MX2008002036A - Polyamines useful as anti-parasitic and anti-cancer therapeutics and as lysine-specific demethylase inhibitors - Google Patents

Abstract

Polyamine, polyamine/guanidino, and polyamine/biguanide compounds are disclosed. The compounds are useful as anti-cancer and anti-parasitic treatments. The compounds are also useful as inhibitors of the enzyme lysine-specific demethylase-1.

Description

USEFUL POLYAMINES AS THERAPEUTIC AGENTS ANTIPARASITARIES AND ANTICANCERIGENOS AND AS INHIBITORS OF THE SPECIFIC DESMETILASA OF THE USINA CROSS REFERENCE TO RELATED REQUESTS This application claims the priority benefit of United States Provisional Patent Application No. 60 / 707,420, filed on August 10, 2005. All content of that application is incorporated herein by reference.

TECHNICAL FIELD This invention pertains to polyamine compounds, including polyamine / guanidine compounds and polyamine / biguanide compounds, useful in the treatment of cancer and / or parasitic infections, and for the inhibition of lysine-specific demethylase.

BACKGROUND Polyamines are found in eukaryotic and prokaryotic cells and figure predominantly in cell cycle regulation and cell division. The agents directed specifically towards the biosynthesis of polyamine, such as polyamine analogs, have been shown to have a therapeutic effect in the treatment of cancer, parasitic diseases and other indications. These antiproliferative effects have been shown to be, in part, a result of the agent-induced decreases in the natural intracellular polyamines resulting from the inhibition, deregulation of polyamine biosynthesis and / or up-regulation of polyamine catabolism. See, for example, Wang and Casero, J, Biochem. 139: 17 (2006); Casero et al., Proc. West. Pharmacol. Soc. 48:24 (2005); Casero et al., J. Med. Chem. 44: 1 (2001); Patents of E.U.A. Nos. 5,889,061, 6,392,098 and 6,794,545; Patent Application Publications of E.U.A. Nos. 2003/0072715, 2003/0195377 and International Patent Applications WO 98/17624, WO 00/66587, WO 02/10142 and WO 03/050072. Bi et al., Bioorgan. Med. Chem. Letters 16: 3229 (2006) discusses new alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity. The enzyme demethylase specific for lysine-1 (LSD1) has been shown to play an important role in the regulation of gene expression; see Shi et al., Cell 119: 941 (2004). WO 2006/071608 discusses certain methods involving the specific demethylase of lysine-1. In view of the importance of gene regulation in areas such as cancer therapy and cancer prophylaxis, LSD1 inhibitors are of great interest in the treatment and prevention of cancer and uncontrolled cell growth.

BRIEF DESCRIPTION OF THE INVENTION The invention encompasses the polyamine, polyamine guanidine and polyamine / biguanide compounds and the uses of those compounds for the treatment and prevention of cancer. The invention also encompasses the uses of these compounds for the inhibition of lysine-1-specific demethylase, and the treatment of diseases involving the specific demethylase of lysine-1. In one embodiment, the invention encompasses the compounds of the formula (M): E-X-A-NH-B-NH-A-X-E (M) wherein each E is independently selected from hydrogen, substituted or unsubstituted C 8 alkyl, unsubstituted or substituted C 4 -C 15 cycloalkyl, substituted or unsubstituted C 3 -C 15 branched alkyl, substituted C 6 -C 2 aryl or heteroaryl or unsubstituted, aralkyl or heteroaralkyl or substituted or unsubstituted C7-C24 heteroaralkyl, substituted or unsubstituted C3-C24 heteroaryl; each A is independently an n-C-Cß alkyl; B is independently selected from n-C12 alkyl or C3-C8 cycloalkyl; and each X is independently selected from -NH-, -NH-C (= NH) -NH- and -NH-C (= NH) -NH-C (= NH) -NH-; and all the salts, solvates, hydrates and stereoisomers thereof. In another embodiment, B is independently selected from n-C 1 alkyl- In another embodiment, at least one X is selected from -NH-C (= NH) -NH- and -NH-CC = NH) -NH-CC = NH) -NH-. In another embodiment, at least one X is -NH-C (= NH) -NH-. In another modality, at least one X is -NH-C (= NH) -NH-CO = NH) -NH-. In another embodiment, each X is independently selected from -NH-C (= NH) -NH- and -NH-C (= NH) -NH-C (= NH) -NH-. In another embodiment, both groups X are -NH-C (= NH) -NH-. In another embodiment, both groups X are -NH-C (= NH) -NH-C (= NH) -NH-. In another embodiment, one X is -NH-C (= NH) -NH- and another X is -NH-C (= NH) -NH-C (= NH) -NH-. In one embodiment, the invention encompasses N-alkylated polyamine / guanidine or polyamine / guanidine compounds, such as a polyaminobisguanidine or polyaminobiguanide or an N-alkylated variation thereof. An N-alkylated polyaminoguanidine is a polyaminoguanidine wherein the nitrogen of the guanidine mine is alkylated, such as in a 2-methylguanidine derivative. In one embodiment, each A is - (CH2) 3- and B is - (CH2) 4-- In another embodiment, each A is - (CH2) 3- and B is - (CH2) 7-. In one embodiment, the compound is a polyaminoguanidine of the formula (I): or a salt, solvate or hydrate thereof, wherein n is an integer from 1 to 12, m and p are independently an integer from 1 to 5, q is 0 or 1, each Ri is independently selected from the group consisting of unsubstituted or substituted Cs Cs alkyl, unsubstituted or substituted C4-C15 cycloalkyl, substituted or unsubstituted C3-C15 branched alkyl, unsubstituted or substituted C6-C2 aryl, substituted or unsubstituted C6-C2 heteroaryl , substituted or unsubstituted C7-C24 aralkyl and substituted or unsubstituted C7-C24 heteroaralkyl and each R is independently selected from hydrogen or a substituted or unsubstituted C8 alkyl. In one embodiment, the compound is of the formula (I), wherein at least one or both of R1 is a substituted or unsubstituted C6-C20 aryl, such as a substituted or unsubstituted single-ring aryl, including, non-exclusively, substituted or unsubstituted phenyl. In one embodiment, the compound is of the formula (I) and each R1 is phenyl. In one embodiment, q is 1, myp is 3 and n is 4. In another embodiment, q is 1, myp is 3 and n is 7. In one embodiment, the compound is of the formula (I), where at least one or both of R1 is a C8-C or CrC8 alkyl substituted or not substituted, such as a linear alkyl. One or both of Ri can be a linear alkyl of substituted or unsubstituted CrC8, such as methyl or ethyl. In one embodiment, each Ri is methyl. Each or both of R-i may comprise or be a C4-C15 cycloalkyl group, such as a cycloalkyl group containing a linear alkyl group, wherein the cycloalkyl group is connected to the molecule via its alkyl or cycloalkyl moiety. For example, each or both of Ri can be cyclopropylmethyl or cyclohexylmethyl. In one embodiment, one of Ri is cyclopropylmethyl or cyclohexylmethyl and the other Ri is a linear alkyl group, such as a linear alkyl group of unsubstituted CrCa, including, but not limited to, an ethyl group. In one embodiment, R1 is a branched alkyl group of C3-C15, such as isopropyl. When Ri is a substituted CrC8 alkyl, the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine. Accordingly, in one embodiment, Ri is a C 8 alkyl group substituted with an amine, such that Ri can be, for example, an alkyl-NH 2 or alkyl-amino-alkyl portion, such as - (CH 2) and NH (CH2) zCH, where y and z are independently, an integer from 1 to 8. In one embodiment, Ri is - (CH2) SNH2. In one embodiment, the compound is of the formula (I), wherein at least one Ri is a substituted or unsubstituted C7-C2 aralkyl, which in one embodiment, is an aralkyl connected to the molecule via its alkyl portion (per example, benzyl). In one embodiment, each Ri is an aralkyl portion wherein the alkyl portion of the portion is substituted with two aryl groups and the portion is connected to the molecule via its alkyl group. For example, in one embodiment, at least one or both of Ri is a C7-C24 aralkyl wherein the alkyl portion is substituted with two phenyl groups, such as when R is 2,2-diphenylethyl or 2,2-dibenzylethyl. In one embodiment, each Ri of formula (I) is 2,2-diphenylethyl and n is 1, 2 or 5. In one embodiment, each Ri of formula (I) is 2,2-diphenylethyl, n is 1, 2 or 5. ymyp are each 1. In one embodiment, at least one RT is hydrogen. When at least one Ri is hydrogen, the other R-i may be any portion listed above for Ri, including an aryl group such as benzyl. Any of the compounds of formula (I) listed above includes the compounds wherein at least one or both of R2 is hydrogen or a substituted or unsubstituted CrC8 alkyl. In one embodiment, each R2 is an unsubstituted alkyl, such as methyl. In another embodiment, each R2 is hydrogen. Any of the compounds of formula (I) listed above can be compounds wherein q is 1 and m and p are the same. In consecuense, the polyaminoguanidines of formula (I) can be symmetric with reference to the core of the polyaminoguanidine (for example, excluding Ri). Alternatively, the compounds of formula (I) can be asymmetric, for example, when q is 0. In one embodiment, myp is 1. In a modality, q is 0. In a modality, n is an integer of 1 to 5. It is clearly understood and transmitted by this description that each Rt, R2, m, n, p and q described with reference to formula (I), encompass they include all combinations thereof, as if each and every combination of R ^ R2, m, n, p and q are listed in a specific and individual manner. Representative compounds of formula (I) include, for example: 8181 B182 In one embodiment, the compound is a N-alkylated polyaminobiguanide or polyaminobiguanide. An N-alkylated polyaminobiguanide refers to a polyaminobiguanide wherein at least one imine nitrogen of at least one biguanide is alkylated. In one embodiment, the compound is a polyaminobiguanide of the formula (II): (D) or a salt, solvate or hydrate thereof, wherein n is an integer from 1 to 12, m and p are independently an integer from 1 to 5, q is 0 or 1, each Ri is independently selected from the group consisting of C8-substituted or unsubstituted C8-alkyl, unsubstituted or substituted C6-C20 aryl, substituted or unsubstituted C6-C2o heteroaryl, substituted or unsubstituted C7-C24 aralkyl and substituted or unsubstituted C7-C24 heteroaralkyl; each R2 is independently hydrogen or a substituted or unsubstituted CrC8 alkyl. In one embodiment, at least one or each of R1 is a substituted or unsubstituted CrC8 alkyl, such as those listed above with reference to formula (I). For example, when R-i is a C 8 C alkyl substituted, the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine. Accordingly, in one embodiment, Ri is an alkyl group of CrC8 substituted with an amine, so that Ri can be, for example, a portion of alkyl-NH2 or alkyl-amino-alkyl, such as - (CH2) and NH ( CH2) zCH3 where y and z are independently an integer from 1 to 8. In one embodiment, R1 is - (CH2) sNH2. Ri may also be a substituted or unsubstituted C4-C15 cycloalkyl or a substituted or unsubstituted C3-C15 branched alkyl, as described for formula (I) above. In one embodiment, at least one or each of Ri is a substituted or unsubstituted C6-C20 aryl, such as those described above with reference to formula (I). In one modality, q is 1, myp is 3, and n is 4. In another modality, q is 1, myp is 3, and n is 7. In one modality, the compound is of formula (II), where at least one or both of Ri is a substituted or unsubstituted C7-C24 aralkyl, which in one embodiment, is an aralkyl connected to the molecule via its alkyl portion. In one embodiment, each R-i is an aralkyl portion wherein the alkyl portion of the portion is substituted with one or two aryl groups and the portion is connected to the molecule via its alkyl portion. For example, in one embodiment, at least one or both of R i is an aralkyl, wherein the alkyl portion is substituted with two phenyl or benzyl groups, such as when R 1 is 2,2-diphenylethyl or 2,2-dibenzylethyl. In one modality, each Ri of formula (II) is 2,2-diphenylethyl and n is 1, 2 or 5. In one embodiment, each Ri of formula (II) is 2,2-diphenylethyl and n is 1, 2 or 5 and m and p are each 1. Any of the compounds of formula (II) listed above includes the compounds wherein at least one or both of R2 is hydrogen or a substituted or unsubstituted CrC8 alkyl. In one embodiment, each R2 is an unsubstituted alkyl, such as methyl. In another embodiment, each R2 is a hydrogen. Any of the compounds of formula (II) listed above includes the compounds wherein q is 1 and m and p are the same. Accordingly, the polyaminobiguanides of formula (II) can be symmetric with reference to the polyaminobiguanide core (eg, excluding R1). Alternatively, the compounds of formula (II) can be asymmetric, for example, when q is 0. In one embodiment, myp is 1. In a modality, q is 0. In a modality, n is an integer of 1 to 5. In one embodiment, q, m and p are each 1 and n is 1, 2 or 5. It is clearly understood and transmitted by this description, that each R1, R2, m, n, p and q described with reference to formula (II) encompasses and includes all combinations thereof, as if each and every combination of Ri, R2) m, n, p and q are listed specifically and individually. Representative compounds of the formula (II) include, for example: XBI-5 -12D In one embodiment, the compound is a polyamine. In one embodiment, the polyamine is of the formula (III): (Tíí) or a salt, solvate or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted CrC8 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C7-C24 aralkyl; R5, R9, Re, R7 and R8 are independently selected from the group consisting of hydrogen and unsubstituted or substituted CrC8 alkyl; and wherein m and p are not the same integer or at least one of R5, Rg, Re, R7 and Re is a substituted or unsubstituted CrC8 alkyl.

