ES2344780B1 - USEFUL BISTIAZOLIC COMPOUNDS FOR THE TREATMENT OF CANCER. - Google Patents

Abstract

Bistiazole compounds useful for cancer treatment

Compounds of formula (I), their salts pharmaceutically acceptable, or its solvates, where R1 is select from phenyl, optionally mono-, di-, or tri-substituted by a radical independently selected from F, Cl, Br, I, (C 1 -C 4) -alkyl, N, N- (C 1 -C 4) -alkylamino, hydroxy, (C 1 -C 4) -alkoxy, phenoxy, methylenedioxy, trifluoromethoxy, trifluoromethyl, carboxy, 4-phenoxyphenyl and (C 1 -C 4) -alkoxycarbonyl; 2-thiazolyl; 2-pyridinyl; 2,2'-bipyridinyl; 2,2'-bistiazole; naphthyl; 4-phenoxyphenyl and isoquinolyl; R2 is select from the same group as R_ {1} and also independent of H and I; and R 3 and R 4 are independently selected from H, Br and F; inhibit cell proliferation of tumor cells independently of the p53 protein and can also induce apoptosis in several tumor cells regardless of the p53 protein, proving useful for the treatment of various types Of cancer.

Description

Bistiazole compounds useful for cancer treatment

The present invention is related to new bistiazole compounds, pharmaceutical compositions that They contain and their use for cancer treatment.

Prior art

Cancer is a heterogeneous disease. characterized by the accumulation of tumor cells, which can cause the death of both animals and humans. Methods Conventional treatments for cancer include those surgical treatments, agent administration chemotherapeutic, and more recently treatments based on the immune response, which involve the administration of a antibody or a fragment of the antibody that can be conjugated to A therapeutic unit However, so far, such Treatments have had limited success.

The development of antitumor therapies of general applicability is one of the main objectives in chemistry medical Among the strategies planned to develop new antitumor treatments, inducing apoptosis is particularly attractive In this context, the development of new compounds that can act as efficient inducers of apoptosis at maximum number of possible types of cancer would be of enormous interest scientific, social and economic impact.

Although many drugs have been used in cancer therapies, today there is no curative therapy for most of them. Many of the drugs currently used in the treatment of cancer induce apoptosis of these cells at least partially, through the activation of the pathway of the p53 protein. When acid damage occurs deoxyribonucleic (DNA), p53 prevents the cell from its replication stopping the cell cycle and induces apoptosis. The mechanisms of resistance to drugs currently used they include the inactivation of the p53 protein that is mutated in the half of all types of cancer analyzed, demonstrating the importance of the p53 pathway in the development of cancer.

Chemotherapy works by killing the cells that they divide quickly, one of the main properties of the tumor cells. This means that it also damages cells that are Quickly divide under normal conditions. Most of the Chemotherapeutic regimens may cause system depression immune.

Various bioactive natural products maintain the presence of thiazole rings in their structures as a common characteristic, many of them have anti-tumor properties. There is a great structural diversity of these compounds such as cyclic peptides, polyheterocyclic alkaloids, or compounds of mixed biosynthetic origin that have structural motifs of bicar- and polycyanolic nature. The biosynthetic origin of these sub-structural units is related to the cyclodehydration procedures generated by the thiol of the cysteine side chain and the neighboring peptide bond. However, the synthesis of these natural products is usually complicated, both by solid phase peptide synthesis, and by condensation protocols (Hantszch synthesis) or through transition metal coupling reactions, from products that already contain its structures the thiazole ring (cf. eg N. Haginova et al ., Bioorg. Med. Chem . 2004. vol. 12, pp. 5579-5586).

Also, in the literature there are few examples of symmetric bistiazole compounds and, more especially, by means of a 2,2 'joint. Some compounds bistiazole with the ability to inhibit cell proliferation is They have described previously. Thus, WO 2004/016622 describes type structure compounds 4,4'-bipyridyl-2,2'-bisoxazole Y 4,4'-bipyridyl-2,2'-bistiazole with antiproliferative activity, in particular, on cells HT-29 All examples cited in said patent They have a bridge between the two thiazole nuclei.

In short, despite all the efforts invested so far, there is still a need to find new antitumor agents that are effective, and in In particular, it would be of great interest to find antitumor therapies acting independently of p53.

