WO2014053691A1 - Bis-pyridinium cyclophane derivatives as anti-protozoa drugs - Google Patents

Description

 CYCLOPHANIC DERIVATIVES OF BIS-PYRIDINIUM AS ANTI-PROTOZOAR DRUGS

Technical sector

 The present invention relates to leishmanicidal compounds and which find application in the treatment of other protozoan diseases by trypanosomatids both in humans and animals, as well as with a method for the preparation of the compounds of the invention, and certain intermediates of said method.

 State of the art

 Leishmaniasis is a complex disease caused by parasitic protozoa of the genus Leishmania. The parasites are transmitted through female flies via anthroponotic or zoonotic cycles. Leishmania parasites have a dimorphic life cycle: the promastigote form develops in the intestine of female flies and represents infectious forms that are transmitted to the mammalian host. Inside mammalian cells, the promastigote forms survive and multiply as amastigote forms inside the parasitophous vacuoles of macrophages. The most relevant clinical manifestations include visceral leishmaniasis (LV) and cutaneous leishmaniasis (LC); There are other clinical manifestations such as mucocutaneous leishmaniasis and post-kala-azar dermal leishmaniasis. 350 million people in the world are at risk of infection or contracting the disease. The annual incidence is estimated between 1, 5 and 2 million people with 59,000 annual deaths. Leishmaniasis is included in the group of forgotten tropical diseases and is related to poverty.

 The treatment of leishmaniasis is complicated and the disease has a high morbidity, so expedited therapies are often required, since otherwise, there may be complications. Among the drugs of first choice may be mentioned pentavalent antimonials (meglumine antimonate and sodium stibogluconate) that have been used for the treatment of LV and LC for more than 60 years. Other treatments include the amphotericin B pollenic antibiotic (particularly the liposome formulation), alkyl phosphocholine, miltefosine, initially developed as an anti-cancer drug, and paromomycin, an aminoglycoside antibiotic that has antibacterial and antiprotozoal activity. There are other drugs used in the second line, mainly in cases of leishmaniasis that do not respond to treatment with antimonials such as pentamidine and azoles (ketoconazole).

 Pentamidine is an aromatic diamidine, still in use as a drug of first choice for certain forms of LC. It is also used only as a second-line treatment in LV due to its toxicity and its effectiveness. The biggest safety problem related to pentamidine is the induction of diabetes mellitus that depends on insulin and its use in India for the treatment of LV has been abandoned.)

More recent works involve mitochondria in the mode of action of pentamidine. Electron microscopy studies in Leishmania have shown that pentamidine induces morphological changes with inflammation of the mitochondria and fragmentation of the kinetoplastid DNA {Langreth, SG; Berman, JD; Riordan, GP; Lee, LSJ Protozool. 1983, 30, 555-561). Likewise, it has been observed that the Pentamidine induces in promastigote forms of L. donovani an in situ decoupling in the mitochondria with collapse of the mitochondrial membrane potential; An alkalinization of acidocalcisomas in promastigote forms of L donovani treated with pentamidine has also been described {Vercesi, AE; Rodrigues, CO; Catisti, R .; Docampo, R. FEBS Lett. 2000, 473, 203-206). In a recent study, mitochondria have been suggested as the place of accumulation of pentamidine in promastigotes of L. donovani and resistance to this drug is associated with mitochondrial abnormalities {Mukherjee, A .; Padmanabhan, PK; Sahani, MH; Barrett, MP; Madhubala, R. Mol. Biochem Parasite!. 2006, 145, 1-10). Pentamidine enters the promastigotes and intracellular amastigotes of Leishmania through a transporter that recognizes diamidines with high affinity {Basselin, M .; Denise, H .; Coombs, GH; Barrett, MP Antimicrob. Chemother Agents 2002, 46, 3731-3738). The mechanism of leishmanicidal action of pentamidine is not well defined but probably acts via inhibition of polyamine biosynthesis, through interference in DNA synthesis and modification in mitochondrial membrane potential.

 There is therefore a need to develop compounds that have good leishmanicidal activity and at the same time have low levels of toxicity.

Description of the Invention

 The authors of the present invention have found that certain modifications in structures related to pentamidine have a significant decrease in the levels of toxicity of said compounds, as well as notable values of leishmanicidal activity, both in promastigote forms and in intracellular amastigote forms of the parasite Leishmania

 Accordingly, the invention provides in its first aspect a family of compounds having general formula I,

Formula I

or any of its conjugate bases, where L is a group of formula II,

Formula II such that the compound of formula I is a compound of formula la or formula lb,

Formula l-a Formula l-b and where:

 Q is the conjugate base of an organic or inorganic acid, and has between 1 and 3 negative charges;

 - q is the number of negative charges of Q;

R ¹ and R ² are independently selected from at least one substituent of the group consisting of: hydrogen, a halogen, an alkyl group containing from a carbon atom up to 10 (C ₁ -C ₁₀ alkyl), a haloalkyl group containing 1 to 10 carbon atoms (CrC ₁₀ haloalkyl), an amino group, an alkylamino group which may have between 1 and 10 carbon atoms, a hydroxyl group and an alkoxy group;

- X ¹ and X ² are independently selected from at least one of the group consisting of: NH, NR ³ , O, S and CH ₂ , and where R ³ is independently selected from at least one of the following list: an alkyl group , an aryl group, an alkylaryl group and an arylalkyl group, said groups containing from 1 to 10 carbon atoms;

- A and B, which may be the same or different, are independently selected from spacer groups with a chain length between 2 and 15 carbon atoms (C ₂ -C ₁₅ spacer), preferably between at least one of the following: a alkanediyl chain spacer, an alkenodiyl chain spacer, an alkynediyl chain spacer and an aromatic spacer, such as the groups shown later in the present description, such that when the compound of formula I consists of the compound of formula where R ¹ and R ² are H, and X ¹ and X ² are NH, if the spacer A consists of an aromatic spacer group of formula III or an aromatic spacer group of formula IV,

 Formula III Formula IV

 then the spacer B is different from said groups of formula III and formula IV.

To maintain charge neutrality in the compound of formula I, the cyclic bispyridinium compound and the conjugate base Q defined above are in stoichiometric ratio 1: 2 / q, where q is the number of negative charges that presents Q. This means that, for example, the counterion [(2 / q) Q] consists of: [2Q] when Q is the conjugate base of a monobasic acid (for example [2Br] ^2® when Q is the bromide anion Br ^® , that is, the conjugate base of HBr); [Q] ^2® when Q is the conjugate base of a dibasic acid or a dicarboxylic acid (such as sulfate [S0 ₄ ] ^2® or oxalate ^® OOC-COO ^® ); [(2/3) Q] ^2® when Q is the conjugate base of a tribasic acid (for example [(2/3) P0 ₄ ] ^2® when Q is the phosphate anion P0 ₄ ^3® , that is, the base acid conjugate H ₃ P0 ₄ ). According to the invention, those pharmaceutically acceptable organic or inorganic acid conjugate bases are preferred. Examples thereof are described later in the present description. More preferably, said conjugate base refers to an anion derived from the dissociation of an inorganic acid, and even more preferably to the bromide anion.

In the scope of the present invention, "alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms, or a branched saturated monovalent hydrocarbon radical of three to ten carbon atoms, for example and not limited to , methyl, ethyl, n-propyl, 2-propyl, ferc-butyl, pentyl, and the like. Throughout the present description, the term "alkyl" may also be referred to as "CrC ₁₀ alkyl".

In the scope of the present invention, "haloalkyl" means alkyl substituted with one or more, same or different, haloatoms, e.g. ex. and not limited to, -CH ₂ CI, -CF ₃ , -CH ₂ CF ₃ and -CH ₂ CCI ₃ and the like, and also includes those alkyl groups such as perfluoroalkyl, in which all hydrogen atoms are replaced by atoms of fluoride Throughout the present description the term "haloalkyl" may also be referred to as "C ₁ -C ₁₀ haloalkyl".

Within the scope of the present invention, "alkylamino" group refers to a radical - NHR ⁵ wherein R ⁵ is a radical containing between 1 and 10 carbon atoms that is selected from the group consisting of: alkyl; substituted or unsubstituted heteroalkyl; haloalkyl; cycloalkyl, substituted or unsubstituted, having from 3 to 10 atoms; cycloalkylalkyl in which the rest of cycloalkyl has between 3 and 6 carbon atoms; aryl, substituted or unsubstituted, such as benzene, naphthalene or anthracene; aralkyl; aralkenyl, such as p. ex. vinylphenyl, 2-propenylphenyl, vinylnaphthyl or (2-propenyl) anthranyl; heteroaryl as p. ex. furan, thiophene, pyrrole or pyridino; heteroaralkyl such as thienylalkyl, tenylalkyl, furyl alkyl, furfurylalkyl, pyrrolyl alkyl, pyrrolylmethylalkyl or pyridinalkyl; heteroaralkenyl such as thienylvinyl, tenylvinyl, furylvinyl, furfurylvinyl, pyrrolylvinyl, pyrrolylmethylvinyl, thienyl- (2-propenyl), tenyl- (2- propenyl), furyl (2-propenyl), furfuryl- (2-propenyl), pyrrolyl- (2 -propenyl), pyrrolylmethyl- (2- propenyl), pyridinvinyl or pyridin- (2-propenyl); heterocyclyl consisting of a cycle of 3 to 6 units, one or two of them being heteroatoms of type O and / or N; and heterocyclylalkyl consisting of a cycle of 3 to 7 units with an alkyl substituent (between 1 and 6 carbon atoms), one or two of them being heteroatoms of type O and / or N, as defined herein, e.g. eg, methylamino, ethylamino, phenylamino, benzylamino or the like. Throughout the present description the term "alkylamino" may also be referred to as "CrC ₁₀ alkylamino".