In one embodiment, Rg is a substituted or unsubstituted CrC8 alkyl. When R9 is a substituted CrC8 alkyl, the substituted alkyl can be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine. Accordingly, in one embodiment, Rg is an alkyl group of CrC8 substituted with an amine, so that Rg can be, for example, an alkyl-NH2 or alkyl-amino-alkyl moiety, such as - (CH2) and NH (CH2) ) zCH3 where y and z are independently an integer from 1 to 8. In one embodiment, R9 is - (CH2) sNHCH2CH3. In one embodiment, one or both of R3 and R4 is hydrogen. If only one of R3 and R4 is hydrogen, the R3 or R4 that is not hydrogen can be any portion described herein, such as a substituted or unsubstituted CrC8 alkyl group, including a cyclic alkyl group such as cyclopropylmethyl or cycloheptylmethyl. In one embodiment, one or both of R3 and R4 is a substituted or unsubstituted CrC8 alkyl, including, but not limited to, a substituted or unsubstituted n-alkyl (such as n-pentyl), branched alkyl of (C3-) C8) substituted or unsubstituted (such as 2-methylbutyl) or substituted or unsubstituted (C3-C8) cycloalkyl (such as cyclohexylmethyl). The longer chain alkyl (linear, branched and cyclic) is also considered, such as a substituted or unsubstituted C8-C15 alkyl. Where one or both of R3 and R4 is a substituted or unsubstituted C-C8 alkyl, the portion may be any n-alkyl, such as methyl or ethyl. In one embodiment, both of R3 and R4 are a substituted or unsubstituted CrC8 alkyl, wherein one of R3 and R4 is an n-alkyl portion and the other is a cyclic portion, which is understood to contain at least three carbon atoms. Alternatively, both of R3 and R4 may be a substituted or unsubstituted C-C8 alkyl. When one or both of R3 and R is a substituted alkyl, whether linear, branched or cyclic, the alkyl may be substituted with one or more substituents, such as those listed under "Substituted alkyl", and includes alkyl substituted with any halogen, such as a monohaloalkyl, diahaloalkyl, trihaloalkyl or multihaloalkyl, including a perhaloalkyl, for example, perfluoroalkyl and perchloroalkyl, such as trifluoromethyl or pentachloroethyl. In one embodiment, one or both of R3 and R4 is a substituted or unsubstituted C6-C2o aryl. In one embodiment, one or both of R3 and R4 is a substituted C6-C2o aryl, aryl groups which may be substituted with one or more substituents, such as those listed under "Substituted aryl". In one embodiment, one or both of R3 and R4 is a substituted C6-C2o aryl, aryl groups which may be substituted with one or more alkyloxy groups (such as -OCH3), alkyl (including a branched alkyl such as tert-butyl) ) or halo (such as fluorine). In one embodiment, one or both of R3 and R4 is an aryl substituted with halo or a halo substituted aralkyl, such as 2,4,5-trifluorophenyl or 2,4,5-trifluorobenzyl. In one embodiment, one or both of R3 and R4 is an aryl or aralkyl substituted with a di-alkyl-monoalkoxy, such as 4,5-di-tert-butyl-2-methoxybenzyl or 4,5-di-tert-butyl -2-methoxyphenyl. In one embodiment, one or both of R3 and R4 is a substituted or unsubstituted C7-C24 aralkyl or heteroaralkyl, such as an aralkyl or heteroaralkyl connected to the molecule via its alkyl portion. In one embodiment, one or both of R3 and R4 is an aralkyl or heteroaralkyl connected to the molecule, via its alkyl portion. A substituted aralkyl may be substituted with one or more substituents, such as those listed under "Substituted aralkyl" and a substituted heteroaralkyl may be substituted with one or more substituents, such as those listed under "substituted eteroaralkyl." In one embodiment, one or both of R3 and R4 is a substituted heteroaralkyl having at least one nitrogen atom In one embodiment, one or both of R3 and R4 is a heteroaralkyl of a single ring having at least one nitrogen atom. or both of R3 and R4 is 1- (2-N-methy1-pyrrolyl) -methyl In one embodiment, at least 1 or at least 2 or at least 3 of R5, Rg, Re, 7 and Rs is an alkyl of C Ca substituted or unsubstituted R5, Rg, Re, R7 and R8 can be a substituted or unsubstituted CrC8 alkyl In one embodiment, at least 1 or at least 2 or at least 3 of R5, R9, R6, R7 is a n-unsubstituted CrC8 alkyl, such as methyl or ethyl In one embodiment, both of R6 and R5 are methyl or ethyl. In one embodiment, at least one of R7 and R8 is methyl or ethyl. In one embodiment, R7 is methyl. It is clearly understood and transmitted by this description that each R3, R, R5, Rg, RT, R7, Rs, m, n, y, z and p described with reference to formula (III) embraces and includes all combinations thereof, as if each and every combination of R3, R4, R5, Rg, Re, R7, Rs, rn, n, y, z and p were listed in a specific and individual way.

Representative compounds of the formula (III) include, for example: 44-DHEJ-4C YZ33049 In one embodiment, the polyamine is of the formula (IV): (IV) or a salt, solvate or hydrate thereof, wherein A, R10 and Rn are independently (CH2) p or eten-1, 1 -diyl; n is an integer from 1 to 5; R12 and R13 are independently selected from the group consisting of of hydrogen, substituted or unsubstituted C2-C8 alkenyl and substituted or unsubstituted CrC8 alkyl; and at least one of A, R 10, R-n, R 2 and R 13 comprises an alkenyl portion. In another embodiment, when any of A, R 10 and R 11 is alkenyl, the alkene portion branches off the direct chain connecting the nitrogen atoms; that is, no more than one hybridized sp2 carbon appears at the carbon nodes, along the shorter path of a nitrogen flanking A, R10 and / or Rn to the other flanking nitrogen. For example, when A is ethene, the segment that contains A is of the form -CH2C (= CH2) -CH2- and the three nodes in the shortest carbon path between the nitrogens that contain part A have only one carbon Hybridized sp2. When A is propene, the segment containing A can be of the form -CH2C (= CHCH3) -CH2- or -CH2C (-CH = CH2) -CH2-. In one modality, A is (CH2) n and n is 1. In one modality, A is eten-1, 1-only. In one embodiment, A is (CH2) n and one or both of R12 and 33 comprise an alkenyl portion, such as propen-2-yl. In one embodiment, at least one or both of R10 and Rn is eten-1, 1-diyl. In one embodiment, both of R10 and Rn are (CH2) n such as CH2 (where n = 1). In one embodiment, at least one or both of R12 and R13 is hydrogen. In one embodiment, at least one or both of R12 and R13 is a substituted or unsubstituted C2-C8 alkenyl, such as propen-2-yl. In one embodiment, at least one or both of R12 and R13 is a substituted or unsubstituted CrC8 alkyl, such as methyl or ethyl or any CrC8 alkyl substituted or unsubstituted mentioned with reference to any of the formulas (I), (II) or (III). It is clearly understood and transmitted by this description that each A, n, Rio, Rn, R? 2 and R? 3 described with reference to formula (IV) covers and includes all combinations thereof, as if each and all the combinations of A, n, R10, Rn, R12 and R13 were listed in a specific and individual way. Representative compounds of the formula (IV) include, for example: H H H H ZQW-44 ZQW-35-7C ZQW-35-8 H H H H SV-53-18C2 H H H || H ZGW-46 In one embodiment, the polyamine is of the formula (V): SW or a salt, solvate or hydrate thereof, wherein n is an integer from 1 to 8; m is an integer from 1 to 8; R15 and R1 are independently selected from the group consisting of hydrogen, substituted or unsubstituted CrC8 alkyl or branched (C3-C8) alkyl, substituted or unsubstituted C6-C2o aryl or heteroaryl and aralkyl or heteroaralkyl C7-C24 substituted or unsubstituted; R 6 and R 17 are independently hydrogen or a substituted or unsubstituted C 8 alkyl; and wherein the compound contains no more than three secondary amino groups, except when R 7 is a substituted or unsubstituted CrC 8 alkyl and wherein the compound is free from a portion of methylphosphonate or hydroxy. In one embodiment, at least one or both of R15 and R14 is hydrogen. When only one of R15 and R14 is hydrogen, R-? 5 or R14 which is not hydrogen can be any other portion listed above, such as a substituted or unsubstituted C6-C20 aryl or heteroaryl (e.g., 4-iopropylbenzyl) , 2-phenylbenzyl, 3,3-diphenylpropyl and the like or any substituted C6-C2o aryl or heteroaryl or any unsubstituted aryl or heteroaryl listed above, with reference to any of formulas (I) - (IV)).

