and R4 are both methyl and RS and R6 are both -H; R-L and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and RS and R6 are both -H; RA and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl, RS is methyl and R6 is -H; R1 and R2 are both 3-cyanophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; RX and R2 are both 3-fluorophenyl, R3 and R4 are both methyl and RS | and R6 are both -H; RX and R2 are both 4-chlorophenyl, R3 and R4 are both methyl, RS is methyl and RS is -H; RX and R2 are both 2-dimethoxyphenyl, R3 and R4 are both methyl and RS and RS are both -H; RX and R2 are both 3-methoxyphenyl, R3 and R4 are both methyl and RS and R6 are both -H; RX and R2 are both 2,3-dimethoxyphenyl, R3 and R4 are both methyl and RS and R6 are both -H; R- and R2 are both 2,3-dimethoxyphenyl, R3 and R4 are both methyl, RS is methyl and R6 is -H; RX and R2 are both 2-, 5-difluorophenyl, R3 and R4 are both methyl and RS and R6 are both -H; R-L and R2 are both 2,5-difluorophenyl, R3 and R4 are both methyl, RS is methyl and R6 is -H; Ri and ¾ are both 2, 5-dichlorophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; Ri and ¾ are both 2,5-dimethylphenyl, R 3 and R 4 are both methyl and RS and RS are both -H; R and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and R5 and R6 are both -H; R1 and R2 are both phenyl, R3 and R4 are both methyl and RS and RS are both -H; R1 and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl, Rs is methyl and Rs is -H; R-L and R2 are both cyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both cyclopropyl, R3 and R4 are both ethyl and Rs and R6 are both -H; R1 and R2 are both cyclopropyl, R3 and R4 are both methyl, Rs is methyl and Rs is -H; R1 and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Ra and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, Rs is ethyl and R6 is -H; Rx and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, Rs is n-propyl and R6 is -H; R1 and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both methyl; R1 and R2 are both 1-methylcyclopropyl, R3 and R4 are both ethyl and Rs and Rs are both -H; R1 and R2 are both 1-methylcyclopropyl, R3 is methyl, R4 is ethyl and R5 and g are both -H; R1 and R2 are both 2-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 2-phenylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; R1 and R2 are both 1-phenylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both cyclobutyl, R3 and R4 are both methyl and Rs and R6 are both -H; R and R2 are both cyclopentyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rj_ and R2 are both cyclohexyl, R3 and R4 are both methyl and Rs and Rg are both -H; x and R2 are cyclohexyl arabos, R3 and R4 are both phenyl, R5 and R6 are both -H; Ri and ¾ are both methyl, R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both methyl, R3 and R4 are both t-butyl and Rs and R6 are both -H; Rx and R2 are both methyl, R3 and R4 are both phenyl and Rs and R6 are both -H; Rx and R2 are both t-butyl, R3 and R4 are both methyl and Rs and R6 are both -H; R and R2 are ethyl, R3 and R4 are both methyl and Rs and R6 are both -H; or Rx and R2 are both n-propyl, R3 and R4 are both methyl and R5 and R6 are both -H. 35. A composition consisting of a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula: 36. A composition consisting of a pharmaceutically acceptable carrier or diluent and a compound represented by a structural formula selected from: Na + Na + Na + Na + 37. A method of treating a subject with a cancer, which method consists of administering to the subject an effective amount of a compound represented by the following structural formula: where: Y is a covalent bond or a substituted or unsubstituted straight chain hydrocarbyl group; x-R4 are independently -H, an aliphatic group, a substituted aliphatic group, an aryl group or a substituted aryl group, or Rx and R3, taken together with the carbon and nitrogen atoms to which they are attached, and / or R2 and R4, taken together with the carbon and nitrogen atoms to which they are attached, they form a non-aromatic heterocyclic ring optionally fused to an aromatic ring; Z is -O or -S, and 'M + is a pharmaceutically acceptable monovalent cation and M2 + is a pharmaceutically acceptable divalent cation. 