Within the scope of the present invention, the term "alkoxy group" refers to a radical -OR ⁶ wherein R ⁶ is a radical containing between 1 and 10 carbon atoms that is selected from the group consisting of: alkyl, aryl , aralkyl and heteroaralkyl, as defined herein, e.g. eg, methoxy, phenoxy, pyridin-2-ylmethyloxy, benzyloxy, or the like. Throughout the present description the term "alkoxy group" may also be referred to as "CrC ₁₀ alkoxy group". Within the scope of the present invention, the term "arylalkyl" or "aralkyl" refers to a radical -R ⁷ R ⁸ containing from 1 to 10 carbon atoms (it may also be referred to herein as "C ₁ arylalkyl" -C ₁₀ "or" aralkyl d-C ₁₀ "), wherein R ⁷ is an alkyl group and R ⁸ is an aryl group, as defined in this description. In other words, aralkyl refers to a radical comprising between 1 and 10 carbon atoms consisting of an alkyl radical R ⁷ substituted by an aryl group R ⁸ . Without limitation, examples of aralkyl radicals are among others benzyl, phenylethyl (or phenethyl), phenylpropyl, 3-phenyl-2-propanyl or the like.

Within the scope of the present invention, the term "alkylaryl" means a radical -R ⁹ R ¹⁰ containing from 1 to 10 carbon atoms (it may also be referred to herein as "CrC ₁₀ alkylaryl"), wherein R ⁹ is an aryl group and R ¹⁰ is an alkyl group, as defined herein. Without limitation, examples of alkylaryl radicals are among others methylphenyl radicals (eg 2- methylphenyl, 3-methylphenyl or 4-methylphenyl), ethylphenyl (eg 2-ethylphenyl, 3-ethylphenyl or 4- ethylphenyl) or the like. Consequently, the difference between the aralkyl and alkylaryl groups refers to the location of the radical character; for example in the case of an aralalkyl group the radical is located in the alkyl chain attached to the aromatic moiety, such as a benzyl or phenylethyl radical, while in the case of a alkylaryl group, the radical character is located in the rest aryl, such as methylphenyl or ethylphenyl radicals.

 Within the scope of the present invention, the term "heteroalkyl" refers to substituted or unsubstituted heteroalkyl and substituted or unsubstituted aryl such as thienylmethyl, tenylmethyl, furylmethyl, furylmethyl, pyrrolylmethyl, pyrrolylmethylmethyl, pyridinmethyl or the like.

 Within the scope of the present invention, the term "cycloalkyl" refers to a cycloalkane radical containing between 3 and 6 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.

 Within the scope of the present invention, the term "cycloalkylalkyl" refers to alkyl groups substituted with cycloalkyl groups, or cycloalkyl groups substituted with alkyl groups, such that the cycloalkyl moiety has between 3 and 6 carbon atoms and the rest alkyl may contain between 1 and 5 carbon atoms, such as, for example, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, ethylcyclopropyl, ethylcyclobutyl, propylcyclopentyl, propylcyclopropyl, propylcyclobutyl, propylcyclopentyl or the like.

 Within the scope of the present invention, the term "aryl" refers to substituents such as phenyl, naphthyl, anthranyl or the like.

 Within the scope of the present invention, the term "aralkenyl" refers to groups such as, for example, vinylphenyl, 2-propenylphenyl, vinylnaphthyl, (2- propenyl) anthranyl or the like.

 Within the scope of the present invention, the term "heteroaryl" refers to a radical of a heterocycle such as furan, thiophene, pyrrole, pyridine or the like radicals.

In the scope of the present invention, the term "heteroaralkyl" refers to, but is not limited to thienylalkyl, tenilalquilo, furylalkyl, furfurilalquilo, pirrolilalquilo, pirrolilmetilalquilo, piridinalquilo or heteroaralkenyl such tienilvinilo, tenilvinilo, furilvinilo, furfurilvinilo, pirrolilvinilo, pyrrolylmethylvinyl, thienyl- (2-propenyl), tenyl- (2-propenyl), furyl- (2-propenyl), furfuryl- (2-propenyl), pyrrolyl- (2-propenyl), pyrrolylmethyl- (2-propenyl), pyridinvinyl or pyridin- (2-propenyl).

 Within the scope of the present invention, the term "heteroaralkenyl" refers to, but is not limited to thienylvinyl, tenylvinyl, furylvinyl, furfurylvinyl, pyrrolylvinyl, pyrrolylmethylvinyl and thienyl- (2-propenyl), tenyl- (2-propenyl), furyl (2-propenyl), furyl- (2- propenyl), pyrrolyl- (2-propenyl), pyrrolylmethyl- (2-propenyl), pyridinvinyl, pyridin- (2-propenyl) or the like.

 Within the scope of the present invention, the term "heterocyclyl" refers to a radical of a heterocycle of 3 to 6 units, one or two of them being heteroatoms of type O and / or N, as for example, but not limited to radicals of oxirane, tiirane, aziridine, oxetane, tiethane, azetidine, tetrahydrofuran, tetrahydrotiofuran or pyrrolidine.

Within the scope of the present invention, the term "eterocyclylalkyl" refers to a heterocycle radical of 3 to 6 units with an alkyl substituent (between 1 and 6 carbon atoms), one or two of them being heteroatoms of type O and / or N, as for example, but which is not limited to methyloxyran, methylthirano, methyllaziridine, methylxetane, methyltiethane, methyllazetidine, methyltetrahydrofuran, methyltetrahydrotiofuran or methylpyrrolidine.

Therefore, this aspect of the invention refers to any compound of formula I or any of its conjugate bases as defined above, except when it consists of a compound of formula where R ¹ and R ² are H and X is NH, in whose case A and B cannot simultaneously be a group of formula III or a group of formula IV, nor can A be a group of formula III and B a group of formula IV, nor can A be a group of formula IV and B a group of formula III. That is, the four possible combinations of A and B with the groups of formula III and formula IV.

The term "chain length", which will be used throughout this invention and the claims, means the smallest number of atoms between one end and the other of the spacer group. This spacer group may contain rings, such as cycloalkyl and aromatic, including substituted or unsubstituted heterocycles, such as a monovalent monocyclic or bicyclic aromatic hydrocarbon, of 6 to 10 ring atoms, which is independently substituted with one another, with one or more substituents, preferably one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyano, methylenedioxy, ethylenedioxy, cycloalkyl, optionally substituted phenyl, heteroaryl, haloalkoxy, optionally substituted phenoxy, heteroaryloxy, -COR ¹¹ (in where R ¹¹ is optionally substituted alkyl or phenyl), - (CR ¹² R ¹³ ) _nr COOR ¹⁴ (where n1 is an integer from 0 to 5, R ¹² and R ¹³ are independently hydrogen or alkyl, and R ¹⁴ is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl) or - (CR ¹⁵ R ¹⁶ ) _n2 -CONR ¹⁷ R ¹⁸ (where n2 is an integer from 0 to 5, R ¹⁵ and R ¹⁶ are independent Among them, hydrogen or alkyl, and R ¹⁷ and R ¹⁸ are independently hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached, form a heterocyclic ring). More specifically, the term "aryl" includes, but is not limited to phenyl, 1-naphthyl, and 2-naphthyl and derivatives thereof. The spacer group may contain one or more atoms of O or S as part of the chains. Possible types of bonds with these atoms can be, for example, ether bonds (-0-), sulfur bonds (-S-) and (-SS-). To avoid instability, these unions should not be located contiguously to group X, if this is NH, O or S. The chain length of the spacer groups preferably ranges from 2 to 10, the preferred length being between 4 and 7. In preferred embodiments, the spacer chain length is between 5 and 6 carbon atoms.

The substituents of the groups of the invention, such as the alkyl, alkylamino, alkoxy, aryl, arylalkyl and alkylaryl groups mentioned above may optionally be substituted by other substituents, such as those defined above, which do not eliminate the desired effect. of the compound.

