ES2341215B1 - MODIFIED NUCLEOSIDS FOR THE TREATMENT OF INFECTIONS BY LEISHMANIA. - Google Patents

Abstract

Modified nucleosides for the treatment of Leishmania infections.

Compounds derived from nucleosides and their use for the treatment of infectious diseases caused by Leishmania . In addition, the invention relates to pharmaceutical compositions containing said compounds.

Description

Modified nucleosides for the treatment of Leishmania infections.

The present invention relates to nucleoside derived compounds, their use for the treatment of Leishmania infections, in addition to pharmaceutical compositions containing said compounds.

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Prior art

Parasites of the genus Leishmania owe their name to WB Leishman, who developed the first parasite detection techniques in 1901. This parasite is the cause of leishmaniasis, a disease present in 22 countries of America and 66 nations of the old world, with special incidence in Southeast Asia, East Africa and Brazil. In Europe it is possible to find cases of infection in humans in 16 countries, including France, Italy, Greece, Malta, Spain and Portugal. The disease has several manifestations that, for the most part, depend on the species that causes the infection. Most of the cases correspond to the cutaneous form, which affects the skin of the patients, being responsible for severe disfigurements. However, the most relevant cases from the point of view of health correspond to the visceral form of the disease (LV), which causes thousands of deaths per year.

Approximately 60% of cases of LV, also known as Kala azar, occur in the Indian subcontinent (Bangladesh, India and Nepal), mainly among the poorest population in rural areas. The rest of the cases are located in East Africa (Ethiopia, Kenya and Sudan) and in Brazil. LV is caused by two different species, L. donovani and L. infantum , each with its own geographical distribution. L. infantum primarily infects children and immuno-suppressed individuals, while L. donovani infects individuals of all ages. It is estimated that about 50,000 deaths occur each year due to this disease and 500,000 new cases are recorded. Among diseases caused by parasites, this death rate is only exceeded by malaria.

The dog is the main reservoir of the species causing LV. There is evidence that demonstrates a decrease in the incidence of the disease, both in dogs and children, as a result of a broad serological analysis of the dog population and the subsequent elimination of infected animals. However, this control strategy is considered as unacceptable and other measures leading to disease control in these animals would be desirable. Recent data show a very high incidence of infection in domestic dogs of the countries of the Mediterranean basin, being considered in fact one of the most frequent and lethal diseases among these animals (Solano-Gallego, L., P. Morell, et al . 2001. J Clin Microbiol 39: 560-3).

The treatment of LV is based on the use of anti-leishmania drugs and an aggressive control of any concomitant bacterial or parasitic infection, of possible anemias, hypovolemia and malnutrition. Pentavalent antimonials sodium stibogluconate and meglumine antimoniato have been the first line of treatment in many areas of the planet for more than 70 years. Antimonials are toxic drugs with frequent adverse effects such as cardiac arrhythmias, and acute pancreatitis. Patients under 2 years of age or older than 45 with advanced disease and / or severe malnutrition have a high risk of death during antimonial therapy as a result of their high cytotoxicity, slow action and / or complications of disease (Chappuis, F., S. Sundar, et al . 2007. Nat Rev Microbiol 5 (11): 873-82).

Conventional Amphotericin B treatment has replaced antimonials in the treatment of LV in some areas, in which the failure rate of antimonials exceeds 60%. Fever, chills and rigor are almost universal effects of conventional Amphotericin B treatment and it is not uncommon to find adverse effects with serious risk to life such as the drop in blood potassium concentration, nephrotoxicity and even anaphylactic shocks after the first dose. In addition, this drug is expensive and its administration regimen is complicated (15 slow infusions on alternate days) (Chappuis, F., S. Sundar, et al . 2007. Nat Rev Microbiol 5 (11): 873-82).

Despite the existence of some alternatives to these treatments, as is the case with amphotericin B liposomal miltefosine (an originally developed drug as an anti-tumor), paramomycin (antibiotic aminoglycoside), and Sitamaquine (8-aminoquinoline), there is still a large need to advance research and development of new drugs that improve the repertoire of strategies available for Disease control

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Description of the invention

The present invention provides a group of molecules capable of inhibiting the growth of the parasite, Leishmania , which constitutes a new tool with importance both from a medical and veterinary point of view.