In one embodiment, at least one or both of R15 and Ru is an unsubstituted or substituted N-alkyl of branched (C3-C8) alkyl, such as methyl, ethyl, 3-methyl-butyl, 2-ethyl- butyl, 5-NH2-pent-1-yl, prop-1-methyl-methyl (phenyl) phosphinate and the like or any unsubstituted or substituted C-C8-alkyl or branched (C3-C8) alkyl listed above with reference to the formulas (l) - (IV). In one embodiment, at least one or both of R15 and R14 is a substituted or unsubstituted C-C8 alkyl, such as an n-alkyl substituted with a portion of methyl (phenyl) phosphinate or an n-alkyl substituted with NH2 . In one embodiment, both of R15 and R14 are unsubstituted or unsubstituted nC alkyl portions of branched (C3-C8) alkyl, such as when R15 and R-14 are both 3-methyl-butyI or when R15 and R are both 2-ethyl-butyl. R15 and Ru can be different portions of substituted or unsubstituted CrC8 alkyl, such as when one of R15 and R14 is propyl and the other is ethyl. In one embodiment, at least one or both of R15 and R is a substituted or unsubstituted aralkyl or heteroaryl of C7-C24. In one embodiment, at least one or both of R15 and R14 is a substituted or unsubstituted C7-C24 aralkyl or heteroaralkyl, having two rings, such as 2-phenylebenzyl, 4-phenylbenzyl, 2-benzylbenzyl, 3-benzylbenzyl, 3,3-diphenylpropyl, 3- (benzoimidazolyl) -propyl and the like. In one embodiment, at least one or both of R15 and R14 is a substituted or unsubstituted C7-C24 aralkyl or heteroaralkyl, having a ring, such as 4-isopropylbenzyl, 4-fIuorobenzyl, 4-tert-butylbenzyl, 3- imidazolyl-propyl, 2-phenylethyl and the like.

In one embodiment, one of R15 and R14 is a substituted or unsubstituted C7-C24 aralkyl or heteroaralkyl, such as any of the substituted or unsubstituted aralkyl or heteroaralkyl specific portions listed for any other formula, and the other of R? 5 and R14 is hydrogen or a substituted or unsubstituted CrC8 alkyl or branched (C3-C8) alkyl, such as ethyl, methyl, 3-methylbutyl and the like. For any compound of formula (V), m and n may be the same or different. In one embodiment, m is not equal to n, such as when m is 1 and n is 2. For example, in one embodiment, m is 1, n is 2 and both of R15 and R14 are 2-benzylbenzyl. However, it is understood that all possible combinations of m, n, R15 and R14 are included. In one embodiment, at least one or both of R and R17 is hydrogen. In one embodiment, at least one or both of R16 and R17 is a substituted or unsubstituted CrC8 alkyl., such as methyl, ethyl and a CrC8 alkyl substituted with, for example, a CrC8-NH alkyl such as when at least one or both of R16 and R17 is - (CH2) 3 NHCH2CH3. It is clearly understood and transmitted by this description that each R-14, R15, R-iß, R17, m and n described with reference to formula (V) covers and includes all combinations thereof, as if each and all combinations of R14, R15, Rie, R17, myn were listed specifically and individually. Representative compounds of the formula (V) include, for example: YZ33035 In one embodiment, the polyamine is of the formula (VI): (SAW) or a salt, solvate or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; R 8 and R ig are independently selected from the group consisting of hydrogen, unsubstituted CrC 8 alkyl (for example, methyl, ethyl, tert-butyl, isopropyl, pentyl, cyclobutyl), n-C 8 -alkyl substituted with a cycloalkyl group comprising at least two substituted or unsubstituted C7-C2 aralkyl or heteroaralkyl rings, comprising at least two rings and wherein: n is 1 when Rie and Rig are identical n-alkyl portions of CrC8 substituted with a cycloalkyl group comprising at least two rings, or are identical aryl groups comprising at least two rings; and at least one of R 8 and R 19 is an N-alkyl of CrC 8 substituted with a cycloalkyl group comprising at least two rings or a substituted or unsubstituted C 7 -C 24 aralkyl comprising at least two rings. In one embodiment, at least one or both of R18 and Rig is a CrC8 n-alkyl substituted with a cycloalkyl group comprising at least two rings. The cycloalkyl group comprising at least two rings may be a spiro, fused or bridged cycloalkyl group. Representative examples of a d-C8-n-alkyl substituted with a cycloalkyl group comprising two rings include the portions such as 2- (6,6-dimethylbicyclo [3.1.1] heptyl) ethyl and 2- (decahydronaphthyl) ethyl. In one embodiment, both Rie and Rig are 2- (6,6-dimethylbicyclo [3.1.1] heptyl) ethyl. In one embodiment, both Ris and R19 are 2- (decahydronaphthyl) ethyl. In one embodiment, one of R? 8 and R19 is 2- (6,6-dimethylbicyclo [3.1.1] heptyl) ethyl or 2- (decahydronaphthyl) ethyl and the other of R18 and Rig is hydrogen or an unsubstituted CrC8 alkyl, such as ethyl. In one embodiment, at least one or both of R? 8 and R? G is a substituted or unsubstituted C7-C24 aralkyl or heteroaralkyl comprising at least two rings, which rings may, but need not be fused. An aralkyl or substituted heteroaralkyl with reference to formula (VI) encompasses and includes alkanoyl portions substituted with an aryl group Or heteroaryl, ie, -C (= 0) -aryl, -C (= 0) -aralkyl, -C (= 0) -heteroaryl and -C (= 0) -heteroaralkyl. In one embodiment, the alkyl portion of the aralkyl or heteroaralkyl portion is connected to the molecule via its alkyl portion. For example, at least one or both of R 8 and R 19 may be an aralkyl portion such as 2-phenylbenzyl, 4-phenylbenzyl, 3,3, -diphenylpropyl, 2- (2-phenylethyl) benzyl, 2-methyl-3. phenylbenzyl, 2-naphthylethyl, 4- (pyrenyl) butyl, 2- (3-methylphaphthyl) ethyl, 2- (1,2-dihydroacenaft-4-yl) ethyl and the like. In another embodiment, at least one or both of Ris and Rig may be a heteroaralkyl portion such as 3- (benzoimidazolyl) propanoyl, 1 - . 1- (benzoimidazoyl) methanoyl, 2- (benzoimidazolyl) ethanoyl, 2- (benzoimidazolyl) ethyl and the like. In one embodiment, each of m, n and p is the same, such as when m, n and p are each 1. It is clearly understood and transmitted by this description that each R-iß, Rig, m, n and p described with reference to the formula (VI) covers and includes all combinations thereof, as if each and all combinations of R? 8, Ri, m, n and p were listed specifically and individually. Representative compounds of the formula (VI) include, for example: In one embodiment, the polyamine is of the formula (VII): (vp > or a salt, solvate or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; q is 0 or 1; R20 and R21 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C8 alkyl, -C (= 0) -substituted or unsubstituted CrC8 alkyl, -C (= O) -CrC8 alkenyl substituted or unsubstituted, -C (= O) -substituted or unsubstituted CrC8alkynyl and substituted or unsubstituted C7-C24 aralkyl; and wherein the compound comprises at least a portion selected from the group consisting of t-butyl, isopropyl, 2-ethylbutyl, 1-methylpropyl, 1-methylbutyl, 3-butenyl, isopent-2-enyl, 2-methylpropan-3-. olyl, ethylthiyl, phenylthiyl, propynyl, 1-methyl-1H-pyrrol-2-yl, trifluoromethyl, cyclopropanecarbaldehyde, phenyl substituted with halo, phenyl substituted with nitro, phenyl substituted with alkyl, 2,4,6-trimethylbenzyl, substituted phenyl with halo-S (such as para- (F3S) -phenyl, azido and 2-methylbutyl) In one embodiment, q is 1. In one embodiment, q is 1 and n is 1. In one embodiment, at least one of R20 and R21 is hydrogen In one embodiment, at least one of R and R2 is unsubstituted or substituted CrC8 alkyl, such as any of the substituted or unsubstituted alkyl portions mentioned above for formulas (1) - (VI). a modality, at least one of R20 and R2? is a substituted or unsubstituted C7-C24 aralkyl, such as any of C7-C2 substituted or unsubstituted aralkyl mentioned above for formulas (1) - (VI). It is clearly understood and transmitted by this description that each R20, R2 ?, m, n, q and p described with reference to the formula (VII) embraces and includes all combinations thereof, as if each and every combination of R2o , R21, m, n, q and p were listed in a specific and individual way. Representative compounds of the formula (VII) include, for example: 49-TDW-15 44-DHEJ-41 > Y In one embodiment, the polyamine is of the formula (VIII): or a salt, solvate or hydrate thereof, wherein m and p are independently an integer from 1 to 5; X is - (CH2) n- or cyclohex-1,3-diyl; n is an integer from 1 to 5; R22 and R23 are independently selected from the group consisting of hydrogen, n-butyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, cycloheptylmethyl, cyclohexylethyl-2-yl and benzyl; and when n is 5, at least one of R22 and R23 is hydrogen; when R22 is ethyl, R23 is hydrogen, n-butyl, cyclopentylmethyl, cyclohexylethyl-2-yl or benzyl; and when R23 is ethyl, R22 is hydrogen, n-butyl, cyclopentylmethyl, cyclohexylethyl-2-yl or benzyl; when X is cyclohex-1,3-diyl, R 2 and R 23 are not both benzyl or cyclopropylmethyl. In one embodiment, X is - (CH2) n (for example, CH2 where n is 1). In one embodiment, X is CH2 and and p are both 1. In one embodiment, X is cyclohex-1,3-diyl. In one embodiment, X is cyclohex-1,3-diyl and m and p are both 1. In other embodiments, m and p are not the same, for example, when m is 3 and p is 4. It is clearly understood and transmitted by this description that each R22 , R23, m, n and p described with reference to formula (VIII) is intended and includes all combinations thereof, as if each and every one of the combinations of R22, R23, rn, n and p were listed so specific and individual.