 Suitable spacer groups A and B according to the present invention are among others:

- a C ₃ -C ₁₀ alkanediyl chain, wherein said C ₃ -C ₁₀ alkane chain means a linear hydrocarbon chain of three to ten carbon atoms or a branched hydrocarbon chain of three to ten carbon atoms that can having at least one heteroatom such as O and / or S, preferably a chain - (CH ₂ ) pZ- (CH ₂ ) p-, where Z is selected from CH ₂ , an oxygen atom or an S atom; and p is a value between 1 and 5, such as the spacers - (CH ₂ ) ₂ -0- (CH ₂ ) ₂ - and - (CH ₂ ) ₅ , where p is 2 and Z is an oxygen atom or a CH ₂ group, respectively;

- a C ₃ -Ci ₀ alkenodiyl chain with one or two double C = C bonds, wherein said C ₃ -C ₁₀ alkene chain means a linear hydrocarbon chain of three to ten carbon atoms or a branched hydrocarbon chain from three to ten carbon atoms, which contain at least one double bond, e.g. ex. 1-propene-1, 3-diyl, 1-butene-1, 4-diyl, 2-butene-1, 4-diyl, 1,3-butadiene-1, 4-diyl, and the like;

- alkynediyl-chained C ₂ - CIO with one or two triple bonds C≡C wherein said chain alkyne type C ₂ - CIO means a straight hydrocarbon chain of two to ten carbon atoms or a hydrocarbon chain branched two at ten carbon atoms, which contain at least one triple bond, e.g. eg, 1-propyne-1, 3-diyl, 1 -butyne-1,4-diyl, 2-butyne-1,4-diyl, 2,4-hexadiino-1,6-diyl, and the like;

- a C ₅ -d ₂ aromatic spacer selected from a group of formula III;

 Formula III

a group of formula IV,

 Formula IV

 a group of formula V,

Fórmula V

Formula V

where R ⁴ is selected from OH or OMe;

a group of formula VI,

 Formula VI

a group of formula VII,

 Formula VII

where D joins the rings through the meta or para positions, and is selected from (CH ₂ ) „, CH = CH, C≡C and a heterocyclic ring, where n is equal to 0, 1 or 2;

a group of formula VIII.

 Formula VIII

Based on the above spacers, and as previously mentioned, when the compound of general formula I is a compound of formula la wherein R ¹ and R ² are H, X ¹ and X ² are NH and A is a spacer of formula III or a spacer of formula IV, then B is an alkanediyl type chain - (CH ₂ ) _{P -} Z - (CH ₂ ) _P -, or a C ₃ -C ₀ alkenodiyl type chain, or a C ₂ alkynediyl type chain - Ci ₀ , or the aromatic spacer of formula V, or an aromatic spacer of formula VI, or an aromatic spacer of formula VII or the aromatic spacer of formula VIII as defined above.

The term "pharmaceutically acceptable inorganic or organic acid conjugate base", which will be used throughout this invention and the claims, refers to a conjugate base of an acid with properties, such as for example toxicity, suitable to be administered to a human or animal being. These compounds are widely known to those skilled in the pharmaceutical sector and are described in industry manuals. Preferably, said conjugate base of the present invention refers to anions derived from the dissociation of organic acids, but without limitation, such as maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bismethylene-salicylic, methanesulfonic acids, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, α-ketoglutaric, alpha-glutaphoreal trifluoroacetic, glucose-1-phosphoric and theophyllinacetic, as well as 8- haloteophyllins, such as: 8-bromoteophylline, or anions derived from the dissociation of inorganic acids, but not limited to, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, phosphorous, hypophosphorous, boric, metabolic, tetraboric acids and nitric More preferably, said conjugate base refers to an anion derived from the dissociation of an inorganic acid, and even more preferably to the bromide anion.

In a preferred embodiment, the compound of formula I consists of a compound of formula l-a,

Formula L-A

or any of its conjugate bases, where the groups Q, R ¹ , R ² , X ¹ , X ² , A and B, are independently selected as defined above.

In another preferred embodiment of the compound of formula I or any of its conjugate bases, both in its variants of formula la and / or of formula lb, X ¹ and X ² are NH.

In another preferred embodiment of the compound of formula I or any of its conjugate bases, both in its variants of formula la and / or of formula lb, R ¹ and R ² are H. In a more preferred embodiment of the above, in addition, X ¹ and X ² are NH.

In another preferred embodiment of the compound of formula I or any of its conjugate bases, both in its variants of formula la and / or of formula lb, spacers A and B are independently selected from at least one of the following group: a type chain alkanediyl - (CH ₂ ) pZ- (CH ₂ ) p-, where Z is CH ₂ or an oxygen atom, and p is a value between 1 and 3; and an aromatic spacer selected from a group of formula III, or a group of formula IV, or a group of formula V where R ⁴ is selected from OH or OMe;

 Formula III Formula IV

Formula V

so that if the compound of general formula I corresponds to a compound of formula where R ¹ and R ² are H, X ¹ and X ² are NH, when A is a spacer of formula III or a spacer of formula IV, then B is the alkanediyl type chain above or the aromatic spacer of formula V. In preferred embodiments of the above, X ¹ and X ² are NH and / or R ¹ and R ² are H.

 In another preferred embodiment, the compound of general formula I (preferably the compound of formula l-a) or any of its conjugate bases, consists of one of the group consisting of:

a) 2,6-Diaza-1, 7 (4,1) -dipyridine-4 (1, 3) -benzeclocyclodedecafan-1 ¹ , 7 ¹ -bis (ilium) dibromide [Compound 1, code VGP-222];

b) 10-oxa-2,6-diaza-1, 7 (4,1) -dipyridine-4 (1, 3) -benzenecyclododecafan dibromide-1 ¹ , 7 ¹ -bis (ilium)

 [Compound 2, code VGP-234];

c) 2,6-Diaza-1, 7 (4,1) -dipyridine-4 (1, 4) -benzeclocyclodedecafan-1 ¹ , 7 ¹ -bis (ilium) dibromide [Compound 3, code VGP-310];

d) Dibromide of 10-oxa-2,6-diaza-1, 7 (4,1) -dipyridine-4 (1, 4) -benzenecyclododecafan- 1 ¹ , 7 ¹ -bis (ilium)

 [Compound 4, code VGP-312];

e) 2,8-Diaza-1, 9 (4,1) -dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium) dibromide [Compound 5, VGP-318 code];

f) 9-oxa-6,12-diaza-1, 5 (1, 4) -dipyridine-3 (1, 3) -benzeclocyclodedecafan- 1 ¹ , 5 ¹ -bis (ilium) dibromide

 [Compound 6, code VGP-328];

g) 5-oxa-2,8-diaza-1, 9 (4,1) -dipyridine-cyclotetradecafan- ¹ , 9 ¹ -bis (ilium) dibromide [Compound 7, code VGP-334];

h) 5,12-dioxa dibromide 2,8-diaza--1, 9 (4,1) -dipiridinaciclotetradecafan-1 ¹ 9 ¹ - bis (ilium) [Compound 8, VGP-340 code];

i) Dibromide of 12-oxa-2,8-diaza-1, 9 (4,1) -dipyridine-cyclotetradecafan- ¹ , 9 ¹ -bis (ilium) [Compound 9, code VGP-352].

 Throughout the present description, any of the compounds of formula I (which includes both derivatives of formula la and lb) or of their conjugate bases may also be referred to as "compound of the invention" or "compound of the present invention".

 A second aspect of the present invention provides a method for producing a compound of general formula I as any of those defined above, which comprises an intermolecular cyclization step of a compound of formula VIII.

Formula VIII with a derivative of formula IX,

ZBY ²

 Formula IX

where:

- R ¹ , X ¹ , A and B are selected as defined above in the compound of formula I,

 - Z is a good leaving group of a nucleophilic displacement reaction, known to any expert, such as a halogen selected from Cl, Br, I or the sulphonate moiety,

- one of the groups Y ¹ or Y ² is a group of formula X (preferably group Y ¹ ),

 Formula X

and the other of the groups Y ¹ or Y ² (preferably the group Y ² ) is selected from Cl, Br, I or sulfonate, such that when Y ¹ is the group of formula X, then Y ² is selected from Cl , Br, I or sulfonate thus obtaining a compound consisting of the formula the one or any of its conjugate bases;

Formula L-A

and when Y ² is the group of formula X, then Y ¹ is selected from Cl, Br, I or sulfonate, thus obtaining a compound consisting of the formula lb or any of its conjugate bases.

Formula L-B

The reaction conditions for obtaining the compounds of formula la and lb are the usual conditions in nucleophilic displacement reactions and known by any average expert in the field. By way of example, the compounds of the formula were obtained by reacting the pyridine derivative substituted in 4 (VIII) with the corresponding molecule IX in glacial acetic acid at reflux. After cooling, the solution is treated with a basic solution (eg sodium hydroxide) and the resulting suspension is subsequently concentrated and purified by flash chromatography. The method for obtaining the compounds of formula lb consists in reacting the corresponding heterocyclic derivative of formula VIII and the derivative of formula XI in 2: 1 molar amounts in an aprotic polar organic solvent, such as acetonitrile, at reflux or at room temperature .

According to this method, the compounds of formula la or lb are obtained in the form of salts where Q is a chloride, bromide, iodide or sulfonate anion, depending on whether the group Z and the group Y ¹ or Y ² have been selected from chlorine, bromine , iodine or sulfonate, respectively. However, obtaining compounds of formula la or lb in the form of salts with Q anions other than chlorine, bromine, iodine or sulphonate is trivial to any average expert by means of the usual anionic exchange techniques known and described in the state of the art By way of example, from the chloride, bromide, iodide or sulfonate salt, the above method would further comprise dissolving in water of said initially formed bis salt, to which an excess of another organic or inorganic acid is added, until the new salt that is filtered under vacuum precipitates, resulting in the exchange of the anionic part.