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A first aspect of the present invention is refers to a compound of general formula (I) (hereafter compounds of the invention):

one

where:

Z is selected from the list comprising hydrogen, halogen, (C 1 -C 4) alkyl, ester (-COOR b) or amide
(-CONH2 or -CONHR_d);

W is CH or nitrogen (N);

Y is a hydrogen (H) or alkyl (C 1 -C 4);

X is selected from O, NH or S;

R_ {1} is a nitrogen base.

R2 is an ester group (-OCOR_c);

R 3 is selected from hydrogen (H), hydroxyl (OH) or alkoxy (-OR a);

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By "halogen" is meant herein invention to a bromine, chlorine, iodine or fluorine atom.

The term "alkyl" refers, in the present invention, to aliphatic, linear or branched chains, having 1 to 4 carbon atoms, for example, methyl, ethyl, n- propyl, i- propyl, n -butyl, tert -butyl or sec -butyl. Preferably the alkyl group is a methyl.

The term "alkoxy" refers to the present invention to a group of formula -OR_ {a} in which R_ {a} it is a (C 1 -C 4) alkyl, for example, but not limited to methoxy, ethoxy or propoxy. It is preferably a methoxy group.

By "nitrogen base" is understood in the present invention to cyclic organic compounds, which include Two or more nitrogen atoms. Preferably the bases nitrogenated are selected from among puric or pyrimidine, if it is purine bind through N9 and if it is pyrimidine bind through of N1. More preferably the nitrogen bases are selected of the group comprising timin-1-il, uracil-1-il, cytosin-1-yl, hypoxantin-9-il, adenin-9-il or guanin-9-il. Even more preferably The nitrogen base is thymine.

The term "ester" refers to the present invention to a group of formula -OCOR_ or of formula -OCOR_ {c}. When Z is an ester, R b is a hydrogen or a (C 1 -C 4) alkyl group as has been previously described. When R2 is an ester R_ {c} is a alkyl group, linear or branched and / or substituted by a group Not me. Preferably it is any free amino acid (as per example, but not limited to valine, alanine or isoleucine) or protected, such as, but not limited to groups t-butoxycarbonyl, phenylxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc). Plus preferably R2 is selected from the following groups:

2

R2 can also be of formula -OCOCH 2 CH 2 COOCH 2 CH 2 O-R e, where R_e is a group, free or protected amino acids, such as described above. R2 may contain an amino acid as spacer and a valine in the distal position of the type -OCOCHR'NHCOCH (CH3) NH2, where R 'is the chain side amino acid spacer.

The term "amide" refers to the present invention to a group of the formula -CONH2 or -CONHR_d wherein R d is a (C 1 -C 4) alkyl, as described above.

R_ {3}, is a radical on the 2 'position of nucleoside ribose, giving rise to deoxy compounds (when R 3 is H), ribo or arabino (when R 3 is OH, depending on its stereochemistry) or ribo (when R3 is -OR_ {a}, preferably -OCH 3).

In a preferred embodiment of the present invention the radicals Y and / or Z are in positions 3 and 4 of their respective aromatic rings. In another embodiment preferred Y is hydrogen. More preferably Z is hydrogen and / or W it's CH. More preferably X is oxygen and even more preferably R 3 is hydrogen.

In another preferred embodiment the compounds of The invention is selected from the list comprising:

(S) -3'- O - [ N - (Fluorenylmethoxycarbonyl) valyl] -5'- O- tritylthymidine;

3'- O- L-Valyl-5'- O- tritylthymidine; or

Acid 4 - [(2R, 3S, 5R) -5- (timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yloxy] -4-oxobutanoic;

[(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate of 2-hydroxyethyl;

[(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate from 2 - [(S) -2 - (((9H-fluoren-9-yl) methoxy) carbonylamino) -3-methylbutanoyloxy] ethyl; or

[(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate from 2 - [(S) -2-amino-3-methylbutanoyloxy] ethyl.

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More preferably, the compounds of the Invention have the formulas:

3'- O- L-Valyl-5'- O- tritylthymidine; or

[(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate from 2 - [(S) -2-amino-3-methylbutanoyloxy] ethyl

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Another aspect of the present invention relates to to a process for obtaining the compounds of the invention that any subject matter expert could deduce from the following reaction schemes, in addition to the content of the examples.