Representative compounds of the formula (VIII) include, example: UMS-31-7A 'K' * N 'H H H H ZQW-14C 'N' * N '~ NH2 H H H ZQW-160 -CHENspm mess In one embodiment, the polyamine is of the formula (IX): (DO or a salt, solvate or hydrate thereof, where p is an integer from 1 to 5; R24 is a cycloalkyl substituted with amino (e.g., a group cycloalkyl substituted with a primary, secondary, tertiary amine or quaternary) or substituted or unsubstituted C2-C8 alkanoyl (substituted alkanoyl) which may be substituted with one or more substituents such as those listed for "Substituted alkyl", including, but not limited to, an alkanoyl substituted with a methyl group and an alkylazide); and R25 is a substituted or unsubstituted CrC8 alkyl or a substituted or unsubstituted C7-C24 aralkyl, such as those listed above for any of formulas (I) - (VIII). In one embodiment, R24 is a C3-C24 cycloalkyl substituted with amino, such as 5-NH2-cycloheptyl, 3-NH2-cyclopentyl and the like. In one embodiment, R 25 is a substituted or unsubstituted CrC 8 alkyl, which includes an n-alkyl group substituted with a cycloalkyl, such as in cyclopropylmethyl. In one embodiment, R25 is cyclopropylmethyl or ethyl and R24 is 5-NH2-Cycloheptyl or 3-NH2-cyclopentyl. In one embodiment, R 4 is a substituted or unsubstituted C-C8 alkanoyl and R24 is a substituted or unsubstituted C7-C24 aralkyl, such as 4-phenylbenzyl. It is clearly understood and transmitted by this description that each R24, R25 and p described with reference to formula (IX) encompasses and includes all combinations thereof, as if each and all combinations of R24, R25 and P were listed specific and individual way. Representative compounds of the formula (IX) include, for example: UNS-31-18 UNS-31-19c For all the formulas listed in this, such as formulas (I) - (IX), even if not explicitly stated, any substituent mentioned in a formula is intended to describe the same substituent in any other formula, to the extent that the description complies with the structural characterization of the formula described. For example, Ri in formula I is intended to describe any other Ri found in any other formula, to the extent that the description meets the structural characterization of the formula described. Similarly, any description of, for example, substituted or unsubstituted CrC8 alkyl is intended to describe any other substituted or unsubstituted CrC8 alkyl found in any other formula, to the extent that the description meets the structural characterization of the formula described. . It is also recognized that any compounds listed as a particular salt thereof, is not intended to limit the compound to such salt or form of the same. Similarly, where the compounds are listed as a salt, the structure may or may not explicitly indicate the positive or negative charges or the location thereof, and all possibilities thereof are included. For example, a compound listed as a 4HBr salt does not limit the compound to only the HBr salt and the compound may or may not show the + or - charges of the HBr salt, without, instead, all possibilities being included. . Any of the polyamine compounds, such as the compounds of the formulas (I) - (IX) may be in a protected form, such as when any one or more amines (e.g., -NH-) are protected by a protecting group ( Pg), as in (-NPg-). Pg can be any protecting group, such as mesityl (for example, NMes), Boc (for example, -NBoc) or any other protective group, such as those described in, for example, TW Green, PGM Wuts, Protective Groups in Organic Synthesis, Wiley-lnterscience, New York, 1999, which is incorporated herein by reference in its entirety. Compounds within the scope of this invention and / or as described by any one or more of formulas (I) - (IX) include (non-exclusively) the compounds listed in Table A below. In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (M).

In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (I). In another embodiment, the invention encompasses a method for treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (II). In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (III). In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (IV). In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (V). In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (VI). In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (VII).

In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (VIII). In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds of formula (IX). In another embodiment, the invention encompasses a method of treating cancer by administering a therapeutically effective amount of one or more of the compounds listed in Table A or Table B. In another embodiment, the invention encompasses a method of inhibiting an enzyme of histone demethylase, such as LSD1, by contacting the enzyme with an amount of one or more compounds, wherein the compound has at least one guanidine moiety or at least one biguanide moiety, in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (M) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (I) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (II) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (III) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (IV) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (V) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (VI) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting an enzyme of histone demethylase, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (VII) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (VIII) in an amount sufficient to inhibit the enzyme The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds of formula (IX) in an amount sufficient to inhibit the enzyme The enzyme it can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In another embodiment, the invention encompasses a method for inhibiting a histone demethylase enzyme, such as LSD1, by contacting the enzyme with an amount of one or more of the compounds listed in Table A or Table B, in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 describes the 96-hour MTS dose response experiments for compound 46-TDW-23c in H157, A549, H82 Beas2B cells. Figure 2 depicts the 96-hour MTS dose response experiments for compound 49-TDW-9 in H157, A549, H82 and Beas2B cells.

Figure 3 describes the 96-hour MTS dose response experiments for compound 42-TDW-21C in H157, A549, H82 and Beas2B cells. Figure 4 depicts the 96-hour MTS dose response experiments for compound 46-TDW-19c in H157, A549, H82 and Beas2B cells. Figure 5 describes the 96-hour MTS dose response experiments for compound 49-TDW-17c in H157, A549, H82 and Beas2B cells. Figure 6 describes the dose response experiments of 96-hour MTS for compound 40-TDW-37 in H157, A549, H82 and Beas2B cells. Figure 7 describes the 96-hour MTS dose response experiments for compound 42-TDW-4 in H157, A549, H82 and Beas2B cells. Figure 8 describes the 96-hour MTS dose response experiments for compound 49-TDW-29c in H157, A549, H82 and Beas2B cells. Figure 9 describes the 96-hour MTS dose response experiments for compound 49-TDW-32c in H157, A549, H82 and Beas2B cells.

Figure 10 describes the 96-hour MTS dose response experiments for compound 46-TDW-35C in H157, A549, H82 and Beas2B cells. Figure 11 describes the 96-hour MTS dose response experiments for compound 39-TDW-3 in H157, A549 and H82 cells. Figure 12 depicts 96-hour MTS dose response experiments for compound 39-TDW-12c in H157 and A549 cells. Figure 13 describes the 96-hour MTS dose response experiments for compound 39-TDW-20c in H157 and H82 cells. Figure 14 describes the 96-hour MTS dose response experiments for compounds 39-TDW-47c and 39-TDW-43 in H157 cells. Figure 15 describes the 96-hour MTS dose response experiments for compounds 42-TDW-9, 42-TDW-4c / 6, 40-TDW-35, 42-TDW-38 and BENSpm in H157 cells. Figure 16 describes the 96-hour MTS dose response experiments for compounds 46-TDW-34C, 42-TDW-12, 40-TDW-48, 46-TDW-44C and BENSpm in H157 cells. Figure 17 describes the 96-hour MTS dose response experiments for compounds 42-TDW-20C, 46-TDW-22, 46-TDW-39, 49-TDW-29C and BENSpm in H157 cells.

Figure 18 describes the 96-hour MTS dose response experiments for compounds 39-TDW-43, 42-TDW-48C, 46-TDW-9, 46-TDW-23C and BENSpm in H157 cells. Figure 19 describes the 96-hour MTS dose response experiments for compounds 42-TDW-35C, 46-TDW-44 and BENSpm in H157 cells. Figure 20 describes an MTT assay after 96 hours of treatment with compound 9-TDW-47c. Figure 21 describes the chronological course for compound 39-TDW-47c in cells 231. Figure 22 describes the chronological course for compound 39-TDW-47c in 435 cells. Figure 23 describes the chronological course for compound 39- TDW-47c in MCF7 cells. Figure 24 describes the inhibition of LSD1 activities by certain polyaminoguanidines and polyaminobiguanides. Figure 25 describes the effects of XB1-54-13B on the growth of tumor cells. Figure 26 describes the effects of B182 on the growth of tumor cells. Figure 27 describes a kinetic assay of the dose-dependent inhibition of LSD1 activity by XBI-54-13B.

Figure 28 describes a kinetic assay of the dose-dependent inhibition of LSD1 activity by B182. Figure 29 depicts a Lineweaver-Burk plot for the inhibition of LSD1 activity by XBI-54-13B. Figure 30 describes the gels that demonstrate the effect of XBI-54-13B in the levels of dimethyl H3K4, dimethyl H3K9 and the nuclear antigen of the proliferating cells. Figure 31 describes the quantitative effect of XBI-54-13B on levels of methylated histone H3K4. Figure 32 describes the quantitative effect of XBI-54-13B on levels of methylated histone H3K9. Figures 33A and 33B describe the effects of XBI-54-13B and B182 on the secreted proteins related to shirring 1, 2, 4 and 5 and on GAPDH.

DETAILED DESCRIPTION OF THE INVENTION The description includes all salts of the compounds described herein. The invention also includes all compounds that are not salts of any salt of a compound named herein, as well as other salts of any salt of a compound named herein. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. The pharmaceutically acceptable salts are those salts that maintain the biological activity of the free compounds and that can be administered as drugs or pharmaceutical products or human and / or animals. The desired salt of a basic compound can be prepared by methods known to those skilled in the art, treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, masonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid. , cinnamic acid, mandelic acid, sulfonic acids and salicylic acid. Salts of the basic compounds with amino acids, such as the aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those skilled in the art, treating the compound with a base. Examples of inorganic salts of acidic compounds include, but are not limited to, alkali metal and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts and calcium salts; Ammonium salts and aluminum salts. Examples of organic salts of acidic compounds include, but are not limited to, salts of procaine, dibenzylamine, N-ethylpiperidine, N, N'-dibenzylethylenediamine and triethylamine. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared.