In a preferred embodiment of the method described in this aspect of the invention, when a compound of formula la is obtained, that is, when Y ¹ is the group of formula X defined above and Y ² is a halogen selected from Cl, Br, I or sulfonate, further comprising the preparation of the compound of formula VIII prior to the intermolecular cyclization step, by reaction of a compound of formula XI where A is a spacer group as defined previously,

H ₂ N - A - NH ₂

 Formula XI

with a compound of formula XII and with a compound of formula XIII,

Formula XII Formula XIII

where:

R ¹ and R ² are independently selected as defined previously in the present description,

- Y ³ and Y ⁴ are independently selected from Cl, Br, I or sulfonate.

In this way the compound of formula VIII consisting of formula VIII- a is obtained,

 Formula Vlll-a

wherein A, R ¹ , R ² , X ¹ and X ² are defined as above.

In a preferred embodiment of the method for producing a compound of general formula I, Y ¹ is a Cl, Br, I or sulfonate atom and Y ² is the group of formula X, thus obtaining a compound of formula lb, so that said intermolecular delation reaction consists in the reaction of the derivative of formula VIII with the derivative of formula IX-b,

 Formula VIII Formula IX-b

where A, B, R ¹ , R ² , X ¹ and X ² are defined as above and Y ¹ and Z are independently selected from Cl, Br, I and sulfonate, to obtain said compound of formula lb or any of its conjugate bases . By this variant, compounds VIII and IX-b can be identical when simultaneously A is equal to B, R ¹ is equal to R ² , X ¹ is equal to X ² and Y ¹ is equal to Z.

 Throughout the present description, any of the methods of obtaining the compounds of formula I (which includes both derivatives of formula la and lb) can also be referred to as "method of the invention" or "method of the present invention".

 The compounds of formula I (preferably of formula la and / or lb, and more preferably of formula la) are useful for the treatment of protozoases such as leishmaniasis, and other protozoan diseases also caused by trypanosomatids such as the so-called sleeping sickness ( African trypanosomiasis) or Chagas disease (American trypanosomiasis). Therefore, another aspect of the invention consists in providing pharmaceutical formulations or compositions comprising at least one compound of formula I (i.e. at least one compound of formula la and / or lb) for the treatment of protozoan diseases caused by trypanosomatids. , preferably leishmaniasis, sleeping sickness and / or Chagas disease.

The invention provides, in its third aspect, a pharmaceutical composition comprising a compound of the present invention wherein Q is a pharmaceutically acceptable organic or inorganic acid conjugate base. Said composition may also be referred to herein as "pharmaceutical composition of the invention" or "composition of the invention", and may simultaneously comprise more than one compound of formula la and / or formula lb, resulting in preferred those compositions comprising at least one compound of formula la.

 In accordance with the present invention, the pharmaceutical compositions of the invention can be administered to humans or can be used in veterinary medicine, particularly with other mammals. The administration will be carried out with a "therapeutically effective amount", being sufficient to demonstrate a benefit to the patient. Such benefit may be the improvement of at least one symptom. The amount administered, and the speed and administration over time, will depend on the nature and what is being treated. The prescription of treatment, that is, decisions about doses, etc., will fall under the responsibility of the general practitioner or the specialist.

 Within the scope of the present invention, the term "therapeutically effective amount" refers to the amount of the active compound that causes the biological response in the parasite sufficient to achieve the trypanocidal effect (eg leishmanicide) characterized by the initial inhibition of the growth and subsequent lysis of parasites.

The pharmaceutical compositions, according to the present invention, may comprise, in addition to the active ingredient, a pharmaceutically acceptable excipient (water, alcohol, glycerin, propylene glycol, acetone ...), a transporter (such as liposomes, polymers of vinyl alcohol and derivatives, such as polyvinylpyrrolidone or vinyl pyrrolidone, alanine and thyroxine or lysine polypeptides, microspheres made with synthetic polymers of the polyacrylamide type, polyacryldextran and ethylene vinyl acetate copolymers), buffer system (eg carbonate / ammonium bicarbonate / anion ammonium, acetic acid / acetate anion, citric acid / citrate anion ...), stabilizer (such as nanoparticles, nanocapsules, micellar systems, dendrimers, fullerenes or carbon nanostructures) or other materials known to those skilled in the art. Such materials must not be toxic and also not interfere with the effectiveness of the active ingredient. The precise nature of the transporter or other material will depend on the route of administration, which may be oral, or by injection, for example, cutaneous, subcutaneous or intravenous.

 The pharmaceutical forms for oral administration may be in the form of tablets, capsules, powder or liquid. A tablet may contain a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, animal, vegetable or synthetic oils. Physiological saline solutions may contain dextrose or other saccharide or glycol solution such as ethylene glycol, propylene glycol or polyethylene glycol.

 For intravenous, cutaneous or subcutaneous injection, or injection at the site of the ailment, the active substance will be in the form of a parenterally acceptable aqueous solution, which is non-pyrogenic and has an appropriate pH, stability and tonicity. Those skilled in the art may prepare appropriate solutions using, for example, isotonic vehicles such as a saline injection, injection with Ringer's solution and injection with Ringer's solution with lactate. When required, preservatives, stabilizers, buffer systems, antioxidants and / or other additives may be included.

 A fourth aspect of the invention relates to the use of a compound of the invention of formula I (preferably of formula l-a) for the manufacture of a pharmaceutical composition.

The above pharmaceutical composition may be useful for the treatment and / or prevention of a protozoan disease caused by a trypanosomatid, such as others, and without limitation, a leishmaniasis or a trypanosomiasis. The present invention demonstrates the activity of the compounds of formula I (preferably of formula la) against the Leishmania parasite (responsible for leishmaniasis); However, the proximity of these parasites with other protozoa of the Kinetoplastid Order, such as Trypanosoma cruzi (Chagas disease) and Trypanosoma brucei (sleeping sickness), allow us to predict their validity for these other trypanosomiasis.

 A fifth aspect of the invention relates to the use of at least one compound of the invention of formula I (preferably of formula l-a) for the manufacture of a pharmaceutical composition for the treatment and / or prevention of a protozoan disease caused by a trypanosomatid.

 In a preferred embodiment, said compound of the invention (preferably of formula la) is used for the manufacture of a pharmaceutical composition for the treatment and / or prevention of a leishmaniasis, preferably a leishmaniasis produced by Leishmania major (L. major) or by Leishmania donovani (L. donovani).

In another preferred embodiment, said compound of the invention (preferably of formula l-a) is used for the manufacture of a pharmaceutical composition for the treatment and / or prevention of a trypanosomiasis.

 However, it should be understood from this aspect of the invention, that the present invention also protects the method of treatment and / or prevention of a protozoan disease caused by a trypanosomatid in a subject (preferably against a leishmaniasis such as those produced by Leishmania major or by Leishmania donovani), which comprises the administration to said subject of a therapeutically effective amount of at least one of the compounds of the invention of formula I, preferably of formula la, which also includes the administration of said compound in any pharmaceutical composition or form described above.

 Similarly, in said aspect of the present invention the protection of the compound of the invention or of the pharmaceutical composition comprising it as defined above is also contemplated, for use in the treatment and / or prevention of a protozoan disease caused by a trypanosomatid as described here.

Examples of embodiment of the invention

The scope of the invention will be detailed below by way of examples. Syntheses of various compounds of the invention, identified as compounds 1, 2, etc., as well as intermediates will be described. The melting point will be referred to as pf. MeOH is CH ₃ OH, EtOAc is ethyl acetate, Et ₂ 0 is diethyl ether, DMF is N, N-dimethylformamide and DMSO is dimethyl sulfoxide.

The structures of compounds 1 to 9 of the invention can be represented by the general formula:

 An alternative structural representation is as follows:

which represents the conjugate base.

 Groups A and B are detailed in Table 1 for each of compounds 1 to 9.

 Table 1. Structure of the examples explained in this invention.

Los intermedios VIII-1 y VIII-2 tienen la fórmula estructural:

Intermediates VIII-1 and VIII-2 have the structural formula:

where A consists of a group defined in Table 2:

 Table 2. Structural modifications of intermediates VIII-1 and VIII-2.

 The following known compounds were prepared as starting materials by the method published in the respective reference provided for each case.

 I) KNOWN GAME REAGENTS

The compounds α, α'-dibromo-m-xylene (A), α, α'-dibromo-p-xylene (B), 1, 5- diaminopentane (C), bis (2-aminoethyl) ether (D), 1,5-dibromopentane (E), bis (2- bromoethyl) ether (F) and 4-bromopyridine (G) are commercial and supplied by Sigma-Aldric Química SA

 A.- α, α'-Dibromo-m-xylene B.- α, α'-Dibromo-p-xylene

H ₂ N ^' ^ ^ ^" NH H ₂ N ^' w ^" NH ₂ C- 1, 5-Diaminopentane D.- Bis (2-aminoethyl) ether

Br " ^{^} Br

E.- 1, 5-Dibromopentane F.- Bis (2-bromoethyl) ether

 G.- 4-Bromopyridine.