3

Where: R_ {1}, R2_, R_ {3}, X, Z, Y and W They are defined above. In step (i) the addition takes place of the ester groups, introducing amino acids previously protected or amino acid groups together with other spacer groups as defined in the group R2, also previously protected.

Another aspect of the present invention relates to to the use of the compounds of the invention for the preparation of a pharmaceutical composition

Another aspect of the present invention relates to the use of the compounds of the invention for the preparation of a pharmaceutical composition for the treatment of infectious diseases caused by Leishmania .

Leishmaniasis is a disease that affects, especially to vertebrates, that is, both in humans or animals vertebrates, such as marsupials, canids, rodents or Primates

There are several types of leishmaniasis depending on the type of organs are affected by this disease and they are: visceral leishmaniasis (LV), which is mainly caused by two species L. donovani and L. infantum . cutaneous leishmaniasis or mucocutaneous or mucocutaneous leishmaniasis. Given the similarity of the different Leishmania species, the compounds of the invention are used for the treatment of any type of leishmaniasis.

Yet another aspect of the present invention is refers to a pharmaceutical composition comprising at least one of the compounds of the invention, together with a vehicle pharmaceutically acceptable. The use of said composition for Infectious disease treatment will be in an amount Therapeutically effective

Pharmaceutical adjuvants and vehicles Acceptable that can be used in such compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the preparation of compositions therapeutic

The compounds of the invention, their salts pharmaceutically acceptable, prodrugs and / or solvates, as well as pharmaceutical compositions that contain them, can be used together with other drugs, or active ingredients, additional to Provide a combination therapy. Such additional drugs they can be part of the same pharmaceutical composition or, alternatively, they can be provided in the form of a separate composition for simultaneous administration or not to that of the pharmaceutical composition comprising a compound of formula (I), or a prodrug, solvate, derivative or a pharmaceutically salt acceptable of them.

In the sense used in this description, the expression "therapeutically effective amount" refers to the amount of agent or compound capable of carrying out the action therapeutic determined by its pharmacological properties, calculated to produce the desired effect and, in general, will come determined, among other causes, by the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and of the route and frequency of administration.

Said therapeutic composition can be prepared in the form of a solid form or aqueous suspension, in a diluent pharmaceutically acceptable. Therapeutic composition provided by this invention can be administered by any appropriate route of administration, for which said Composition will be formulated in the appropriate pharmaceutical form to the route of chosen administration. In a particular embodiment, the administration of the therapeutic composition provided by this invention is carried out orally, topically, rectally or parenterally (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous, etc.). A review of the different pharmaceutical forms of drug administration and of excipients necessary to obtain them can found, for example, in the "Galenic Pharmacy Treaty", C. Faulí i Trillo, 1993, Luzán 5, S.A. Ediciones, Madrid, or others usual or similar of the Spanish and State Pharmacopoeias United.

Throughout the description and the claims the word "comprises" and its variants not they intend to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be partly detached of the description and in part of the practice of the invention. The The following examples are provided by way of illustration, and are not It is intended to be limiting of the present invention.

Examples

The invention will be illustrated below through tests carried out by the inventors, which puts manifest the specificity and effectiveness of the compounds of the invention.

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Example 1 Synthesis of compound 3

It is described in the following scheme 1:

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4

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Scheme 1: where (i) is Fmoc-Val-OH, BOP, CH 2 Cl 2, Et 3 N, DMAP, room temperature, 16 h. (ii) piperidine, DMF, room temperature, 5 min.

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(S) -3'- O - [ N - (Fluorenylmethoxycarbonyl) valyl] -5'- O -tritylthymidine (2)

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5

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To a solution of 5'- O- tritylthymidine (1) (Gilham, PT; Khoraka HG 1958, J. Am. Chem. Soc ., 80, 6212-6222) (150 mg, 0.31 mmol) in CH 2 Cl_ {2} (2 ml), Fmoc-L-Val-OH (210 mg, 0.62 mmol) is added, using BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoride) (165 mg, 0.37 mmol) as agent coupling and Et 3 N (51 µL, 0.37 mmol). The mixture is stirred at room temperature overnight, diluted with ethyl acetate (25 ml) and washed with a 5% citric acid solution (10 ml). The organic phase is washed with a saturated NaHCO 3 solution (10 ml) and brine, dried over anhydrous MgSO 4, filtered and evaporated. The crude obtained is purified by CCTLC thin layer centrifugal circular chromatography on the Chromatotron using CH2 Cl2 as eluent. 199 mg (80%) are obtained as a white solid.