The description describes all solvates of the compounds described herein, such as hydrates (in any ratios, for example, monohydrates, dihydrates, hemihydrates, sesquihydrates), methanolates, ethanolates, etc. Any compound described herein may appear in a combined form of salt and solvate, for example, in the form of hyclate (monohydrochloride of the semietanolate semihydrate). The description includes all stereoisomers of the compounds described herein, including the diastereomers and enantiomers in optically pure or substantially optically pure form, as well as mixtures of stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless the stereochemistry is explicitly indicated in a chemical structure or a chemical name, the chemical structure or chemical name is intended to encompass all possible stereoisomers of the described compound. The description includes all crystalline and non-crystalline forms of the compounds described herein, including all polymorphic, polycrystalline and amorphous forms and any mixtures thereof. The term "alkyl" refers to saturated aliphatic groups including straight chain, branched chain, cyclic groups and combinations thereof, having the specified number of carbon atoms, or if a number is not specified, having up to 12 atoms of carbon. The groups "straight chain alkyl" or "linear alkyl" refer to alkyl groups which are not cyclic or branched, commonly referred to as "n-alkyl" groups. The n-alkyl of CrC8 consists of the following groups: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2- and -CH2CH2CH2CH2CH2CH2CH2CH2-. Other examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, heptyl. , octyl, nonyl, decyl, undecyl, dodecyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl. The cycloalkyl groups may consist of a ring including, but not limited to, groups such as cycloheptyl, or rings with multiple or fused bridges including, but not limited to, groups such as the adamantyl or norbomyl groups. The cycloalkyl groups may also contain alkyl groups in addition to the cyclic portion, for example, 2,6,6-trimethylbicyclo [3.1.1 jheptane, 2-methylocaine (2-methyldecahydronaphthalene), cyclopropylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like. "Substituted alkyl" refers to alkyl groups substituted with one or more substituents including, but not limited to, groups such as halogen (including alkyl substituted with fluorine, chlorine, bromine and / or iodine, such as a monohaloalkyl, dihaloalkyl, trihaloalkyl or multihaloalkyl, including a perhaloalkyl, for example, perfluoroalkyl, perchloroalkyl, trifluoromethyl or pentachloroethyl), alkoxy, acyloxy, amino (including NH2, NH-alkyl and N (alkyl) 2), hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, acyl, acylamino, amidino, alkyl amidino, thioamidino, aminoacyl, aryl, substituted aryl, aryloxy, azido, thioalkyl , -OS (0) 2-alkylamino, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality which may be suitably blocked, if necessary, for the purposes of the invention, with a protecting group. Examples of substituted alkyl groups include, but are not limited to, CF3, CF2CF3, and other perfluoro and perhalo groups; -CH2-OH; -CH2CH2CH (NH2) CH3, etc. The alkyl groups may be substituted with other alkyl groups, for example, C3-C24 cycloalkyl groups. The term "alkenyl" refers to unsaturated aliphatic groups, including straight chain (linear), branched chain, cyclic groups, and combinations thereof, having the specified number of carbon atoms, or if no number, which have up to 12 carbon atoms, which contains at least one double bond (-C = C-). Examples of alkenyl groups include, non-exclusively, -CH-CH = CH-CH3; and -CH2-CH2-cyclohexenyl, wherein the ethyl group can be attached to the cyclohexenyl portion at any valency of available carbon. The term "alkynyl" refers to unsaturated aliphatic groups, including straight chain (linear), branched chain, cyclic groups, and combinations thereof, having the specified number of carbon atoms, or if no number, which have up to 12 carbon atoms, which contain at least one triple bond (-G = C-). "Hydrocarbon chain" or "hydrocarbyl", refers to any combination of straight chain, branched chain or cyclic alkyl, alkenyl or alkynyl groups, and any combination thereof. "Substituted alkenyl", "substituted alkynyl" and "substituted hydrocarbon chain" or "substituted hydrocarbyl", refer to the respective group substituted with one or more substituents, including, but not limited to, groups such as halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "Substituted alkyl" or a functionality that may be adequately blocked, if necessary for the purposes of the invention, with a protecting group. "Aryl" or "Ar" refers to an aromatic carbocyclic group having a single ring (including, but not limited to, groups such as phenyl), two or more rings connected to each other (including, but not limited to, groups such as biphenyl and p-diphenylbenzene) or two or more fused rings (including, but not limited to, groups such as naphthyl, anthryl or pyrenyl), and include both unsubstituted and substituted aryl groups. Aryls, unless otherwise specified, contain 6 to 20 carbon atoms in the ring portion. A preferred range of aryls contains from 6 to 12 carbon atoms in the ring portion. "Substituted aryls" refer to aryls substituted with one or more substituents, including, but not limited to, groups such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, unsubstituted or unsubstituted alkynyl substituted, substituted or unsubstituted hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "Alkyl" "substituted," or a functionality that can be blocked appropriately, if necessary, for the purposes of the invention with a protecting group. "Aralkyl" designates an aryl group substituted with alkyl, wherein any aryl may be attached to the alkyl; the alkyl portion may comprise one, two or three linear chains of 1 to 6 carbon atoms each or one, two or three branched chains of 3 to 6 carbon atoms each or any combination thereof. The aralkyl groups may consist of two aryl groups connected by an alkyl group, such as diphenylmethane or 2-methyl-1- (phenethyl) benzene. When an aralkyl group is indicated as a substituent, the aralkyl group can be connected to the rest of the molecule at any available valence in any of its alkyl or aryl portions; for example, the tolyl aralkyl group can be connected to the rest of the molecule by replacing any of the five hydrogens in the aromatic ring portion with the rest of the molecule, or by replacing one of the alpha hydrogens of the methyl portion with the rest of the molecule . Preferably, the aralkyl group is connected to the rest of the molecule via the alkyl portion. A preferred aryl group is phenyl, which may be substituted or unsubstituted. Substituents for substituted phenyl groups include lower alkyl (-C 4 alkyl), or a halogen (chloro (Cl), bromo (Br), iodo (I) or fluorine (F); hydroxy (-OH), or lower alkoxy (-C1-C4 alkoxy), such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy or i-propoxy), and butoxy (either n-butoxy, -butoxy, sec-butoxy or tert-butoxy); A preferred alkoxy substituent is methoxy. Preferred substituted phenyl groups have one or two substituents; more preferably, a substituent. "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl", refer to alkyl, alkenyl and alkynyl group, respectively, containing the specified number of carbon atoms (or if a number is not specified, having up to 12 carbon atoms) , which contain one or more heteroatoms as part of the main, branched or cyclic chains in the group. The heteroatoms include, but are not limited to, N, S, O and P; N and O are preferred. Heteroalkyl, heteroalkenyl and heteroalkenyl groups can be attached to the rest of the molecule in any valence, where a hydrogen can be removed, for example, in a heteroatom or a carbon atom (if a valence is available in such an atom by removing a hydrogen) . Examples of heteroalkyl groups include, but are not limited to, groups such as -O-CH3, -CH2-0-CH3, -CH2-CH2-0-CH3, -S-CH2-CH2-CH3, -CH2-CH ( CH3) -S-CH3, -CH2-CH2-NH-CH2-CH2-, 1-ethyl-6-propylpiperidino and morpholino. Examples of heteroalkenyl groups include, but are not limited to, groups such as -CH = CH-NH-CH (CH3) -CH2-. "Heteroaryl" or "etAr", refer to an aromatic carbocyclic group having a single ring (including, but not limited to, examples such as pyridyl, imidazolyl, thiophene or furyl) or two or more fused rings (including, do not exclusive, examples such as indolicinyl, indole, benzimidazole, benzotriazole or benzothienyl), and having at least one heteroatom, including, but not limited to, heteroatoms such as N, O, P or S, within the ring. Unless otherwise specified, the heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups have between one and five heteroatoms and between one and twelve carbon atoms. The groups "substituted heteroalkyl", "substituted heteroalkenyl", "substituted heteroalkynyl" and "substituted heteroaryl", refer to heteroalkyl groups, heteroalkenyl, heteroalkynyl and heteroaryl substituted with one or more substituents, including, but not limited to, groups such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted benzyl, hydrocarbon chains substituted or unsubstituted, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "substituted alkyl", or a functionality that can be blocked appropriately, if necessary, for the purposes of the invention, with a protecting group. Examples of such substituted heteroalkyl groups include, but are not limited to, piperazine, substituted on a nitrogen or carbon with a phenyl or benzyl group, and attached to the rest of the molecule by any valence available on a carbon or hydrogen, -NH-S02 phenyl, -NH- (C = 0) 0 -alkyl, -NH- (C = 0) 0 -alkyl-aryl and -NH- (C = 0) -alkyl. If it is chemically possible, the heteroatoms and / or the atoms of Carbon of the group can be replaced. A "heteroaralkyl" group is a heteroaryl group substituted with at least one alkyl group. Heteroatoms may also be in oxidized form, if chemically possible. The term "alkoxy", as used herein, refers to an alkyl, alkenyl, alkynyl or a hydrocarbon chain linked to an oxygen atom and having the specified number of carbon atoms, or if no number, has up to 12 carbon atoms. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy or -propoxy), and butoxy (either n-butoxy, i-butoxy, sec. -butoxy or tert-butoxy). The terms "halo" and "halogen", as used herein, refer to the elements of the Vlla Group (Group of 17 elements in the Periodic Table IUPAC 2005, IUPAC Nomenclature of Inorganic Chemistry), and include Cl substituents, Br, F and I. "Protective group" refers to a chemical group that exhibits the following characteristics: 1) selectively reacts with the desired functionality in good performance to provide a protected substance that is stable to the reactions projected for which protection is desired; 2) is selectively removed from the protected substrate to provide the desired functionality; and 3) it is eliminated in a good yield by the reactants compatible with other functional groups present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1999) Protective Groups in Organic Synthesis, (Wiley-lnterscience., New York). Amino protecting groups include, but are not limited to, mesitylsulphonyl (Mts), benzyloxycarbonyl (CBz or Z), t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS or TBDMS), 9-fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl , 2-pyridylsulfonyl or suitable photolabile protecting groups such as 6-nitroveratryloxycarbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzyl, 5-bromo-7-nitroindolinyl and the like. The hydroxyl protecting groups include, but are not limited to, Fmoc, TBS, photolabile protecting groups (such as nitroveratril oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether), NPEOC (4- nitrofenetiloxycarbonyl) and NPEOM (4-nitrophenethyloxymethyloxycarbonyl).

Specific compounds Examples of the compounds useful in the invention are described in Table A. Although the compounds are described as salts, such as hydrobromide or trifluoroacetate salt, it will be understood that the description in the Table covers all salts, hydrates and solvates of the compounds described herein, as well as the non-non-salt, non-hydrate / or solvate form of the compound, as is well understood by the skilled person.

TABLE A UNS-31-7A 4I-IBr UNS-31-18 UNS-31-19C 3HBr (18) s 3CF3COOH (19C) UNS-31-21C 3 CF3CGOH -methyl CHENspm 4 HBr 4TrD3r ZQW-44 4 HBr ZQW-46 4 HBr 4 HBr ZGW ~ 357C 4 HBr ZQW-35-8 * 4HBr ZQ -35-8C "HBr H H H H YZ33049C "HBr YZ33035 * 5 jjgr YZ33050C 4 HBr YZ33049 4 HBr Y233041 5 HBr • WH2"N * H H H YZ33046 4 HBr CHEXSpm 4 HBr CPENTSpm 4 HBr 39-TD -11 4 HBr 3T-TDW-10 4 HBr 39-TDW-12C 4 HBr 3? -TDW-12 4 HBr 4 HBr i = 3C H H H H - 40-TDW-1S 4 HBr 40-TDW-31C 4 HBr 4 HBr % N '' W 'SN' H H H H 44-DHEJ-48C 4 HBr TT * N * * NHZ H H H 44-DHEJ-49 4 HBr B181 4 HBr B 179-1 4 HBr B182 4 HBr 49-TDW-1í > 4 HBr 49-TDW-17C 4 HBr 44-DHEJ-41 2HF 4HF 51-DHEJ-18 4 HBr 51-DHEJ-20 2 CF3C0OH N 'H H H 53-SV-3C R-iPENSpm 4 HBr N '* N' "N * H H H H YZ3604C S-IPE Spm 4 HBr "* M 'H H H 53-SV-2C 4 HBr 51-DHEJ-49C 4 HBr 6 HBr 4 CFjCOOH DG-52-27C 4 HBr DG-52-28 4 HBr 'N' '' H H DG-52-29C 4 HBr SV-53-17C2 4 HBr SV-53-22C1 4 HBr twenty SV-53-18C2 4 HBr 55-DHEJ-37C 4 HBr Synthetic methods, synthesis of alkyl polyamines Various synthetic methods are available for the synthesis of polyamine analogs, including both symmetrically substituted and asymmetrically substituted polyamine analogs. Some of these methods are described in the following publications: Saab et al, J. Med. Chem. 36: 2998 (1993); Bellevue et al., Bioorg. Med. Chem. Lett. 6: 2765 (1996); Sirisoma et al., Tetrahedron Lett. 39: 1489 (1998); Zou et al., Bioorg. Med. Chem. Lett. 11: 1613 (2001), and Casero et al., J. Med. Chem. 44: 1 (2001) REACTION SCHEME 1"Mest" indicates a portion of mesitylene sulfonyl (2,4,6-trimethylbenzene-1-sulfonyl) NaH DMF NaH. DMF R-X R, -X (2.2 equivalents). . . { 2.2 equivalents) Reaction Scheme 1 illustrates a useful trajectory for various polyamine analogues. The tetramesitylated intermediate 8 can be easily alkylated at both terminal nitrogens, since the hydrogens on these nitrogens become acidic by the adjacent mesityl protecting group. Alkylation in the presence of 1.2 to 1.4 equivalents of alkyl halide or tosylate mainly provides the monosubstituted product 9, and disubstituted materials and unreacted raw material can be separated and recycled (Bellevue et al., Bioorg. Med. Chem. Lett. 6: 2765 (1996), Zou et al., Bioorg, Med Chem. Lett 11: 1613 (2001)). The resulting monoalkylated derivative 9 can then be deprotected (30% HBr in AcOH), or alkylated again with a different alkyl halide to provide the asymmetrically substituted intermediate 11. The deprotection of 11 then provides the substituted alkyl polyamine in a desired asymmetric manner. The treatment of 8 with 2.2 equivalents of Alkyl halide in the presence of NaH and DMF, provides the substituted 10a intermediate, which upon deprotection, provides the corresponding symmetrically substituted alkyl polyamine. Thus, three different alkyl polyamines can be easily synthesized from a single intermediate, and the central carbon chain can be made of any desired length (n = 0-8). The synthesis of intermediate 8 is easily achieved in large quantities using previously reported synthetic strategies (Bellevue et al., Bioorg, Med Chem. Lett 6: 2765 (1996), Zou et al., Bioorg, Med. Chem. Lett. 11: 1613 (2001)). A similar strategy can be used to access the spermidine-like analogs of the form: Other methods can be used for the synthesis of the required polyamine backbone structures, which involve the formation of a carbon-nitrogen bond and the selective protection of nitrogen; some of these procedures are shown in the Scheme of Reaction 2.