The following known compounds, 1,3-bis [(pyridin-4- yl) aminomethyl] benzene dibromydrate and 1,4,4-bis [(pyridin-4-yl) aminomethyl] benzene dibromydrate, were prepared as substances of heading according to the method indicated in the reference: Conejo-García, A .; Campos, JM; Sánchez-Martín, R .; Gallo, MA; Prickly AJ Med. Chem. 2003, 46, 3754-3757.

 1,3-bis [(pyridin-4-yl) aminomethyl] benzene dibromydrate

 1,4-bis [(pyridin-4-yl) aminomethyl] benzene dibromydrate

II) PREPARATION OF NEW STARTING SUBSTANCES

 Intermediates VIII-1 and VIII-2 that have the structural formula:

where group A is defined in Table 2, they were prepared by reacting 4- bromopyridine with the corresponding diamine in phenol, at the reflux temperature of the mixture. After cooling, the solution was acidified with HBr in 33% glacial HOAc. The dibromide obtained was obtained as a base using 1M NaOH.

 The preparation of the compounds of formulas VIII-1 and VIII-2 is exemplified below:

 11.1) Intermediate VIII-1. VGP-314. A /, A / -bis - [(4-pyridyl) pentane] -1,5-diamine:

A mixture of pentane-1,5-diamine (0.28 mL, 2.3 mmol) and 4-bromopyridine (720 mg, 4.6 mmol) in phenol (3 mL) was heated under an argon atmosphere at 170 ^e C for 20 hours After cooling to room temperature the reaction crude was dissolved in methanol and acidified to pH 1-2 with HBr in 33% glacial HOAc. Et ₂ 0 was added and the solid was collected by vacuum filtration. The dibromide obtained was passed as a base by adding 1 M NaOH to basic pH to obtain a microcrystalline brown solid (0.80 g, 61%); mp 256 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 13.03 (s, 2H); 8.65 (sa, 2 H); 8.20 (d, 2H, J = 7.1 Hz); 8.05 (d, 2H, J = 7.0 Hz); 6.98-6.79 (m, 4H); 3.25 (m, 4 H); 1.59 (m, 4H); 1, 46-1, 34 (m, 2H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 158.31; 141, 14; 138.78; 1 10.17; 105.07; 42.45; 27.94; 24.07. HRMS (m / z): Calculated for C ₁₅ H ₂₁ N ₄ (M + H) ⁺ 257.1766; found 257.1761. Analysis for C ₁₅ H _{2 or} N ₄ . Caled .: C 70.28; H 7.86; N 21, 86; Found: C 70.03; H 7.97; N 21, 62.

 11.2) Intermediate VIII-2. VGP-320. bis- [2- (4-pyridyl) aminoethyl] ether:

A mixture of bis-2- (aminoethyl) ether (0.90 g, 5.1 mmol) and 4-bromopyridine (0.40 g, 10.2 mmol) in phenol (4 ml_), was heated under an argon atmosphere at 170 ^e C for 20 hours. After cooling to room temperature the reaction crude was dissolved in methanol and acidified to pH 1-2 with HBr in 33% glacial HOAc. Et ₂ 0 was added and the solid was collected by vacuum filtration. The dibromide obtained was passed as a base by adding 1 M NaOH to basic pH to obtain a microcrystalline brown solid (1.30 g, 61%); mp 238 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 7.99 (d, 4H, J = 6.1 Hz); 6.49 (d, 4H, J = 6.3 Hz); 3.56 (t, 4H, J = 5.7 Hz); 3.23 (d, 4H, J = 5.6 Hz). ¹³ C NMR (126 MHz, DMSO-cfe) δ 153.98; 149.82; 107.58; 69.07; 41, 98; HRMS (m / z): Calculated for Ci ₄ H ₁₉ N ₄ 0 (M + H) ⁺ 259.1559; found 259.1556. Analysis for Ci ₄ H ₁₈ N ₄ 0. Caled .: C 65.09; H 7.02; N 21, 69; Found: C 65.21; H 7.18; N 21, 51.

III) PREPARATIONAL EXAMPLES

111.1) Compound 1, code VGP-222, dibromide 2,6-diaza-1, 7 (4,1) -dipyridine- 4 (1, 3) -benzeclocyclodedefan-1 ¹ , 7 ¹ -bis (ilium):

A solution of 1,5-dibromopentane (47 μΙ_, 0.34 mmol) in acetonitrile (35 ml_) is added dropwise onto a suspension of 1,3-bis [(pyridin-4-yl) aminomethyl] benzene (100 mg, 0.34 mmol) in acetonitrile (50 ml_) at reflux. The reaction mixture was allowed to stir at reflux for 5 days. After cooling, a precipitate appeared which was filtered under vacuum, after washing with EtOAc and Et ₂ 0. A white microcrystalline solid was obtained (60.4 mg, 34%); mp 330 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 9.35 (t, J = 6.5 Hz, 2H); 8.1 1 (dd, J = 7.3; 1, 4 Hz, 2H); 8.06 (d, J = 7.3 Hz, 2H); 7.48-7.30 (m, 3H); 7.22 (s, 1 H); 6.96 (dd, J = 7.3; 2.8 Hz, 2H); 6.64 (dd, J = 7.3; 2.7 Hz, 2H); 4.56 (d, J = 6.3 Hz, 4H); 4.23 ^ 1.07 (m, 4H); 1; 77 (c, J = 1 1, 4 Hz, 4H); 0.68-0.50 (m, 2H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 156.49; 143.36; 141, 58; 137.71; 129.14; 127.12; 123.48; 1 10.68; 104.98; 55.99; 44.84; 28.05; 19.99. HRMS (m / z): Calculated for C ₂₃ H ₂₈ N ₄ Br (M - Br) ⁺ 439.1497; found 439.1508. Analysis for C ₂₃ H ₂₈ N ₄ Br ₂ . Caled .: C 53.09; H 5.42; N 10.77; Found: C 53.21; H 5.31; N 10.83.

111.2) Compound 2, VGP-234, 10-oxa-2,6-diaza-1, 7 (4,1) -dipyridine-dibromide-4 (1, 3) -benzecyclododecafan-1 ¹ , 7 ¹ -bis (ilium ):

A solution of bis (2-bromoethyl) ether (43.2 μΙ_, 0.34 mmol) in acetonitrile (35 ml_) is added dropwise onto a suspension of 1,3-bis [(pyridin-4-yl) aminomethyl ] benzene (100 mg, 0.34 mmol) in acetonitrile (50 ml_) at reflux. The reaction mixture was allowed to stir at reflux for 5 days. After cooling, a precipitate appeared which was filtered under vacuum, after washing with EtOAc and Et ₂ 0. A white microcrystalline solid was obtained (50.2 mg, 28%); mp 320 ^e C. ¹ H NMR (500 MHz, DMSO-efe) δ 9.37 (t, 2H, J = 6.5 Hz); 8.10 (dd, 2H, J = 7.3; 1, 6 Hz); 7.99 (d, 2H, J = 7.4 Hz); 7.51 (s, 1 H); 7.45-7.37 (m, 1 H); 7.36-7.28 (m, 2H); 6.95 (dd, 2H, J = 7.3; 2.8 Hz); 6.72 (dd, 2H, J = 7.4; 2.8 Hz); 4.51 (d, 4H, J = 6.5 Hz); 4.34-4.26 (m, 4H); 3.77-3.66 (m, 4H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 156.59; 143.70; 141, 87; 137.48; 129.32; 127.29; 126.07; 1 10.66; 104.95; 68.38; 56.51; 44.91. HRMS (m / z): Calculated for C ₂₂ H ₂₆ N ₄ OBr (M - Br) ⁺ 441, 1290; found 441, 1300. Analysis for C ₂₂ H ₂₆ N ₄ OBr ₂ . Caled .: C 50.59; H 5.02; N 10.73; Found: C 50.60; H 4.93; N 10.85. 111.3) Compound 3, VGP-310, 2,6-diaza-1, 7 (4,1) -dipyridine-4 (1, 4) dibromide - benzenecyclododecafan-1 ¹ , 7 ¹ -bis (ilium):

A solution of 1,5-dibromopentane (51.6 μΙ_, 0.38 mmol) in acetonitrile (40 mL) is added dropwise onto a suspension of 1,4-bis [(pyridin-4-yl) aminomethyl] benzene (10 mg, 0.80 mmol) in acetonitrile (55 mL) at reflux. The reaction mixture was allowed to stir at reflux for 10 days. After cooling, a precipitate appeared which was filtered under vacuum, after washing with AcOEt and Et ₂ 0. A white microcrystalline solid was obtained (11 mg, 58%); mp> 350 ^e C. ¹ H NMR (300 MHz, DMSO-cfe) δ 9.38 (t, 2H, J = 6.3 Hz); 8.07 (d, 2H, J = 7.0 Hz); 7.99 (d, 2H, J = 7.1 Hz); 7.37 (s, 4H); 6.94 (d, 2H, J = 4.5 Hz); 6.35 (d, 2H, J = 7.4 Hz); 4.56 (d, 4H, J = 5.9 Hz); 4.12 (s, 4H); 1.68 (m, 4H); 0.68 (m, 2H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 156.48; 142.91; 141, 50; 136.23; 128.09; 1 1 1, 48; 105.72; 57.06; 44.89; 29.14; 21, 82. HRMS (m / z): Calculated for C ₂₃ H ₂₈ N ₄ Br (M - Br) ⁺ 439.1497; found 439.1518. Analysis for C ₂₃ H _{28 4} Br ₂ . Caled .: C 53.09; H 5.42; N 10.77; Found: C 53.00; H 5.35; N 10.51.