38. The method of Claim 37, wherein the pharmaceutically acceptable cation is Na + or K +. 39. The method of Claim 38, wherein the pharmaceutically acceptable cation is Na +. 40. The method of Claim 39, wherein the cancer is a cancer resistant to multiple drugs. 41. The method of Claim 39, wherein the compound is coadministered with an anticancer agent that stabilizes the microtubules. 42. The method of Claim 39, wherein the compound is coadministered with taxol or a taxol analogue. 43. The method of Claim 39, wherein Z is O, R-L and R2 are the same and R3 and R4 are the same. 44. The method of Claim 43, wherein: Y is a covalent bond or a group -C (RSR6) -, - (CH2CH2) -, trans- (CH = CH) -, cis- (CH = CH) - or - (CC) - and Rs and R6 are each independently -H or a substituted aliphatic or aliphatic group, or Rs is -H and Rs is a substituted or unsubstituted aryl group, or Rs and Rs, taken together, are a group substituted or unsubstituted C2-C6 alkylene. 45. The method of Claim 43, wherein:? is -C (R5R6) -, R2 and R2 are each a substituted or unsubstituted aryl group and R3 and R4 are each a substituted or unsubstituted aliphatic group. 46. The method of Claim 43, wherein Rs is -H and R6 is -H or a substituted aliphatic or aliphatic group. 47. The method of Claim 46, wherein R3 and R4 are each an alkyl group and R6 is -H or methyl. 48. The method of Claim 47, wherein Rx and R2 are each a substituted or unsubstituted phenyl group and R3 and R4 are each methyl or ethyl. 49. The method of Claim 48, wherein the phenyl group represented by Rj and the phenyl group represented by R 2 are optionally substituted with one or more groups selected from: -Ra, -OH, -Br, -Cl, -I, - F, -0Ra, -0-CORA, -C0Ra, -CN, -N02, -C00H, -S03H, -NH2, -NHRa, -N (RaRb), -COORa, -CHO, -C0NH2, ~ CONHRa, - CON (RaRb), -NHC0Ra, -NRcC0Ra, -NHC0NH2, NHC0NRaH, -NHCON (RaRb), -NRcC0NH2, -NRcCONRaH, -NRcCON (RaRb), -C (= NH) -NH2, -C (= NH) -NHRa, C (= NH) -N (RaRb), - C (= NRC) -NH2, C (= NRC) -NHRa, -C (= NRC) -N (RaRb), -NH-C (= MH) -MH2, -NH-C (= NH) -NHRa, -NH-C (= NH) -N (RaR), -NH-C (= NRC) -NH2, -NH-C (= NRC) -NHRa, -NH-C (= NRC) -N (RaR), NRdH-C (= NH) -NH2, -NRd-C (= NH) -NHRa, -NRd-C (= NH) -N (RaRb), -NRd-C (= NRc) -NH2, -NRd- C (= NRC) -NHRa, -NRd-C (= NRC) -N (RaRb), -NHNH2, -NHNHRa, -NHRaRb, -S02NH2, -S02NHRa, -S02NRRb, -CH = CHRa, -CH = CRaRb, -CRc = CRaRb, -CRc = CHRa, -CRc = CRaRb, -CCRa, -SH, -SRa, -S (0) Ra and -S (0) 2Ra, where R-Rd are each independently a group alkyl, an aromatic group or a non-aromatic heterocyclic group, or -N (RaRb), taken together, form a substituted or unsubstituted non-aromatic heterocyclic, wherein the heterocyclic aromatic or non-aromatic alkyl group represented by Ra-Rd and the non-aromatic heterocyclic group represented by -N (RaRb) are each optionally and independently substituted with one or more groups represented by Rs; R # is R \ -OR +, -O (haloalkyl), -SR +, -N02, -CN, -NCS, -N (R +) 2, -NHC02R +, -NHC (0) R +, -NHNHC (0) R +, -NHC (O) N (R +) 2, - NHNHC (0) N (R +) 2, -NHNHC02R +, -C (0) C (0) R +, -C (O) CH2C (O) R +, -C02RC (0) R +, -C (0) N (R +) 2 / -OC (0) R +, -OC (O) N (R +) 2, -S (0) 2R +, S02N (R +) 2, -S (0) R +, -NHS02N (R +) 2 , - HS02R +, -C (= S) N (R +) 2 or -C (= NH) - N (R +) 2; R + is -H, a Cj- alkyl group, a monocyclic heteroaryl group, a non-aromatic heterocyclic group or a phenyl group optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -N02, amine , alkylamine or dialkylamine; or -N (R +) 2 is a non-aromatic heterocyclic group, provided that the non-aromatic heterocyclic groups represented by R + and -N (R +) 2 containing a secondary ring amine are optionally acylated or alkylated. 