Mp : 104-106 ° C (CH 2 Cl 2: MeOH)

MS (ES, positive mode): m / z 829 (M + Na) +.

1 H-NMR (DMSO-d 6) : δ 0.83 (m, 6H, CH 3 - γ), 1.46 (s, 3H, 5-CH 3), 2.02 (m , 1H, CH-?), 2.28 (m, 2H, H-2 '), 3.24 (m, 2H, H-5'), 3.93 (t, J = 1.2 Hz, CH-?), 4.02 ( m, 1H, H-4 '), 4.18-4.31 (m, 3H, CH2CH-Fmoc), 5.33 (m, 1H, H-3'), 6.22 (pseudo t, J = 6.9 Hz, 1H , H-1 '), 7.25-7.39 (m, 19H, CPh3, Ph-Fmoc), 7.50 (s, 1H, H-6), 7.71 (pseudo t, J = 6.8 Hz, 2H, Ph- Fmoc), 7.86 (m, 3H, Ph-Fmoc, NH), 11.39 (broad s, 1H, 3-NH).

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3'- O -L-Valyl-5'- O- tritylthymidine (3)

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6

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To a solution of compound 2 (134 mg, 0.17 mmol) in N, N-dimethylformamide (1 ml) is added piperidine (50 µL, 0.51 mmol). The mixture is stirred at temperature. ambient for 5 min and concentrate to dryness under pressure reduced The crude oil obtained is purified by CCTLC in the Cromatotron using CH2Cl2 / MeOH as eluent (10: 1). 89 mg are obtained (92%) as a white solid.

Mp : 88-90 ° C (CH 2 Cl 2: MeOH)

MS (ES, positive mode): m / z 607 (M + Na) +.

1 H-NMR (DMSO-d 6) : δ 0.74 (d, J = 6.5 Hz, 3H, CH 3 - γ), 0.82 (d, J = 6.5 Hz, 3H, CH_ {3} - γ), 1.46 (s, 3H, 5-CH 3), 1.78 (m, 1H, CH-?), 2.30 (m, 2H, H-2 '), 3.10 (d, J = 5.1 Hz, CH-?), 3.25 (m, 2H, H-5 '), 4.02 (m, 1H, H-4'), 5.32 (m, 1H, H-3 '), 6.21 (pseudo t, J = 6.8 Hz, 1H, H-1 '), 7.27-7.39 (m, 15H, CPh_3), 7.52 (s, 1H, H-6), 11.38 (wide s, 1H, 3-NH ).

Analysis (%) for C 34 H 37 N 3 O 6. Calculated: C, 69.96; H, 6.39; N, 7.20. Found: C, 69.85; H, 6.21; N, 6.99.

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Synthesis of compound 7

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7

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Scheme 2.- where: (i) succinic anhydride, CH 2 Cl 2, Et 3 N, room temperature, 4 h (ii) ethylene glycol, BOP, CH 2 Cl 2, Et 3 N, temperature environment, 3 h. (iii) Fmoc-Val-OH, BOP, CH 2 Cl 2, Et 3 N, room temperature, 16 h. (iv) piperidine, N, N-dimethylformamide (DMF), temperature atmosphere, 5 min.

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Acid 4 - [(2R, 3S, 5R) -5- (timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yloxy] -4-oxobutanoic (4)

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8

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A solution of 5'-O-tritylthymidine (1) (Gilham, PT; Khoraka HG 1958, J. Am. Chem. Soc . 80, 6212-6222) (150 mg, 0.31 mmol), in CH2Cl_ { 2} (5 ml) is reacted with succinic anhydride (62 mg, 0.62 mmol) in the presence of Et3N (86 µL, 0.62 mmol) and 4-dimethylaminopyridine (DMAP) (37 mg, 0.31 mmol) for 4 h at room temperature. The reaction mixture is diluted in CH 2 Cl 2 (50 ml), and washed twice with 10% KH 2 PO 4 solution (2 x 30 ml) and with H 2 O (30 ml), the organic phase is dried with anhydrous Na2SO4, filtered and evaporated. The residue is purified through a SPE® Silica cartridge using as eluent a gradient of CH2Cl2 / MeOH (300: 1 to 200: 1). 149 mg (82%) are obtained as a white solid.