111.4) Compound 4, VGP-312, 10-oxa-2,6-diaza-1, 7 (4,1) -dipyridine-dibromide-4 (1, 4) -benzecyclododecafan-1 ¹ , 7 ¹ -bis (ilium ):

A solution of bis (2-bromoethyl) ether (47 μΐ, 0.38 mmol) in acetonitrile (40 mL) is added dropwise on a suspension of 1,4-bis [(pyridin-4-yl) aminomethyl] benzene (100 mg, 0.34 mmol) in acetonitrile (50 mL) at reflux. The reaction mixture was allowed to stir at reflux for 9 days. After cooling, a precipitate appeared which was filtered under vacuum, after washing with AcOEt and Et ₂ 0. A white microcrystalline solid (86 mg, 50%) was obtained; mp 330 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 9.43 (s, 2H); 8.1 1 (d, 2H, J = 7.3 Hz); 7.98 (d, 2H, J = 7.3 Hz); 7.37 (s, 4H); 6.99 (dd, 2H, J = 7.3; 2.8 Hz); 6.04 (dd, 2H, J = 7.4; 2.8 Hz); 4.57 (d, J = 5.0 Hz, 4H); 4.29-4.21 (m, 4H); 3.76-3.59 (m, 4H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 156.49; 143.69; 141, 31; 136.04; 128.12; 1 1 1, 45; 105.61; 69.44; 57.33; 45.37. HRMS (m / z): Calculated for C ₂₂ H ₂₅ N ₄ OBr (M-HBr-Br) ⁺ 361, 2028; found 361, 2021. Analysis for C ₂₂ H ₂₆ N ₄ OBr ₂ . Caled .: C 50.59; H 5.02; N 10.73; Found: C 50.69; H 5.3; N 10.53.

111.5) Compound 5, VGP-318, 2,8-diaza-1, 9 (4,1) dibromide - dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium):

A solution of 1,5-dibromopentane (50 μΐ, 0.37 mmol) in acetonitrile (40 mL) is added dropwise on a suspension of VGP-314 (95 mg, 0.37 mmol) in acetonitrile (50 mL) at reflux. The reaction mixture was allowed to stir at reflux for 14 days. After cooling, a precipitate appeared which was filtered under vacuum, after washing with AcOEt and Et ₂ 0. The solid was recrystallized from MeOH, obtaining a microcrystalline beige solid (60 mg, 33%); mp 305 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 8.64 (t, 2H, J = 6.1 Hz); 8.13 (d, 2H, J = 7.2 Hz); 8.00 (d, 2H, J = 7.3 Hz); 6.80 (ddd, 4H, J = 18.9; 7.3; 2.7 Hz); 4.12 (dd, 4H, J = 15.5; 9.7 Hz); 3.34 (m, 4 H); 1.78 (m, 4H); 1, 53 (m, 4H); 1.30 (m, 2H); 0.64 (m, 2H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 157.17; 144.03; 141, 59; 1 10.70; 104.83; 56.31; 49.04; 41, 84; 28.54; 23.40; 20.56. HRMS (m / z): Calculated for C ₂₀ H ₂₉ N ₄ (M-Br-HBr) ⁺ 325.2392; found 325.2399. Analysis for C ₂ oH ₃₀ N ₄ Br ₂ . Caled .: C 49.40; H 6.22; N 1 1, 52; Found: C 49.61; H 6.20; N 1 1, 38.

111.6) Compound 6, VGP-328, 9-oxa-6,12-diaza-1, 5 (1, 4) -dipyridine- 3 (1, 3) -benzeclocyclodedecafan-1 ¹ , 5 ¹ -bis (ilium ):

A solution of α, α'-dibromo-m-xylene (99 mg, 0.37 mmol) in acetonitrile (40 mL) is added dropwise onto a suspension of VGP-320 (95 mg, 0.37 mmol) in acetonitrile (50 mL) at reflux. The reaction mixture was allowed to stir at reflux for 14 days. After cooling, a precipitate appeared which was filtered under vacuum, after washing with AcOEt and Et ₂ 0. The solid was recrystallized from MeOH to give a microcrystalline beige solid (134 mg, 69%); mp 326 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 8.79 (t, 2H, J = 5.8 Hz); 8.22 (dd, 2H, J = 7.3; 1, 2 Hz); 8.01 (dd, 2H, J = 7.2; 1, 6 Hz); 7.57-7.40 (m, 3H); 6.96-6.82 (m, 4H); 6.20 (s, 1 H); 5.40 (s, 4 H); 3.65-3.56 (m, 4H); 3.55-3.47 (m, 4H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 157.01; 143.77; 141, 78; 137.17; 129.33; 127.47; 122.18; 1 10.43; 105.14; 67.99; 58.83; 42.29. HRMS (m / z): Calculated for C ₂₂ H ₂₅ N ₄ 0 (M-Br-HBr) ⁺ 361, 2028; found 361, 2022. Analysis for C ₂₂ H ₂₆ N ₄ OBr ₂ . Caled .: C 50.59; H 5.02; N 10.73; Found: C 50.24; H 4.99; N 10.67.

111.7) Compound 7 (VGP-334) 5-oxa-2,8-diaza-1, 9 (4,1) dibromide - dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium):

In a microwave vial, VGP-320 (35 mg, 0.14 mmol), 1, 5- dibromopentane (18.8 μmo, 0.14 mmol) and DMF (5 mL) were added and microwave reacted at 160 ^e C for 25 minutes. After cooling, the solvent was removed on a rotary evaporator and the solid was recrystallized from MeOH to obtain a microcrystalline brown solid (14 mg, 21%); mp 314 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 8.66 (s, 2H); 8.14 (d, 2H, J = 7.3 Hz); 8.04 (d, 2H, J = 7.2 Hz); 6.99-6.80 (m, 4H); 4.20-4.07 (m, 4H); 3.58 (t, 4H, J = 4.5 Hz); 3.54-3.45 (m, 4H); 1.78 (m, 4H); 0.72-0.58 (m, 2H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 156.96; 143.33; 141, 31; 1 10.42; 105.00; 68.45; 55.66; 42.32; 27.71; 19.77. HRMS (m / z): Calculated for Ci ₉ H ₂₇ N ₄ 0 (M-Br-HBr) ⁺ 327.2185; found 327.2186. Analysis for Ci ₉ H ₂₈ N ₄ OBr ₂ . Caled .: C 46.74; H 5.78; N 1 1, 47; Found: C 46.73; H 5.63; N 1 1, 58.

111.8) Compound 8, VGP-340, 5,12-dioxa-2,8-diaza-1, 9 (4,1) dibromide - dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium):

In a microwave vial, VGP-320 (31 mg, 0.12 mmol), bis (2- bromoethyl) ether (15 μmo, 0.12 mmol) and acetonitrile (5 mL) were added and microwave reacted at 160 ^e C for 30 minutes. After cooling, a precipitate appeared which was filtered under vacuum, after washing with EtOAc and Et ₂ 0 as a microcrystalline brown solid (21 mg, 35%); mp 283 ^e C. ¹ H NMR (400 MHz, DMSO-cfe) δ 8.04 (d, 2H, J = 7.4 Hz); 7.97 (d, 2H, J = 7.3 Hz); 6.90 (d, 2H, J = 7.4 Hz); 6.84 (dd, 2H, J = 7.3; 2.5 Hz); 4.26 (m, 4H); 3.75-3.65 (m, 4H); 3.56 (m, 4 H); 3.50 (m, 4H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 157.59; 143.93; 142.39; 1 10.73; 105.45; 68.97; 68.92; 56.83; 42.79. HRMS (m / z): Calculated for Ci ₈ H ₂₆ N ₄ 0 ₂ Br (M - Br) ⁺ 409.1239; found 409.1236. Analysis for C ₁₈ H ₂₆ N ₄ 0 ₂ Br ₂ . Caled .: C 44,10; H 5.35; N 1 1, 43; Found: C 44.00; H 5.50; N 1 1, 24.

111.9) Compound 9, VGP-352, 12-oxa-2,8-diaza-1, 9 (4,1) dibromide - dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium):

VGP-314 (30 mg, 0.12 mmol), bis (2- bromoethyl) ether (15 μΐ, 0.12 mmol) and acetonitrile (5 mL) were added in a microwave vial and reacted in microwave at 160 ^e C for 30 minutes. After cooling, a precipitate appeared which was filtered under vacuum, after washing with EtOAc and Et ₂ 0 as a microcrystalline brown solid (19 mg, 33%); mp 267 ^e C. ¹ H NMR (500 MHz, DMSO-cfe) δ 8.67 (t, 2H, J = 6.2 Hz); 8.06 (d, 2H, J = 7.4 Hz); 8.02 (dd, 2H, J = 7.3; 1, 6 Hz); 6.85 (dd, 2H, J = 7.3; 2.8 Hz); 6.79 (dd, 2H, J = 7.4; 2.8 Hz); 4.35-4.21 (m, 4H); 3.78-3.68 (m, 4H); 3.33 (m, 4 H); 1.54 (m, 4H); 1, 37 (m, 2H). ¹³ C NMR (126 MHz, DMSO-cfe) δ 156.76; 143.97; 141, 32; 1 10.13; 104.22; 68.31; 56.25; 41, 32; 27.10; 22.75. HRMS (m / z): Calculated for C ₁₉ H ₂₈ N ₄ OBr (M-Br) ⁺ 407.1446; found 407.1451. Analysis for C ₁₉ H ₂₈ N ₄ OBr ₂ . Caled .: C 46.74; H 5.78; N 1 1, 47; Found: C 46.66; H 5.99; N 1 1, 20.