REACTION SCHEME 2 Method A Method C Pd2 (dba) 3 -R -R-OAc kN 'áppb, THF H R-OAc 12 17 The aminopropyl (or other aminoalkyl) moieties can be added to the selectively protected primary amines such as 12 by standard peptide coupling techniques (Method A, Woster et al., J. Med. Chem. 32: 1300 (1989 )). Thus, treatment of 12 with the protected beta-aminopropionate 13 (DCC, HoBt, N-methylmorpholine), provides the corresponding amide 14, which is then reduced in the presence of diborane (Woster et al., 1989), to provide the desired secondary amine 16. Compound 16 can be synthesized directly by reductive amination (Method B), in which the appropriate aldehyde is added to 12 in the presence of sodium cyanoborohydride. Alkyl acetate-containing substituents may also be linked to 12 using a coupling reaction palladium catalyzed, which proceeds with the retention of the configuration (Method C, Sirisoma et al., Tetrahedron Lett, 39: 1489 (1998)). This method can also be used to introduce the phthalimide or benzylamine to an allylic acetate site as a synthetic equivalent for nitrogen. These nitrogens can then be deprotected and functionalized.

Synthetic methods, synthesis of polyaminoquanidines REACTION SCHEME 3 General structure 3 The synthesis of the polyaminoguanidines can be carried out as set forth in Reaction Scheme 3. The required amine 19 (produced when necessary from the corresponding alkyl or aralkyl cyanide) is reacted with a cyanogen bromide (Goldin et al., U.S. Patent No. 6,288,123 (2001)), to provide the corresponding aminocyanogen. When the desired amine is not commercially available, it can be prepared from the appropriate cyano compound by catalytic reduction (Bellevue et al., 1996, Zou et al., 2001). Intermediate 21 (Bellevue et al., 1996; Zou et al., 2001), is then coupled to 20 (chlorobenzene, reflux), followed by deprotection (30% HBr in AcOH), to produce the structure alkylpolyaminoguanidines 3. Using these methods, substituted polyaminoguanidine analogues (eg, R = H, methyl, ethyl, cyclopropylmethylene, cycloheptylmethylene, phenyl, benzyl) can be synthesized. An analogous route (not shown), which uses the N-Boc protective group was also employed.

Synthetic methods, synthesis of polyaminobiguanides The synthesis of polyaminobiguanides is described in Bi et al., Bioorg. Med. Chem. Lett. 16: 3229 (2006), and is also set forth in Reaction Scheme 4.

REACTION SCHEME 4 General structure 4 A similar strategy is used for the synthesis of the alkylpolyaminobiguanides of general structure 4, as set forth in Reaction Scheme 4. The amines 23 (produced when necessary from the corresponding alkyl or aralkyl cyanide) are converted to the corresponding cyanoguanidines 24 (NaN (CN) 2, BuOH / H20) (Gerhard, R., Heinz, B. Herbert, FJ Praktische Chem. (Leipzig), 1964, 26, 414-418), which were combined with 21 as previously described, to provide the target molecules protected with mesityl. Deprotection as described above then provided the substituted 4-biguanides. An analogous route (not shown) that uses the N-Boc protective group was also employed, as in the above.

Synthetic methods, solid phase synthesis REACTION SCHEME 4 Synthetic solid-phase techniques can be used for the rapid and efficient synthesis of alkylpolyamines and their homologs. alpha-methyl, as shown in Reaction Scheme 4. Compound 22 can be produced using a commercially available trityl chloride resin, as described in Wang et al., J. Am. Chem. Soc, 95 (4) : 1328 (1973), wherein the attached mine is primary or secondary before the union, an alpha-methyl is present or absent, and the group X is a protected amine or a synthetic equivalent such as an azide or a phthalamide. This intermediate is then deprotected or converted to the corresponding primary amine 23. Three strategies can be used for chain elongation: 1. reductive amination with aldehydes 24 in the presence of sodium cyanoborohydride to produce 25; 2. addition of an appropriate carboxylate 26 under peptide coupling conditions (Woster et al., J. Med. Chem. 32: 1300 (1989)), followed by reduction of the diborane of the resulting amide, yielding 27; 3. Direct alkylation with a protected halide (Woster et al., J. Med. Chem. 32: 1300 (1989)), such as 28, to provide intermediates 29. The repetition of these steps then allows the synthesis of a a variety of alkylpolyamines and alpha-methyl-alkylpolyamines with the substituents as desired.

Biological applications, inhibitors of isine-1-specific demethylase (LSD1) Histones are proteins found in eukaryotic cells that act as support structures for DNA (sometimes compared to a protein harvest that supports the DNA strand). Histones, along with other proteins and DNA, form the chromatin of the cell nucleus. Due to its close association with DNA, histones play a role in the regulation of the gene. Queues of histone proteins are a frequent site for covalent modifications that affect gene expression. The enzyme demethylase specific to lysine-1 (LSD1, also known as BHC110 and KIAA0601) is an enzyme that affects the covalent modification of histone tails, demethylating lysine 4 from histone H3. Shi et al. (Cell, 119: 941 (2004)), showed that the inhibition of the LSD1 RNAi leads to an increase in the methylation of the H3 lysine 4, followed by the non-repression of the target genes. Thus, LSD1 apparently represses transcription by demethylation of histone H3. Conversely, the inhibition of LSD1 allows transcription preventing demethylation. Due to the homology observed between the active site of LSD1 and monoamine oxidase (MAO), Lee et al. (Chemistry &Biology 13: 563 (2006)), tested several MAO inhibitors for their ability to inhibit LSD1. They identified tranylcypromine ((1R, 2S) -2-phenylcyclopropan-1 -amine) as an inhibitor with an Cl50 less than 2 micromolar. The treatment of P19 embryonal carcinoma cells with tranylcypromine led to the non-transcriptional repression of the Egr1 and Oct4 genes. The International Patent Application WO 2006/071608, is directed to a method for verifying the activity of histone demethylase eukaryotic methods for upregulating and deregulating genes activated by methylated histone and a method for treating or preventing a disease (e.g., a hyperproliferative disease such as cancer) by modulating the level of protein or activity of a histone demethylase . In view of the importance of gene regulation, and the ability to affect gene regulation by inhibiting or modulating LSD1, inhibitors of the enzyme may have significant therapeutic potential. Table B shows the compounds tested for the inhibitory activity of LSD1. Although the compounds are described as free bases, it is understood that the description in the Table covers all the salts, hydrates and solvates of the compounds described herein, as well as the non-salt form, is not hydrate / is not solvate of the compound, as is well understood by the person with experience. Several of the polyamine, polyamine / guanidine and polyamine / biguanide compounds described herein have activity as inhibitors of LSD1. Figure 24, Figure 25, Figure 26, Figure 27, Figure 28, Figure 29 and Table C), Figure 30, Figure 31, Figure 32 and Figures 33A and 33B show the effects of some of the compounds described herein in the activity of LSD1. The compounds described herein, including the compounds of formulas (I) through (IX), the compounds of Table A, and the compounds of Table B, are useful as inhibitors of LSD1. More specifically, the polyamine / guanidine and polyamine / biguanide compounds are useful as inhibitors of LSD1, such as the compounds of formulas (I) and (II). The enzyme can inhibited by at least about 25%, at a compound concentration of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; by at least about 50%, at a compound concentration of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 75%, at a compound concentration of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 90%, at a compound concentration of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 95%, at a compound concentration of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; or at least about 99% at a compound concentration of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less.

TABLE B Compounds tested for the inhibitory activity of LSD1 Table C shows the values of Vmax (umol / mg protein / minute) and KM (uM).

TABLE C Biological applications, cancer treatment Several polyamine compounds and polyamine analogs have shown potent anticancer activity. It is believed that the polyamines and polyamine analogs enter the cells via the polyamine transport system and deregulate the biosynthetic enzymes of the polyamine omitin decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMet-DC). The antitumor activity of the bis (ethyl) polyamine analogues is thought to be due to their ability to superinduce spermidine / N-acetyltransferase (SSAT), the step that limits the speed in the retro-conversion path of the polyamine. The oxidation mediated by the subsequent polyamine oxidase (PAO) of the resulting acetylated polyamines, then produces hydrogen peroxide which finally initiates the program of cell death. Studies have revealed that analogs that inhibit the growth of tumor cells through the induction of SSAT, initiating apoptosis in the presence and absence of induction with SSAT, and by interfering with the depolymerization of tubulin. Recent data suggest that human polyamine oxidase exists in two forms different, and that the oxidation of polyamine analogues by mammalian spermidine oxidase (SMO (PAOhl), may play a role in the antitumor effects of some analogues.) This hypothesis is supported by the facts that the N-alkylpolyamine analogues -ethyl-11 - [(cycloheptyl) methyl] -4,8-diazaundecane (CHENSpm) are detoxified by the polyamine oxidase, and the antimicrosporidial analog BW-1 (N, N'-bís [3 - [([ 1, 1'-biphenyl] -2-methylmethyl] propyl] -1,7-heptanediamine) is a substrate for the polyamine oxidase of Encephalitoozoon cuniculi It is now evident that alkyl polyamines can affect the growth of tumor cells by "Treating" or "treating" a disease using the methods of the invention, is defined as administering one or more polyamines or polyamine analogs, with or without additional therapeutic agents, in order to palliate, lessen, stabilize, invest, decrease nuir, delay, prevent, reduce or eliminate the disease or symptoms of the disease, or to slow or stop the progression of the disease or the symptoms of the disease. "Therapeutic use" of polyamines and polyamine analogues is defined as using one or more polyamines or polyamine analogs to treat a disease (including to prevent a disease), as defined above. A "therapeutically effective amount" is an amount sufficient to treat (including prevent) a disease, as defined above. The prevention or suppression can be partial or total.