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Mp : 97-99 ° C (CH 2 Cl 2: MeOH)

MS (ES, positive mode): m / z 584 (M) +.

1 H-NMR (CDCl 3) : δ 1.38 (s, 3H, 5-CH 3), 2.41 (m, 1H, H-2 '), 2.51 (m, 1H, H- 2 ''), 2.59-2.72 (m, 4H, CH2CH2), 3.42, 3.48 (dd, J = 10.6, 2.5 Hz, 2H, H-5 '), 4.17 (m, 1H, H-4 '), 5.46 (d, J = 5.7 Hz, 1H, H-3'), 6.38 (dd, J = 9.0, 5.4 Hz, 1H, H-1 '), 7.24-7.41 (m, 15H, CPh 3), 7.61 (s, 1H, H-6), 9.72 (s, 1H, 3-NH).

13 C-NMR (CDCl 3) : δ 12.0 (CH 3), 29.3, 29.7 (CH 2 CH 2), 38.4 (C-2 '), 64.2 (C- 5 '), 76.0 (C-3'), 83.8 (C-4 '), 84.8 (C-1'), 88.1 (C-Ph_ {3}), 112.1 (C-5), 127.9, 129.1 (CH -Ph), 136.1 (C-6), 143.6 (C-Ph), 151.1 (C-2), 164.9 (C-4), 172.0 (COO), 176.4 (COOH).

Analysis (%) for C 33 H 32 N 32 O 8. Calculated: C, 67.80; H, 5.52; N, 4.79. Found: C, 67.56; H, 5.81; N, 4.58.

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[(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate 2-hydroxyethyl (5)

9

To a solution of compound 4 (130 mg, 0.22 mmol) in CH2Cl2 (1 ml), ethylene glycol (50 mul, 0.89 mmol), BOP (119 mg, 0.27 mmol) and finally Et 3 N (37 µL, 0.27 mmol). The mixture is stirred at room temperature. for 3 h. It is then diluted with ethyl acetate (25 ml) and Wash with a 5% citric acid solution (10 ml). The phase Organic is washed with a saturated NaHCO3 solution (10 ml) and brine, dried over anhydrous MgSO4, filtered and evaporated. The crude obtained is purified by CCTLC in the Cromatotron using as eluent CH 2 Cl 2 / MeOH (20: 1). 128 mg (92%) are obtained of a white solid.

Mp : 73-74 ° C (CH 2 Cl 2: MeOH)

MS (ES, positive mode): m / z 651 (M + Na) +.

1 H-NMR (CDCl 3) : δ 1.36 (d, J = 0.9 Hz, 3H, 5-CH 3), 2.47 (m, 2H, H-2 '), 2.67 (m , 4H, OCCH 2 CH 2 CO), 3.47 (d, J = 2.4 Hz, 2H, H-5 '), 3.82 (m, 2H, C H 2 OH), 4.14 (m, 1H, H-4 '), 4.24 (m, 2H, CH2O), 5.49 (d, J = 5.3 Hz, 1H, H-3'), 6.40 (dd, J = 8.8, 5.7 Hz, 1H , H-1 '), 7.24-7.40 (m, 15H, CPh3), 7.60 (d, J = 1.1 Hz, 1H, H-6), 8.24 (s, 1H, 3-NH).

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[(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate from 2 - [(S) -2 - (((9H-fluoren-9-yl) methoxy) carbonylamino) -3-methylbutanoyloxy] ethyl (6)

10

At a solution of 5 (160 mg, 0.25 mmol) in CH 2 Cl 2 (1.5 ml), is added Fmoc-L-Val-OH (130 mg, 0.38 mmol) and BOP (135 mg, 0.30 mmol) and after a few minutes you will be add Et 3 N (37 µL, 0.30 mmol). The mixture is stirred at room temperature overnight. It is then diluted with ethyl acetate (25 ml) and washed with an acid solution 5% citrus (10 ml). The organic phase is washed with a solution saturated with NaHCO3 (10 ml) and brine, dried with MgSO4 anhydrous, filtered and evaporated. The crude obtained is purified by CCTLC in the Chromatotron using as eluent CH 2 Cl 2 / ethyl acetate (6: 4). 170 mg (70%) of a white solid

Mp : 87-89 ° C (CH 2 Cl 2: MeOH)

MS (ES, positive mode): m / z 973 (M + 1) +.