IV) BIOLOGICAL TESTS

 IV.1) Cultivation of promastigote forms of Leishmania.

The promastigote forms of Leishmania major (MHOM / JL / 80 / Friedlin) and Leishmania donovani (MHOM / IND / 80 / Dc / S used in this study were grown in RPMI 1640 modified medium (Invitrogen, Carlsbad, CA) supplemented with a 20% heat-inactivated fetal bovine serum (iFBS, Invitrogen) at 28 ^e C.

 IV.2) Determination of sensitivity to compounds in promastigote forms of Leishmania.

To determine the sensitivity to the compounds, IC ₅₀ is used as reference data. IC ₅₀ ("half maximal inhibitory concentrated", also referred to as Cl ₅₀ in the present description), is defined as the concentration of the compounds required to inhibit the growth of parasites in 50% culture, when the culture in the absence of they reach the late logarithmic phase of growth. The IC ₅₀ value is calculated using a colorimetric method based on the reduction of MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide; MTT) (Sigma), following a protocol previously described by our group {Kennedy, ML; Cortés-Selva, F .; Pérez-Victoria, JM; Jiménez, IA; González, AG; Muñoz, OM; Gamarro, F .; Castanys, S .; Ravelo, AGJ Med. Chem. 2001, 44, 4668-4676). The method is based on the ability of the parasitic dehydrogenase enzymes to convert the MTT substrate, soluble and yellow, into the formazan, insoluble and blue colored product. The amount of product formed depends on the number of cells and their viability.

To perform the sensitivity tests, 3 3 10 ⁵ parasites / well were seeded in a final volume of 100 μΙ of culture medium in 96-well microtiter plate, and incubated for 72 hours at 28 ^e C in the presence of different concentrations of the different compounds, in triplicate. Next, 10 μΐ of MTT (5mg / mL) was added, and it was incubated 4 hours at 28 ^e C to allow the formation of the formazan crystals. Finally, the crystals were dissolved by adding 50 μΐ of 20% SDS and incubating in the dark at 37 ^e C for 4-6 hours. MTT reduction was determined by reading OD ₅₄₀ in an ELISA reader.

 IV.3) Culture of the human myelomonocytic cell line THP-1.

The human THP-1 monocytic cell line is maintained in culture in RPMI-1640 medium supplemented with 10% iFBS, 2 mM glutamate, 100 U / mL penicillin and 100 μς / ηιΙ streptomycin, at 37 ^e C and 5% C0 ₂ .

 IV.4) Determination of the sensitivity of the compounds in intracellular amastigote forms of Leishmania.

To induce the differentiation of THP-1 monocytes into macrophages, 5 χ 10 ⁵ cells / well in 24-well plates with sterile crystals at the bottom, are treated with 20 ng / mL of 12-myristate 13-acetate phorbol (PMA) for 48 hours, followed by 24 hours in fresh medium {El Fadili, K .; Imbeault, M .; Messier, N .; Roy, G .; Gourbal, B .; Bergeron, M .; Tremblay, MJ; I will arrive, D .; Ouellette, M. Modulation of gene expression in human macrophages treated with the anti-Leishmania pentavalent antimonial drug sodium stibogluconate. 2008. Antimicrobial Agents and Chemotherapy. 2008, 52, 526-533). These cells were infected with late-logarithmic promishigote forms of Leishmania in a 1: 10 macrophage / parasite ratio at 35 ^e C and 5% C0 ₂ overnight. Infected macrophages were maintained in culture medium at 37 ^e C and 5% C0 ₂ for 72 hours in the presence of different concentrations of the compounds. The macrophages were then fixed with 2.5% paraformaldehyde in PBS for 30 minutes and permeabilized with 0.1% Triton X-100 in PBS for another 30 minutes. Intracellular amastigote forms were visualized by staining the nucleus with DAPI (Invitrogen). The activity of the compounds was determined taking into account the percentage of infection and the number of intracellular amastigote forms per cell in relation to untreated cells.

 IV.5) Determination of the cellular toxicity of the compounds.

The cellular toxicity of the compounds was determined by the MTT colorimetric method, as indicated above. For which, 3 χ 10 ⁴ THP-1 / well cells, in 96-well plates, were differentiated into macrophages by treatment with 20 ng / mL of PMA for 48 hours followed by 24 hours in culture in fresh medium. Next, the same procedure described for the determination of the sensitivity of the compounds in promastigote forms of Leishmania was followed, but incubating the plates at 37 ^e C.

 IV.6) Results obtained on the sensitivity of the compounds in promastigote forms and intracellular amastigotes of Leishmania.

 Table 3 summarizes the results obtained in the tests of sensitivity to the compounds in the parasitic protozoa L. major and L. donovani, using the amphotericin B (Sigma-Aldrich (St. Louis, MO) and miltefosine leishmanicidal drugs as sensitivity control). (Zentaris GmbH, Frankfurt am Main, Germany).

Table 3. Sensitivity of cyclophanic pyridinium derived compounds in promastigote and intracellular amastigote forms of Leishmania

IC ₅ or promastigotes (μΜ) IC ₅ or intracellular amastigotes (μΜ) Cell toxicity Cl ₅₀

Product L. major L. donovani L. major L. donovani

 VGP-222 16.84 ± 1.20 51 .97 ± 1.97 5.94 ± 0.93 [32.3] 13.53 ± 1.40 (14.2] 191 .90 ± 8.12

VGP-234 5.97 ± 0.35 33.77 ± 4.68 8.67 ± 1.04 [22.5] 18.92 ± 1.96 (10.3] 195.17 ± 6.41

VGP-312 26.48 ± 2.44 76.87 ± 11 .59 17.15 ± 1 .50 [12.9] 63.67 ± 5.21 [3.5] 221 .89 ± 8.27

VGP-318 0.07 ± 0.004 25.25 ± 0.83 1 .26 ± 0.3 [122.3] 7.62 ± 0.16 [20.2] 154.07 ± 5.95

VGP-310 0.17 ± 0.01 26.41 ± 1 .28 0.97 ± 0.27 [170.2] 38.33 ± 1.74 [4.3] 165.06 ± 21 .29

VGP-334 0.26 ± 0.02 31 .47 ± 2.53 2.59 ± 0.23 [62.7] 33.19 ± 0.57 [4.9] 162.44 ± 6.07

VGP-340 0.19 ± 0.009 23.43 ± 0.57 2.24 ± 0.35 [57.2] 20.72 ± 1.07 [6.2] 128.22 ± 9.78

VGP-352 0.26 ± 0.007 31 .41 ± 3.02 2.18 ± 0.05 [98.5] 12.95 ± 1.86 (16.6] 214.65 ± 13.8

VGP328 2.87 ± 0.36 76.27 ± 4.96 1 .61 ± 0.35 [120.8] 21 .25 ± 2.03 [9.2] 194.41 ± 2.95

Amphotericin B 0.32 ± 0.02 0.21 ± 0.01 0.24 ± 0.001 [59.7] 0.28 ± 0.13 [51 .1] 14.32 ± 4.10

Miltefosine 16.65 ± 1.23 6.60 ± 1.57 10.61 ± 0.89 [2.5] 0.88 ± 0.14 [30.5} 26.86 ± 3.08 - The data are averages of the values of the Cl ₅₀ ± standard deviation of three independent experiments.

 - The sensitivities of the promastigote forms of Leishmania against the compounds were determined by MTT analysis, as previously described (Kennedy, M. L et al. J. Med. Chem. 2001, 44, 4668-4676).

 - The sensitivities of the intracellular amastigote forms of Leishmania against the compounds were determined by counting the intracellular amastigotes of Leishmania after 72 hours of cultivation of the infected THP-1 macrophages.

- The values in square brackets shown to the right of the Cl ₅₀ data in the amastigote forms indicate the relationship between the cellular Cl ₅₀ and the Cl ₅₀ for the parasite. It is an indicative value of the safety of the compounds.