The compounds described herein have anticancer activity, which has been demonstrated in a variety of human tumor cell types that represent the major forms of cancers of the lung, breast, prostate and colon. Thus, the compounds described herein can be used to treat cancer, including lung cancer, breast cancer, prostate cancer and colon cancer, or to prevent cancer, including the prevention of lung cancer, breast cancer. , prostate cancer and colon cancer.

Results and experimental protocols MTS dose response experiments were performed on H157, H82 and A549 cells after a 96 hour exposure with selected compounds. MTS is a standard colorimetric assay used to measure the metabolic activity in cells. Experiments with MTS were performed using a Cell Proliferation Assay in a CelITiter 96® AQUTUos Solution from Promega Corporation. Briefly, the cells were seeded at 3000 cells / well in a 96-well tissue culture plate containing 100 ul of the medium / well and allowed to bind overnight. The medium was then aspirated and replaced with 100 ul of fresh medium containing the appropriate concentration of the compound being tested, and incubated for 96 hours at 37 ° C and 5% C02. The compounds were routinely tested at concentrations ranging from 0.1 micromolar to 50 micromolar. Wells that do not contain the test compound were present and were used as a control. After the treatment, 20 ul of the MTS reagent was added to each well and incubated at 37 ° C for 1.5 hours. The absorbance of each well was then measured at 490 nm and was used to determine the metabolic activity of the cells in the presence of the test compound, relative to the control. The CI5o values for the test compounds were extracted based on the results. The results for cells H157, H82 and A549 are shown in Tables 2, 3 and 4, respectively. Note that the results for a 72-hour exposure, in addition to the 96-hour exposure, are shown for compound 49-TDW-29C in H157 cells. The first column contains the identifier of the compound and the second column contains the values of CI5o (when a range is shown, for example, 1-10 uM, this indicates that the Cl50 falls somewhere between the two endpoints of the interval; end points are the concentrations actually tested, one of which is less than Cl50 and one of which is higher). Figure 1 describes the results of the 96-hour MTS dose response experiments for compound 46-TDW-23c in H157, A549, H82 and Beas2B cells. Figure 2 describes the results of the 96-hour MTS dose response experiments for compound 49-TDW-9 in H157, A549, H82 and Beas2B cells. Figure 3 describes the results of the 96-hour MTS dose response experiments for compound 42-TDW-21 c in H157, A549, H82 and Beas2B cells. Figure 4 describes the results of the dose response experiments of MTS 96 hours for compound 46-TDW-19c in H157, A549, H82 and Beas2B cells. Figure 5 describes the results of the 96-hour MTS dose response experiments for compound 49-TDW-17c in H157, A549, H82 and Beas2B cells. Figure 6 describes the results of the 96-hour MTS dose response experiments for compound 40-TDW-37 in H157, A549, H82 and Beas2B cells. Figure 7 describes the results of the 96-hour MTS dose response experiments for compound 42-TDW-4 in H157, A549, H82 and Beas2B cells. Figure 8 describes the results of the 96-hour MTS dose response experiments for compound 49-TDW-29c in H157, A549, H82 and Beas2B cells. Figure 9 describes the results of the 96-hour MTS dose response experiments for compound 49-TDW-32c in H157, A549, H82 and Beas2B cells. Figure 10 depicts the results of the 96-hour MTS dose response experiments for compound 46-TDW-35c in H157, A549, H82 and Beas2B cells. Figure 11 describes the results of the 96-hour MTS dose response experiments for compound 39-TDW-3 in H157, A549 and H82 cells. Figure 12 depicts the results of the 96-hour MTS dose response experiments for compound 39-TDW-12c in H157 and A549 cells. Figure 13 describes the results of the 96-hour MTS dose response experiments for compound 39-TDW-20c in H157 and H82 cells. Figure 14 describes the results of the 96-hour MTS dose response experiments for compounds 39-TDw-47c and 39-TDW-43 in H157 cells. Figure 15 describes the results of the 96-hour MTS dose response experiments for compounds 42-TDW-9, 42-TDW-4c / 6, 40-TDW-35, 42-TDW-38 and BENSpm in H157 cells. Figure 16 describes the results of the 96-hour MTS dose response experiments for compounds 46-TDW-34c, 42-TDW-12, 40-TDW-48, 46-TDW-44c and BENSpm in H157 cells . Figure 17 describes the results of the 96-hour MTS dose response experiments for compounds 42-TDW-20c, 46-TDW-22, 46-TDW-39, 49-TDW-29c and BENSpm in H157 cells . Figure 18 describes the results of the 96-hour MTS dose response experiments for compounds 39-TDW-43, 42-TDW-48c, 46-TDW-9, 46-TDW-23C and BENSpm in H157 cells. Figure 19 describes the results of the 96-hour MTS dose response experiments for compounds 42-TDW-35c, 46-TDW-44 and BENSpm in H157 cells. MTT dose response experiments were performed in 235, MCF7, 435 and 10A cells. MTT is a standard colorimetric assay used to measure the metabolic activity in cells. Briefly, approximately 200 ul of medium containing no cells was added to column A of a 96-well plate and used as a blank. Next, 200 ul of the medium containing the cells were added to the remaining wells and incubated overnight. The remaining cells contain approximately 4000-5000 MCF7 cells / well, 3000 cells 231 / well, 12,000 cells 468 / well or 9000 cells MCF 10A / well. After of the incubation, the medium in the wells was aspirated and replaced with 200 ul of fresh medium in columns A and B of the 96-well plate. Column B was used as a control. Next, 200 ul of the fresh medium containing the compound being tested were added to the remaining wells and incubated for 96 hours. The compounds were routinely tested at concentrations ranging from 0.1 micromolar to 50 micromolar. After incubation for 96 hours, the medium in each well was aspirated and replaced with 100 ul of a solution of 5 mg / ml of MTT (3- (4,5-dimethylthiazol-2-yl) -2-bromide, 5-diphenyltetrazolium) in serum-free medium, and incubated for 4 hours. After incubation with the MTT solution, the MTT solution was removed from the wells and replaced with 200 ul of a 1: 1 solution of EtOH + DMSO and incubated for 20 minutes. After incubation with the EtOH + DMSO solution, the plates were read at 540 nm and used to determine the metabolic activity of the cells in the presence of the test compound, relative to the control. The IC 50 values for the test compounds were extracted based on the results. The results of an MTT assay after 96 hours of treatment with compound 39-TDW-47c at different concentrations in cells 231, MCF7, 435 and 10A, are shown in Figure 20. A chronological course experiment in 231 cells after of 8, 12 and 24 hours of exposure of the compound 39-TDW-47c at different concentrations is shown in Figure 21. An experiment of the chronological course in 435 cells after 4, 8, 12 and 24 hours of exposure of the compound 39-TDW-47c at different concentrations is shown in Figure 22. An experiment of the chronological course in MCF7 cells after 4, 8, 12 and 24 hours of exposure of the compound 39-TDW-47c at different concentrations is shown in Figure 23. Experiments of SSAT activity (spermidine / spermine-N1-acetyltransferase) were performed on H157, H82 and A549 cells after exposure to select compounds. A detailed protocol for determining SSAT activity is described in Casero et al., Cancer Research, 49: 3829 (1989). Briefly, the SSAT activity was measured by collecting the treated cells at the time of exposure. The cells were then used and treated with spermidine, and 1- [14C] acetyl coenzyme A for 5 minutes. The activity of the enzyme was measured in terms of picomoles of [14 C] acetylspermidine formed per mg of cellular protein per minute (pmol / mg P / minute). The results are shown in Tables 5 (H157), 9 (H82), and 12 (A549), respectively. In Tables 5 and 12, the compound identifier, treatment concentration, control activity, SSAT activity after exposure and exposure time are listed in columns 1, 2, 3, 4 and 5, respectively. The activity in Tables 5 and 12 is reported as picomoles of SSAT per mg of protein per minute. Table 9 lists the compound identifier, exposure concentration, activity and exposure time in columns 1, 2, 3 and 4, respectively. No induction of SSAT was observed for H82 cells and therefore, the values of control and activity after exposure are not listed. The putrescine, spermidine and spermine levels of the polyamine were made in H157 and H82 cells after exposure to select the compounds. Polyamine levels were determined using the reverse phase high pressure liquid chromatography method, with dansylation label in the precolumn, described by Kabra et al., J. Chromotography, 380: 19 (1986). The results are shown in Tables 6 and 11 for cells H157 and H82, respectively. The identifier of the compound, the concentration of the treatment, the level of polyamine observed and the exposure time are listed in columns 1, 2, 3 and 4, respectively. Polyamine levels are reported as increased (nc), decreased (dec), or unchanged (N / C). In some cases, the specific levels of putrescine, spermidine and / or spermine are listed. The activity of SMO (Espermine Oxidase) in H157 cells after treatment with compound 46-TDW-34C, is shown in Table 7. A detailed protocol for measuring SMO activity is described in Wang et al., Cancer Research, 61: 5370 (2001). The compound dentifier, the concentration of the treatment, the activity of the control, the activity after the treatment and the exposure time are listed in columns 1, 2, 3, 4 and 5, respectively. The results of the activity report in picomoles of converted spermine per mg of cellular protein per minute (pmol / mg P / minute). Experiments of ODC activity (Ornithine decarboxylase) were performed on H157. A detailed protocol for measuring ODC activity is described in Pegg et al., Methods Enzymology, 94: 158 (1983). The results are shown in Table 10. The compound identifier, treatment concentration, control activity, activity after treatment and exposure time are listed in columns 1, 2, 3, 4 and 5, respectively . The results of the activity are reported in picomoles of C02 released per mg of cellular protein per hour (pmol / mg P / hour). Measurements of the cell cycle induced by the treatment were made in H157 cells. After exposure of the cells to the compound of interest, at a concentration of 10 uM for 24 hours, the cells were harvested, prepared and transferred to a FACS for cell cycle analysis. (See, Carlisle et al., Clinical Cancer Research 8: 2684 (2002) and references therein). The results are shown in Table 8. The results describe the percentage of cells that are in the G1 phase, the S phase and the G2 / M phases.