1 H-NMR (CDCl 3) : δ 0.83-0.99 (m, 6H, CH 3 - γ), 1.35 (d, J = 0.9 Hz, 3H, 5-CH 3) ), 2.16 (m, 1H, CH-?), 2.45 (m, 2H, H-2 '), 2.63 (s, 4H, CH2CH2), 3.47 (d, J = 2.3 Hz , 2H, H-5 '), 4.12 (m, 1H, H-4'), 4.23 (t, J = 7.2 Hz, 1H, CH-?), 4.32-4.41 (m, 7H, OCH2) CH 2 O, CH 2 -Fmoc, CH-Fmoc), 5.34 (d, J = 9.4 Hz, 1H, H-3 '), 5.41 (m, 1H, NH), 6.40 (dd, J = 8.1, 6.2 Hz, 1H, H-1 '), 7.25-7.44 (m, 19H, CPh 3, Ph-Fmoc), 7.58-7.61 (m, 3H, H-6, Ph-Fmoc), 7.76 ( d, J = 7.5 Hz, 2H, Ph-Fmoc), 8.06 (s, 1H, 3-NH).

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[(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate from 2 - [(S) -2-amino-3-methylbutanoyloxy] ethyl (7)

eleven

At a solution of 6 (79 mg, 0.08 mmol) in Anhydrous N, N-dimethylformamide (1 ml) is added piperidine (50 µL, 0.51 mmol). The mixture is stirred at temperature. ambient for 5 min, and concentrate to dryness under pressure reduced The crude oil obtained is purified by CCTLC in the Cromatotron using CH2Cl2 / MeOH as eluent (10: 1). 60 mg are obtained (96%) of a white solid.

Mp : 62-64 ° C (CH 2 Cl 2: MeOH)

MS (ES, positive mode): m / z 728 (M + 1) +.

1 H-NMR (CDCl 3) : δ 0.90 (d, J = 6.8 Hz, 3H, CH 3 - γ), 0.97 (d, J = 6.8 Hz, 3H, CH 3 } -?), 1.36 (s, 3H, 5-CH3), 2.01 (m, 1H, CH-?), 2.45 (m, 2H, H-2 '), 2.67 (s, 4H, CH 2 CH 2), 3.33 (d, J = 4.9 Hz, 1H, CH-?), 3.47 (d, J = 2.2 Hz, 2H, H-5 '), 4.13 (m, 1H, H-4 '), 4.32 (s, 4H, CH2O), 5.50 (m, 1H, H-3'), 6.40 (dd, J = 8.2, 6.2 Hz, 1H, H-1 '), 7.25-7.43 (m, 15H, CPh3), 7.58 (s, 1H, H-6).

Analysis (%) for C 40 H 45 N 3 O 10 {H 2 O. Calculated: C, 64.42; H, 6.35; N, 5.63. Found: C, 64.03; H, 6.03; N, 5.70.

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Example 2 Inhibitory capacity of promastigote growth in phase Logarithmic growth by compounds (comp. 3 and 7)

Promastigotes of Leishmania infantum in the logarithmic growth phase were incubated in multiwell plates in 200 µL of culture medium at a concentration of 100,000 parasites per ml. A volume of 5 µL of dimethylsulfoxide (DMSO) was added to the positive growth controls. Each of compounds 3 and 7 was added to the cultures at a concentration of 12 µM in a volume of 5 µl of DMSO. The parasite growth was evaluated by adding 20 µl of Alamar Blue at the time of the start of the culture, to reach a final concentration of 10%. The number of cells present in each of the wells was estimated at 24 hours by measuring the absorbances at 570 nm and 630 nm, according to the method described by the manufacturer (Biosource TM). The percentage of growth inhibition of each of the compounds was estimated by comparison with the growth of the controls with DMSO.

The results obtained show a strong inhibitory capacity of parasite growth in the case of compounds 3 and 7.