50. The method of Claim 49, wherein the phenyl groups represented by ^ and R2 are optionally substituted with C-C4 alkyl, Cx-C4 alkoxy, C-C4 haloalkyl, C ^ -C ^ haloalkoxy, phenyl, benzyl, pyridyl, -OH, -NH2, -F, -Cl, -Br, -I, -N02 or -CN. 51. The method of Claim 44, wherein Y is -CRSR6-, Rx and R2 are both a substituted or unsubstituted aliphatic group, R5 is -H and Rs is -H or an optionally substituted aliphatic group. 52. The method of Claim 51, wherein Rx and R2 are both a C3-C3 cycloalkyl group optionally substituted with at least one alkyl group. 53. The method of Claim 52, wherein R3 and R4 are both an alkyl group and R6 is -H or methyl. 54. The method of Claim 53, wherein Rx and R2 are both cyclopropyl or 1-methylcyclopropyl. 55. A method of treating a subject with a cancer, which method consists of administering to the subject an effective amount of a compound represented by the following structural formula: Na + where: R and R2 are both phenyl, R3 and R4 are both methyl and RS and R6 are both -H; RX and R2 are both phenyl, R3 and R4 are both ethyl and R5 and RS are both -H; Ri and ¾ are both 4-cyanophenyl, R3 and R4 are both methyl, RS is methyl and R6 is -H; RX and R2 are both 4-methoxyphenyl, R3 and R4 are both methyl and R5 and R6 are both -H; R1 and R2 are both phenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; RX and R2 are both phenyl, R3 and R4 are both ethyl, R5 is methyl and R6 is -H; R1 and R2 are both 4-cyanophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; RX and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and R5 and R6 are both -H; R1 and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methylo, RS is methyl and R6 is -H; -L and R2 are both 3-cyanophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; X and R2 are both 3-fluorophenyl, R3 and R4 are both methyl and RS and R6 are both -H; R2 and R2 are both 4-chlorophenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Rx and R2 are both 2-dimethoxyphenyl, R3 and R4 are both methyl and RS and R6 are both -H; RX and R2 are both 3-methoxyphenyl, R3 and R4 are both methyl and RS and R6 are both -H; Ri and ¾ are both 2, 3-dimethoxyphenyl, R3 and R4 are both methyl and R5 and R6 are both -H; -L and R2 are both 2,3-dimethoxyphenyl, R3 and R4 are both methylo, R5 is methyl and R6 is -H; R-L and R2 are both 2, 5-difluorophenyl, R3 and R4 are both methyl and RS and R6 are both -H; RX and R2 are both 2,5-difluorophenyl, R3 and R4 are both methyl, RS is methyl and R6 is -H; RX and R2 are both 2, 5-dichlorophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; R2 and R2 are both 2,5-dimethylphenyl, R3 and R4 are both methyl and R5 and R6 are both -H; R1 and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and RS and R6 are both -H; RX and R2 are both phenyl, R3 and R4 are both methyl and RS and RS are both -H; Ri and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; R and R2 are both cyclopropyl, R3 and R4 are both methyl and RS and R6 are both -H; Ri and ¾ are both cyclopropyl, R3 and R4 are both ethyl and RS and R6 are both -H; RX and R2 are both cyclopropyl, R3 and R4 are both methyl, RS is methyl and R6 is -HRX and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and RS and R6 are both -H; RA and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, RS is methyl and R6 is -H; RX and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, RS is ethyl and R6 is -H; RX and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, RS is n-propyl and RS is -H; Ri and R2 are both 1-methylcyclopropyl, R3 and R4 are both meticulous lo and R5 and R6 are both methyl; R-L