 From the data in Table 3 it can be deduced that the compounds of the present invention have the following characteristics:

a) VGP-222, VGP-234, and VGP-312 are compounds that have moderate activity against intracellular amastigote forms of both L. major and L. donovani, with very little toxicity to THP-1 mammalian cells (Cl ₅₀ between 192-220 μΜ).

b) VGP-318: it is a non-toxic compound for THP-1 mammalian cells (Cl ₅₀ = 154 μΜ), which has a good activity against intracellular amastigote forms of L. major (Cl ₅₀ = 1, 3 μΜ) , with a safety margin (122) greater than that obtained with amphotericin B (60). Likewise, this compound has moderate activity against amastigote forms of L. donovani (Cl ₅₀ = 7.6 μΜ)

c) VGP-310, VGP-334, VGP-340 and VGP-352 are compounds derived from VGP318, which are not toxic to THP-1 mammalian cells (Cl ₅₀ = 128-215 μΜ). They have a good activity against intracellular amastigote forms of L. major, with a good safety margin, even higher than that obtained with amphotericin B and miltefosine.

d) VGP328 is a non-toxic compound for TPH-1 mammalian cells (Cl ₅₀ = 194 μΜ) that has good activity against intracellular amastigote forms of L. major (Cl ₅₀ ~ 1, 6 μΜ) with a safety margin good (120), superior to that obtained with amphotericin B (60) and miltefosine (2.5).

 The concretions of the present invention have been previously described by way of examples and it should be understood that other alternative modifications may be made with respect to what has been specifically described and illustrated, always within the scope of the invention, as will be apparent from People skilled in the art.

Claims

 1. A compound of general formula I,

 Formula I or any of its conjugate bases, where L is a group of formula II,

 Formula II where:  - Q is a conjugate base of an organic or inorganic acid, and has between 1 and 3 negative charges;  - q is the number of negative charges of the conjugate base Q; - R ¹ and R ² are independently selected from at least one of the substituents of the group consisting of: hydrogen, halogen, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, amino, C 1 -C 10 alkylamino, hydroxy and C 1 -C 10 alkoxy; - X ¹ and X ² are independently selected from at least one of the substituents of the group consisting of: NH, NR ³ , O, S and CH ₂ , where R ³ is independently selected from C 1 -C 10 alkyl, C 1 -C 10 aryl, C1-C10 alkylaryl and arylalkyl - A and B are independently selected from at least one spacer group with chain length C ₂ -Ci ₅ , such that when the compound of formula I consists of the compound of formula la,

 Formula L-A where R ¹ and R ² are H, and X ¹ and X ² are NH, if the spacer A consists of a group of formula III or a group of formula IV:

 Formula III Formula IV  spacer B is different from said groups of formula III and formula IV. 2. A compound according to claim 1 of general formula l-a,

 Formula L-A or any of its conjugate bases, wherein the groups Q, R ¹ , R ² , X ¹ , X ² , A and B, are independently selected as defined in claim 1. 3. A compound according to any one of claims 1 or 2, or any of its conjugate bases, wherein the C ₂ -C ₁₅ spacer group is selected from the group consisting of: - an alkanediyl type chain - (CH ₂ ) _P - Z - (CH ₂ ) _P -, where Z is selected from CH ₂ , an oxygen atom or an S atom; and p is a value between 1 and 5; - a C ₃ -Ci ₀ alkenodiyl chain with one or two double bonds C = C; - a C ₂ -C ₁₀ alkynediyl chain with one or two triple C≡C bonds; - a C ₅ -C ₁₂ aromatic spacer selected from at least one group from the following list: a group of formula III;

 Formula III a group of formula IV;

 Formula IV a group of formula V where R ⁴ is selected from OH or OMe;

Formula V a group of formula VI;

 Formula VI a group of formula VII, where D joins the rings through the meta or para positions, and is selected from (CH ₂ ) „, CH = CH, C≡C and a heterocyclic ring, where n is equal to 0, 1 or 2;

 Formula VII and a group of formula VIII;

 Formula VIII so that if the compound of general formula I corresponds to a compound of formula where R ¹ and R ² are H, X ¹ and X ² are NH, when A is a spacer of formula III or a spacer of formula IV, B it is the alkyl chain, or the alkyl chain, or the alkyne chain, or the aromatic spacer of formula V, or the aromatic spacer of formula VI, or the aromatic spacer of formula VII or the aromatic spacer of formula VIII defined above. 4. A compound according to any one of claims 1 to 3, or any of its conjugate bases, wherein X ¹ and X ² are NH. 5. A compound according to any one of claims 1 to 4, or any of its conjugate bases, wherein R ¹ and R ² are H.  6. A compound according to any one of claims 1 to 5, or any of its conjugate bases, wherein A and B, are independently selected from: - an alkanediyl type chain - (CH ₂ ) pZ- (CH ₂ ) p-, where Z is CH ₂ or an oxygen atom; and p is a value between 1 and 3; - an aromatic spacer selected from at least one group from the following list: a group of formula III,

Formula III a group of formula IV;

 Formula IV and a group of formula V, where R ⁴ is selected from OH or OMe;

Formula V so that if the compound of general formula I corresponds to a compound of formula where R ¹ and R ² are H, X ¹ and X ² are NH, when A is a spacer of formula III or a spacer of formula IV, B is said anterior alkanediyl chain or said aromatic spacer of formula V above.  7. A compound according to any one of claims 1 to 6, which is selected from the group consisting of: a) 2,6-Diaza-1, 7 (4,1) -dipyridine-4 (1, 3) -benzeclocyclodedecafan-1 ¹ , 7 ¹ -bis (ilium) dibromide; b) 10-oxa-2,6-diaza-1, 7 (4,1) -dipyridine-4 (1, 3) -benzeclocyclodedecafan-1 ¹ , 7 ¹ -bis (ilium) dibromide; c) 2,6-Diaza-1, 7 (4,1) -dipyridine-4 (1, 4) -benzeclocyclodedecafan-1 ¹ , 7 ¹ -bis (ilium) dibromide; d) 10-oxa-2,6-diaza-1, 7 (4,1) -dipyridine-4 (1, 4) -benzeclocyclodedecafan-1 ¹ , 7 ¹ -bis (ilium) dibromide; e) 2,8-Diaza-1, 9 (4,1) -dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium) dibromide; f) 9-oxa-6,12-diaza-1, 5 (1, 4) -dipyridine-3 (1, 3) -benzeclocyclodedecafan-1 ¹ , 5 ¹ -bis (ilium) dibromide; g) 5-oxa-2,8-diaza-1, 9 (4,1) -dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium) dibromide; h) 5,12-dioxa-2,8-diaza-1, 9 (4,1) -dipyridine-cyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium) dibromide; i) Dibromide of 12-oxa-2,8-diaza-1, 9 (4,1) -dipyridinecyclotetradecafan-1 ¹ , 9 ¹ -bis (ilium). 8. A method for producing a compound of general formula I defined in any one of claims 1 to 7, characterized in that it comprises an intermolecular cyclization step of a compound of formula VIII,

 Formula VIII with a derivative of formula IX, ZBY ²  Formula IX where: R ¹ , X ¹ , A and B are selected as defined in claim 1,  - Z is selected from Cl, Br, I or sulfonate, - one of the groups Y ¹ or Y ² is a group of formula X, wherein R ² and X ² are selected as defined in claim 1,

 Formula X and the other of the groups Y ¹ or Y ² is selected from Cl, Br, I or sulfonate. 9. A method according to claim 8 which, when Y ¹ is the group of formula X, comprises preparing the compound of formula VIII prior to the cyclization step, by reaction of a compound of formula XI, H ₂ N - A - NH ₂  Formula XI  compound of formula XII and with a compound of formula XIII,

Formula XII Formula XIII where: - A is a spacer group as defined in claim 1, R ¹ and R ² are independently selected as defined in claim 1, - Y ³ and Y ⁴ are independently selected from the group consisting of: Cl, Br, I and sulfonate. 10. A method according to claim 8 wherein, when Y ² is the group of formula X such that the compound of formula IX consists of the compound of formula IX-b,

 Formula IX-b said compound IX-b is equal to the compound of formula VIII,

 Formula VIII such that A, B, R ¹ , R ² , X ¹ and X ² are defined as in claim 8, and furthermore: R ¹ and R ² are equal, X ¹ and X ² are equal, A and B are equals and Y ¹ and Z are equal.  11. A pharmaceutical composition comprising at least one of the compounds defined in any one of claims 1 to 7.  12. A pharmaceutical composition according to claim 1 1 further comprising an additional component selected from at least one of the following group: a pharmaceutically acceptable excipient, a carrier, a buffer system, a stabilizer and any combination thereof.  13. Use of at least one of the compounds defined in any one of claims 1 to 7 for the manufacture of a pharmaceutical composition.  14. Use of at least one of the compounds defined in any one of claims 1 to 7 for the manufacture of a pharmaceutical composition for the treatment and / or prevention of a protozoan disease caused by a trypanosomatid.  15. Use of at least one of the compounds according to claim 14, wherein the protozoan disease is a leishmaniasis.  16. Use of at least one of the compounds according to claim 15, wherein the leishmaniasis is a leishmaniasis produced by L major or by L donovani. 17. Use of at least one of the compounds according to claim 14, wherein the protozoan disease is a trypanosomiasis. 18. A compound defined in any one of claims 1 to 7, or the pharmaceutical composition of any one of claims 1 1 or 12, for use in the treatment and / or prevention of a protozoan disease caused by a trypanosomatid.  19. A method of treatment and / or prevention of a protozoan disease caused by a trypanosomatid in a subject, characterized in that it comprises the administration to said subject of a therapeutically effective amount of at least one of the compounds defined in any one of claims 1 to 7.