TABLE 2 96-hour MTS dose response experiment in H157 cells (non-small cell lung carcinoma) TABLE 3 96-hour MTS dose response experiments in H82 cells (small lung cell carcinoma) TABLE 4 Experiments on dose response of MTS in 96 hours in A549 cells TABLE 5 Activity of SSAT (spermidine / spermine-N1-acetyltransferase) in H157 cells (non-small cell lung carcinoma) TABLE 6 Polyamine levels in H157 cells (non-small cell lung carcinoma) after treatment TABLE 7 Activity of SMO (Spermine Oxidase) in H157 cells (non-small cell lung carcinoma) TABLE 8 Measurements of the cell cycle induced by the drug in H157 cells (non-small cell lung carcinoma) TABLE 9 SSAT activity in H82 cells (small cell lung carcinoma) TABLE 10 TABLE 11 Polyamine levels in H82 cells after treatment TABLE 12 SSAT activity in A549 cells Descriptions of all publications, patents, patent applications and published patent applications, referred to herein by an identification appointment, are hereby incorporated by reference in their entirety. Although the above invention has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be considered as limiting the scope of the invention.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has a formula selected from the group consisting of:

?,

W,

(III),

-Ríí N Río H H H (IV),

(YOU,

(VII),

(VTII) and

(IX) where: n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; q is 0 or 1; Each Ri is selected independently of the group consisting of unsubstituted or substituted CrC8 alkyl, substituted or unsubstituted C6-C2o aryl or heteroaryl and substituted or unsubstituted aralkyl or C7-C24 heteroaralkyl; each R2 is independently selected from hydrogen or a substituted or unsubstituted CrC8 alkyl; R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted CrC8 alkyl, substituted or unsubstituted C6-C2o aryl and substituted or unsubstituted C7-C24 aralkyl; R5; R9, R6, R7 and R8 are independently selected from the group consisting of hydrogen and unsubstituted or substituted CrC8 alkyl; A, R 10 and R n are independently (CH 2)? - 5 or eten-1, 1 -diyl; R12 and R13 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C2-C8 alkenyl, and substituted or unsubstituted C8 alkyl; R15 and R14 are independently selected from the group consisting of hydrogen, substituted or unsubstituted d-C8 alkyl or branched (C3-C8) alkyl, substituted or unsubstituted C6-C20 aryl or heteroaryl and aralkyl or C7-C24 heteroaralkyl substituted or unsubstituted; R 6 and R 17 are independently hydrogen or a substituted or unsubstituted C 1 -C 8 alkyl; R-? 8 and R19 are independently selected from the group consisting of: hydrogen, unsubstituted CrC8 alkyl, n-CrC8 alkyl substituted with a cycloalkyl group comprising at least two rings, aralkyl or substituted C7-C24 heteroaralkyl or unsubstituted, comprising at least two rings; R2o and R21 are independently selected from the group consisting of hydrogen, substituted or unsubstituted CrC8 alkyl, and

C7-C24 aralkyl substituted or unsubstituted; X of formula (VIII) is - (CH2)? - 5- or cyclohex-1,3-diyl; R22 and R23 are independently selected from the group consisting of hydrogen, n-butyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, cycloheptylmethyl, cyclohexylethyl-2-yl and benzyl; R 4 in a cycloalkyl substituted with amino or a substituted or unsubstituted C-C8 alkanoyl; R 25 is a substituted or unsubstituted C 8 alkyl or a C 7 -C 24 substituted or unsubstituted aralkyl. 2. The compound according to claim 1, further characterized in that the compound is of the formula (I): 0) or a salt, solvate or hydrate thereof, wherein: n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; q is 0 or 1; each R1 is independently selected from the group consisting of unsubstituted or substituted C8 O alkyl, substituted or unsubstituted C4-C15 cycloalkyl, substituted or unsubstituted C3-C15 branched alkyl, substituted or unsubstituted C6-C2 aryl substituted, substituted or unsubstituted C6-C2o heteroaryl, substituted or unsubstituted C7-C24 aralkyl and heteroaralkyl

C7-C24 substituted or unsubstituted and each R2 is independently selected from hydrogen or a substituted or unsubstituted C8 alkyl. 3. The compound according to claim 1, further characterized in that the compound is of the formula (II): 05) or a salt, solvate or hydrate thereof, wherein: n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; q is 0 or 1; each Ri is independently selected from the group consisting of substituted or unsubstituted CrC8 alkyl, C6-C or substituted or unsubstituted aryl and substituted or unsubstituted C7-C24 aralkyl; and each R2 is independently hydrogen or a substituted or unsubstituted CrC8 alkyl. 4. The compound according to claim 1, further characterized in that the compound is of the formula (III):

(III) or a salt, solvate or hydrate thereof, wherein: n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; R3 and R4 are independently selected from the group consisting of hydrogen, substituted or unsubstituted CrC8 alkyl, substituted or unsubstituted C6-C20 aryl and substituted or unsubstituted C7-C24 aralkyl; R5, R9, R6, R7 and R8 are independently selected from the group consisting of hydrogen and unsubstituted or substituted CrC8 alkyl; and wherein: m and p are not the same integer, or at least one of R5, Rg, Re, R7 and Rs is a substituted or unsubstituted C? -C8 alkyl. 5. The compound according to claim 1, further characterized in that the compound is of the formula (IV):

(IV) or a salt, solvate or hydrate thereof, wherein: A, R- and Rn are independently (CH2) n, or eten-1, 1 -diiio; n is an integer from 1 to 5; R12 and R13 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C-C8 alkenyl and unsubstituted or substituted C8 alkyl of C8 and at least one of Ai R10, Rn, R12 and R13 comprises an alkenyl portion . 6. The compound according to claim 1, further characterized in that the compound is of the formula (V): or a salt, solvate or hydrate thereof, wherein: n is an integer from 1 to 8; m is an integer from 1 to 8; R15 and R14 are independently selected from the group consisting of hydrogen, unsubstituted or substituted C-C8-alkyl, substituted or unsubstituted branched C3-C8 alkyl, substituted or unsubstituted C6-C20 aryl or heteroaryl and aralkyl or substituted or unsubstituted C7-C24 heteroaralkyl; R6 and R17 are independently hydrogen or a substituted or unsubstituted CrC8 alkyl and wherein: the compound contains no more than three secondary amino groups, except when R17 is a substituted or unsubstituted Ci-Cs alkyl and the The compound is free of a portion of methylphosphonate or hydroxy. 7. The compound according to claim 1, further characterized in that the compound is of the formula (VI):

(SAW) or a salt, solvate or hydrate thereof, wherein: n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; R? 8 and R19 are selected independently from the group consisting of: hydrogen, unsubstituted CrC8 alkyl, n-CrC8 alkyl substituted with a cycloalkyl group comprising at least two substituted or unsubstituted C7-C24 aralkyl or aralkyl rings, which comprises minus two rings and wherein: n is 1 when R? 8 and Rig are identical C? -C8 n-alkyl portions, substituted with a cycloalkyl group comprising at least two rings, or are identical aryl portions comprising at least two rings and at least one of R 8 and R 19 is an N-alkyl of CrC 8 substituted with a cycloalkyl group comprising at least two rings or a substituted or unsubstituted C 7 -C 24 aralkyl comprising at least two rings. 8. The compound according to claim 1, further characterized in that the compound is of the formula (VII): (vile) or a salt, solvate or hydrate thereof, wherein: n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; q is O or 1; R20 and R21 are independently selected from the group consisting of hydrogen, substituted or unsubstituted CrC8 alkyl, -C (= 0) -substituted or unsubstituted C8 alkyl, -C (= 0) -alkenyl of C- -C8 substituted or unsubstituted, -C (= 0) -substituted or unsubstituted CrC8 alkynyl and substituted C7-C24 aralkyl or not replaced; and wherein the compound comprises at least a portion selected from the group consisting of t-butyl, isopropyl, 2-ethylbutyl, 1-methylpropyl, 1-methylbutyl, 3-butenyl, isopent-2-enyl, 2-methylpropan-3-. olyl, ethylthiyl, phenylthiyl, propynyl, 1-methyl-1H-pyrrol-2-yl, trifluoromethyl, cyclopropanecarbaldehyde (cyclopropylcarbonyl), phenyl substituted with halo, phenyl substituted with nitro, phenyl substituted with alkyl, 2,4,6-trimethylbenzyl , phenyl substituted with halo-S, para- (F3S) -phenyl, azido and 2-methylbutyl. 9. The compound according to claim 1, further characterized in that the compound is of the formula (VIII): or a salt, solvate or hydrate thereof, wherein: m and p are independently an integer from 1 to 5; X is - (CH2) n- or cyclohex-1,3-dyl; n is an integer from 1 to 5; R22 and R23 are independently selected from the group consisting of hydrogen, n-butyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, cycloheptylmethyl, cyclohexyl-2-yl, benzyl and wherein: when n is 5, at least one of R22 and R23 is hydrogen; when R22 TS ethyl, R23 is selected from the group consisting of hydrogen, n-butyl, ethyl, cyclopentylmethyl, cyclohexylethyl-2-yl and benzyl; when R23 is ethyl, R22 is selected from the group consisting of hydrogen, n-butyl, ethyl, cyclopentylmethyl, cyclohexyl-2-yl and benzyl and wherein X is cyclohex-1,3-diyl, R22 and R23 are not identical benzyl or cyclopropylmethyl portions. 10. The compound according to claim 1, further characterized in that the compound is of the formula (IX):

(IX) or a salt, solvate or hydrate thereof, wherein: p is an integer from 1 to 5; R24 is a C3-C5 cycloalkyl substituted with amino or a substituted or unsubstituted C2-C8 alkanoyl and R25 is a substituted or unsubstituted CrC8 alkyl or a substituted or unsubstituted C7-C24 aralkyl. 11. The compound according to claim 1, further characterized in that the compound is a compound listed in Table A. 12. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 13. A device comprising a compound as claimed in claim 1 and instructions for using it as an anticancer or antiparasitic agent. 14. A method for inhibiting a histone demethylase, comprising administering an amount of a polyamine compound, polyaminoguanidine or polyaminobiguanide, sufficient to inhibit histone demethylase by at least about 50%. 15. The method according to claim 14, further characterized in that it comprises administering an amount of a polyaminoguanidine or polyaminobiguanide compound, sufficient to inhibit histone demethylase by at least about 50%.

16. The use of a compound as claimed in claim 1, in the development of a drug useful for treating cancer.

17. The use of a compound as claimed in claim 1, in the preparation of a drug useful for treating unregulated cell growth.

18. The use of a compound as claimed in claim 1, in the preparation of a drug useful for treating a parasitic infection.

19. A method for inhibiting a histone demethylase enzyme, comprising contacting the enzyme with one or more compounds as claimed in claim 1, in an amount sufficient to inhibit the enzyme.

20. The method according to claim 19, further characterized in that the compound contains at least a portion of guanidine or at least a portion of biguanide.

21. - The method according to claim 19, further characterized in that the enzyme is demethylase specific for lysine-1.