and R2 are both 1-methylcyclopropyl, R3 and R4 are both ethyl and R5 and R6 are both -H; Rx and R2 are both 1-methylcyclopropyl, R3 is methyl, R4 is ethyl and R5 and R6 are both -H; Rx and R2 are both 2-methylcyclopropyl, R3 and R4 are both methyl and R5 and R6 are both -H; R2 and R2 are both 2-phenylcyclopropyl, R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both 1-phenylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri and ¾ are both cyclobutyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rj_ and R2 are both cyclopentyl, R3 and R4 are both methyl and R5 and R6 are both -H; Rx and R2 are both cyclohexyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ra and R2 are both cyclohexyl, R3 and R4 are both phenyl, R5 and R6 are both -H; Rx and R2 are both methyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both methyl, R3 and R4 are both t-butyl and Rs and R6 are both -H; x and R2 are both methyl, R3 and R4 are both phenyl and Rs and R6 are both -H; Ri Y ¾ are both t-butyl, R3 and R4 are both methyl and Rs and R6 are both -H; R-L and R2 are ethyl, R3 and R4 are both methyl and Rs and R6 are both -H; or R-L and R2 are both n-propyl, R3 and R4 are both methyl and Rs and R6 are both -H. 56. The method of Claim 55, wherein the cancer is a cancer resistant to multiple drugs. 57. The method of Claim 55, wherein the The compound is coadministered with an anticancer agent that stabilizes microtubules. 58. The method of Claim 55, wherein the compound is co-administered with taxol or a taxol analogue. 59. A method of treating a subject with a cancer, which method consists of administering to the subject an effective amount of a compound represented by the following structural formula: 60. The method of Claim 59, wherein the cancer is a cancer resistant to multiple drugs. 61. The method of Claim 59, wherein the compound is coadministered with an anti-cancer agent that stabilizes the microtubules. 62. The method of Claim 59, wherein the compound is co-administered with taxol or a taxol analogue. 63. A method of treating a subject with a cancer, which method consists of administering to the subject an effective amount of a compound represented by a structural formula selected from: Na + Na + Na + Na + Cancer is a cancer resistant to multiple drugs. 65. The method of Claim 63, wherein the compound is coadministered with an anti-cancer agent that stabilizes microtubules. 66. The method of Claim 63, wherein the compound is coadministered with taxol or a taxol analogue. 67. A method of preparing a bis (thiohydrazide amide) disal, consisting of the steps of: combining a neutral bis (thiohydrazide amide), an organic solvent and a base to form a solution of bis (thiohydrazide amide) and combining the solution and an organic antisolvent, thereby precipitating a disal of the bis (thiohydrazide amide) from the solution of bis (thiohydrazide amide). 68. The method of Claim 67, wherein at least about two molar equivalents of the base are employed per molar equivalent of neutral bis (thiohydrazide amide). 69. The method of Claim 68, wherein the Organic solvent is miscible in water. 70. The method of Claim 69, wherein the organic solvent is selected from an aliphatic alcohol a C2-C4 aliphatic ether, a C2-C4 cycloaliphatic ether, dioxane, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, a glycol, an alkyl glycol ether, dioxane and acetonitrile. 71. The method of Claim 70, wherein the organic solvent is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tert-butyl alcohol, acetone, tetrahydrofuran, and methyl ethyl ketone. 72. The method of Claim 70, wherein the organic solvent is selected from methanol, ethanol and acetone. 