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TABLE 1 Percentage of growth inhibition of logarithmic promastigotes of Leishmania infantum in culture medium

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12

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Comparison of the cytotoxic effect of compounds 3 and 7 in human cells (Jurkat) and Leishmania promastigotes

The cytotoxic effect of compounds 3 and 7 on promastigotes of L infantum and in human cells was evaluated by flow cytometry by analyzing the parameters of cell size / complexity (Forward scatter and Side Scatter; FSC / SSC). The results obtained (table 2) indicate that, after 24 hours of incubation with a concentration of 6.25 µM of compound 3, only 20% of the parasites remain alive. At this same concentration, 38% of Jurkat cells are viable. At a concentration of 12.5 µM of compound 3 under the same culture conditions only 2% of the parasites remain alive, while 14% of Jurkat cells remain viable.

In the case of compound 7, after 24 hours of incubation at a concentration of 6.25 µM, only 14% of The parasites remain alive. At this same concentration 73% of Jurkat cells are viable. At a concentration of 12.5 µM of compound 7 under the same culture conditions, only the 2.5% of the parasites remain alive, while 35% of the Jurkat cells remain viable.

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TABLE 2 Comparison of cellular toxicity of compounds 3 and 7 in human cells (Jurkat) and promastigotes of Leishmania infantum

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13

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Comparison of the cytotoxic effect of compounds 3, 7 and miltefosine in promastigotes of Leishmania infantum

The comparison of the cytotoxic effect of the three compounds against logarithmic promastigotes of Leishmania infantum was carried out by flow cytometry by analyzing the parameters of cell size / complexity (Forward scatter and Side Scatter; FSC / SSC). The results indicate a clearly superior leishmanicidal activity of compounds 3 and 7 in the concentration range between 6.25 and 12.5 µM (table 3).

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TABLE 3 Comparison of the cytotoxic activity of compounds 3, 7 and miltefosine in promastigotes of Leishmania infantum

14

Claims (15)

1. Compound of general formula (I): fifteen where: Z is selected from the list that comprises hydrogen, halogen, (C 1 -C 4) alkyl, ester or amide; W is CH or N; Y is hydrogen or an alkyl group (C 1 -C 4); X is selected from the list comprising O, NH or S; R1 is a nitrogen base; R2 is an ester group; Y R_ {3} is selected from the list comprising hydrogen, hydroxyl or alkoxy.

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2. Compound according to claim 1, wherein Z and / or Y are hydrogen. 3. Compound according to any of the claims 1 or 2, wherein W is the CH group. 4. Compound according to any of the claims 1 to 3, wherein R_ {1} is selected from the list that comprises thymine, uracil, cytosine, guanine, adenine or hypoxanthine 5. Compound according to claim 4, wherein R_ {1} is thymine. 6. Compound according to any of the claims 1 to 5, wherein R 3 is hydrogen. 7. Compound according to any of the claims 1 to 6, wherein R2 is an amino acid, free or protected. 8. Compound according to claim 7, wherein the amino acid is valil, alanyl or isoleucil. 9. Compound according to any of the claims 1 to 8, wherein X is O. 10. Compound according to claim 1 of formula: (S) -3'- O - [ N - (Fluorenylmethoxycarbonyl) valyl] -5'- O- tritylthymidine; 3'- O- L-Valyl-5'- O- tritylthymidine; or Acid 4 - [(2R, 3S, 5R) -5- (timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yloxy] -4-oxobutanoic; [(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate of 2-hydroxyethyl; [(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate from 2 - [(S) -2 - (((9H-fluoren-9-yl) methoxy) carbonylamino) -3-methylbutanoyloxy] ethyl; or [(2R, 3S, 5R) -5- (Timin-1-yl) -2- (trityloxymethyl) tetrahydrofuran-3-yl] succinate from 2 - [(S) -2-amino-3-methylbutanoyloxy] ethyl.

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11. Use of the compound of general formula (I) according to any of claims 1 to 10, for processing of a pharmaceutical composition. 12. Use of the compound of general formula (I) according to any of claims 1 to 10, for the preparation of a pharmaceutical composition for the treatment of infectious diseases caused by Leishmania . 13. Use of the compound according to claim above, for treatment in humans or animals. 14. Pharmaceutical composition comprising minus one of the compounds of general formula (I), according to any of claims 1 to 10, together with a vehicle pharmaceutically acceptable. 15. Pharmaceutical composition according to previous claim, which further comprises another principle active.