73. The method of Claim 68, wherein the base is an amine, an ammonium hydroxide, an alkali metal hydroxide, a C-α-C6 alkali metal alkoxide or an alkali metal amide-hard. 74. The method of Claim 73, wherein the base is sodium hydroxide, potassium hydroxide, alkoxide C-L-C8 of sodium, alkoxide C ^ -Cs of potassium, sodium amide or potassium amide. 75. The method of Claim 74, wherein the base is sodium hydroxide, sodium methoxide or sodium ethoxide. 76. The method of Claim 68, wherein the base is an alkali metal hydride, an alkali metal alkyl or an alkali metal aryl. 77. The method of Claim 76, wherein the base is lithium hydride, sodium hydride, potassium hydride, butyl-lithium, butyl-sodium, butyl-potassium, phenyl-lithium, phe nyl-sodium or phenyl-potassium. 78. The method of Claim 68, wherein the organic antisolvent is selected from a C3-C10 alkane, a C3-C10 cycloalkane, a C3-C10 alkyl ester, a C3-C10 alkylic ether, benzene, toluene and xylene. 79. The method of Claim 78, wherein the organic antisolvent is selected from diethyl ether, dipropyl ether, methyl propyl ether, ethyl propyl ether, methyl acetate, ethyl acetate, propyl acetate, pentane, hexane, cyclohexane, heptane and Petroleum ether. 80. The method of Claim 79, wherein the organic antisolvent is a C3-C10 alkane or a C5-C10 cycloalkane. 81. The method of Claim 68, wherein the neutral bis (thiohydrazide amide) is substantially insoluble in the organic solvent. 82. The method of Claim 81, wherein the neutral bis (thiohydrazide amide) is first combined with the organic solvent to form a mixture and the base is added to the mixture to form the solution of bis- (thiohydrazide amide). 83. The method of Claim 81, wherein between about 0.25 and about 2.5 moles of the neutral bis (thiohydrazide amide) are combined for each liter of organic solvent. 84. The method of Claim 83, wherein between about 0.75 and about 1.5 mole of the neutral bis (thiohydrazide amide) is combined for each liter of organic solvent. 85. The method of Claim 83, wherein between about 2 and about 5 molar equivalents of the base are employed. 86. The method of Claim 85, wherein between about 2.0 and about 2.5 molar equivalents of the base are employed. 87. The method of Claim 85, wherein approximately 1 mole of the bis (thiohydrazide amide) is combined neutral for each liter of the organic solvent. 88. The method of Claim 87, wherein the organic solvent is ethanol. 89. The method of Claim 88, wherein the base is aqueous sodium hydroxide of about 2 molar to about 5 molar. 90. The method of Claim 89, wherein the organic antisolvent is diethyl ether or ethyl acetate. 91. The method of Claim 87, wherein the organic solvent is acetone. 92. The method of Claim 91, wherein the base is ethanolic sodium ethoxide of about 2 molar to about 5 molar. 93. The method of Claim 92, wherein the organic antisolvent is heptane. 94. The method of Claim 67, wherein the neutral bis (thiohydrazide amide) is represented by the following Structural Formula: where: Y is a covalent bond or a straight chain hydrocarbyl group optionally substituted; Rx-R4 are independently -H, an optionally substituted aliphatic group or an optionally substituted aryl group, or Rx and R3, taken together with the carbon and nitrogen atoms to which they are attached and / or R2 and R4, taken together with the carbon and nitrogen atoms to which they are attached, they form a non-aromatic heterocyclic ring optionally fused to an aromatic ring, and The method of Claim 94, wherein neutral bis (thiohydrazide amide) is represented by the following Structural Formula: where: Rx and R2 are both phenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both phenyl, R3 and R4 are both ethyl and Rs and R6 are both -H; R and R2 are both 4-cyanophenyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; x and R2 are both 4-methoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both ~ H; Rx and R2 are both phenyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; Rx and R2 are both phenyl, R3 and R4 are both ethyl, Rs is methyl and R6 is -H; Rx and R2 are both 4-cyanophenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; R and R2 are both 3-cyanophenyl, R3 and R4 are both methyl and R5 and R6 are both -H; R2 and R2 are both 3-fluorophenyl, R3 and R4 are both methyl and Rs and R6 are both -H; R2 and R2 are both 4-chlorophenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; R1 and R2 are both 2-dimethoxyphenyl, R3 and R4 are both methyl and R5 and R6 are both -H; Ri and ¾ are both 3-methoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri Y ¾ are both 2, 3-dimethoxyphenyl, R3 and R4 are both methyl Y R5 and R-s are both -H; R2 and R2 are both 2,3-dimethoxyphenyl, R3 and R4 are both methyl, Rs is methyl and Rs is -H; Ri and ¾ are both 2, 5-difluorophenyl, R3 and R4 are both methyl and Rs and R6 are both -H; R1 and R2 are both 2,5-difluorophenyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Ri and ¾ are both 2,5-dichlorophenyl, R 3 and R 4 are both methyl and R 5 and R 6 are both -H; Ri and ¾ are both 2,5-dimethylphenyl, R 3 and R 4 are both methyl and R 5 and R 6 are both -H; Ri and ¾ are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Rx and R2 are both phenyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri and R-2 are both 2,5-dimethoxyphenyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; Ri Y ¾ are both cyclopropyl, R3 and R4 are both methyl and R5 and Rs are both -H; Rx and R2 are both cyclopropyl, R3 and R4 are both ethyl and Rs and R6 are both -H; Rx and R2 are both cyclopropyl, R3 and R4 are both methyl, R5 is methyl and R6 is -H; Rx and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Y 'is a bond; Rx and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and Rs and R6 are both -H; Ri and ¾ are both 1-methylcyclopropyl, R3 and R4 are both methyl, Rs is methyl and R6 is -H; Ri and K-2 are both 1-methylcyclopropyl, R3 and R4 are both meticulous lo, RS is ethyl and R6 is -H; RX and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl, RS is n-propyl and R6 is -H; Ri and R2 are both 1-methylcyclopropyl, R3 and R4 are both methyl and RS and R6 are both methyl; RX and R2 are both 1-methylcyclopropyl, R3 and R4 are both ethyl and R5 and R6 are both -H; RX and R2 are both 1-methylcyclopropyl, R3 is methyl, R4 is ethyl and RS and R6 are both -H; R-L and R2 are both 2-methylcyclopropyl, R3 and R4 are both methyl and R5 and 6 are both -H; R-L and R2 are both 2-phenylcyclopropyl, R3 and R4 are both methyl and R5 and R6 are both -H; Ri and ¾ are both 1-phenylcyclopropyl, R3 and R4 are both methylo and RS and R6 are both -H; RX and R2 are both cyclobutyl, R3 and R4 are both methyl and RS and R6 are both -H; Ri and R2 are both cyclopentyl, R3 and R4 are both methyl and RS and R6 are both -H; RX and R2 are both cyclohexyl, R3 and R4 are both methyl and R5 and R6 are both -H; RX and R2 are both cyclohexyl, R3 and R4 are both phenyl, R5 and R6 are both -H; RX and R2 are both methyl, R3 and R4 are both methyl and R5 and R6 are both -H; R1 and R2 are both methyl, R3 and R4 are both t-butyl and R5 and R6 are both -H; Ri and ¾ are both methyl, R3 and R4 are both phenyl and RS and R6 are both -H; RX and R2 are both t-butyl, R3 and R4 are both methyl and RS and R6 are both -H; X and R2 are ethyl, R3 and R4 are both methyl and R5 and R6 are both -H; or R-L and R2 are both n-propyl, R3 and R4 are both methyl and RS and R6 They are both -H. 96. The method of Claim 95, wherein the neutral bis (thiohydrazide amide) is: 98. A method of preparing a bis (thiohydrazide amide) disal consisting of the steps of: combining a neutral bis (thiohydrazide amide) and an organic solvent selected from methanol, ethanol, acetone and methyl ethyl ketone to make a mixture; add at least two equivalents of a base selected from sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide to the mixture, thus forming a solution of bis (thiohydrazide amide), and combine the solution and an organic antisolvent selected from pentane, hexane, cyclohexane, heptane, petroleum ether, ethyl acetate and diethyl ether for cipitate the disal of bis (thiohydrazide amide) of the solution of bis (thiohydrazide amide). 99. The method of Claim 98, wherein the organic solvent is acetone. 100. The method of Claim 98, wherein the base is ethanolic sodium ethoxide. 101. The method of Claim 98, wherein the organic solvent is ethanol. 102. The method of Claim 98, wherein the base is aqueous sodium hydroxide. 103. The method of Claim 98, wherein the antisolvent is heptane. 104. The method of Claim 98, wherein the neutral bis (thiohydrazide amide) is: 105. The method of Claim 98, wherein (neutral thiohydrazide amide) is: 106. A method of preparing a disal of bis (thiohydrazide amide) consisting of the steps of: combining a neutral bis (thiohydrazide amide), an organic solvent and a base to form a solution of bis (thiohydrazide amide) and separating a disal from the bis (thiohydrazide amide) solution of bis (thiohydrazide amide). 107. The method of Claim 106, wherein at least about two molar equivalents of the base are employed per molar equivalent of neutral bis (thiohydrazide amide). 108. The method of Claim 107, wherein the organic solvent is selected from an aliphatic alcohol Cx-C4, an aliphatic ketone C ^ -CAI a C2-C4 aliphatic ether, a C2-C4 cycloaliphatic ether, dioxane, dimethylformamide, dimethyl oxide, N-methylpyrrolidone, a glycol, an alkyl glycol ether, dioxane and acetonitrile. 109. The method of Claim 108, wherein the organic solvent is selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tert-butyl alcohol, acetone, tetrahydrofuran, and methyl ethyl ketone. 110. The method of Claim 109, wherein the base is an amine, an ammonium hydroxide, an alkali metal hydroxide, an alkali metal C 1 -C 8 alkoxide or an alkali metal amide-hard. 111. The method of Claim 110, wherein the base is sodium hydroxide, potassium hydroxide, alkoxide C-L-C8 sodium, alkoxide of potassium, sodium amide, or potassium amide. 112. The method of Claim 107, wherein the base is an alkali metal hydride, an alkali metal alkyl or an alkali metal aryl. 113. The method of Claim 112, wherein the base is lithium hydride, sodium hydride, potassium hydride, butyl-lithium, butyl-sodium, butyl-potassium, phenyllithium, phenyl-n-sodium or phenyl-potassium. 114. The method of Claim 107, wherein the neutral bis (thiohydrazide amide) is substantially insoluble in the organic solvent. 115. The method of Claim 114, wherein the neutral bis (thiohydrazide amide) is first combined with the organic solvent to form a mixture and the base is added to the mixture to form the solution of bis (thiohydrazide amide). 116. The method of Claim 114, wherein between about 0.25 and about 2.5 moles of the neutral bis (thiohydrazide amide) are combined for each liter of organic solvent. 117. The method of Claim 116, wherein between about 2 and about 5 molar equivalents of the base are employed. 118. The method of Claim 116, wherein approximately 1 mole of the neutral bis (thiohydra-zide amide) is combined per liter of the organic solvent. 119. The method of Claim 106, wherein the neutral bis (thiohydrazide amide) is represented by the following Structural Formula: where : ? is a covalent bond or an optionally substituted straight chain hydrocarbyl group; R1-R4 are independently -H, an optionally substituted aliphatic group or an optionally substituted aryl group, or R1 and R3, taken together with the carbon and nitrogen atoms to which they are attached and / or R2 and R4 , taken together with the carbon and nitrogen atoms to which they are bound together, form a non-aromatic heterocyclic ring optionally fused to an aromatic ring, and Z is 0 or S.