Summary of the Invention

The inventors have found a new family of compounds with the bistiazole nucleus variously substituted with a great variety of aromatic rings constituting constructions containing in their structures up to three and four rings aromatic, with anti-tumor properties against several lines of cancer cells, and therefore, that are useful for the cancer treatment It has been found that these compounds inhibit cell proliferation of tumor cells regardless of the p53 protein. Additionally it has been seen that some compounds induce apoptosis in several tumor cells regardless of the p53 protein.

The fact that the compounds of the present invention inhibit cell proliferation and even induce Tumor cell apoptosis, in both cases regardless of p53 protein is of great importance since the resistance of Tumor cells to current treatments is partly due to its dependence on the p53 protein pathway. Therefore, the Compounds of the present invention are advantageous because reduce the problems that many antitumor agents have and are active against a wide variety of cell lines carcinogenic

Thus, one aspect of the present invention is to provide a compound of general formula (I), or its pharmaceutically acceptable salts, or their solvates.

one

where: R_ {1} is selected from: optionally mono-, di-, or tri-substituted phenyl by a radical independently selected from the group that It consists of: F, Cl, Br, I, (C 1 -C 4) -alkyl, N, N- (C 1 -C 4) -alkylamino, hydroxyl, (C 1 -C 4) -alkoxy, phenoxy, methylenedioxy, trifluoromethoxy, trifluoromethyl, carboxy, 2- (2-methoxyethoxy) ethoxy, and (C 1 -C 4) -alkoxycarbonyl; 2-thiazolyl; 2-pyridinyl; 2,2'-bipyridinyl; 2,2'bistiazole; naphthyl; 4-phenoxyphenyl and isoquinolyl; R2 is selected from the same group of R_ {1} and also includes independently H and I; and R 3 and R 4 are independently selected from H, Br and F; with the proviso that the compound (I) is not one of the following compounds:

2,2-bistiazole, 5,5'-diphenyl (compound (I) with R 1 = R 2 = phenyl, R 3 = R 4 = H) having the RN 109558-82-9;

2,2'-bistiazole, 5,5'-di-2-naphthalenyl (compound (I) with R 1 = R 2 = 2-naphthyl, R 3 = R 4 = H) having the RN 1087742-85-8;

2,2'-bistiazole, 5,5'-bis [4- (trifluoromethyl) phenyl] - (compound (I) with R1 = R2 = 4-trifluoromethylphenyl, R 3 = R 4 = H) having the RN 869896-77-5;

2,2'-bistiazole, 5,5'-bis (4-butoxyphenyl) - (compound (I) with R 1 = R 2 = 4-butoxyphenyl, R 3 = R4 = H) having the RN 861958-17-0; or

2,2'-bistiazole, 5,5'-bis (4-ethoxyphenyl) - (compound (I) with R 1 = R 2 = 4-ethoxyphenyl, and R 3 = R4 = H) having RN 72997-86-5.

There is no knowledge of the use as anticancer agents of any of the above compounds cited.

The term "pharmaceutically salts acceptable "used in this document covers any salt formed from both inorganic and organic acids or bases non-toxic pharmaceutically acceptable. The salts pharmaceutically Acceptable can also be in the form of hydrates. There is none limitation with respect to salts, except that if used with therapeutic purposes must be pharmaceutically acceptable.

The compounds cited may have a center of asymmetry, and therefore, exist in different forms enantiomeric All optical isomers and stereoisomers Individuals of the compounds herein, and mixtures of them, are considered within the scope of protection of the present invention Thus, the compounds referred to in the This document is intended to represent any form of a racemic, to one or more enanti American forms, to one or more forms atropoisomeric, or a mixture of them.

In a preferred embodiment, the compounds of formula (I) are those where R 1 is selected from phenyl, optionally mono-, di-, or tri-substituted by a radical independently selected from: F, Cl, Br, I, (C 1 -C 4) -alkyl, N, N-dimethylamino, hydroxy, methoxy, ethoxy, isopropoxy, phenoxy, carboxy, and ethoxycarbonyl; 2-thiazolyl;
2-pyridinyl and 2,2'-bipyridinyl; and R2 is selected from the same group as R1 or is H.

In a more preferred embodiment, the compounds of formula (I) are those where R 1 and R 2 are independently selected from the group consisting of 3-isoproproxyphenyl, 3-chlorophenyl, 4-ethoxycarbonylphenyl, 4-ethylphenyl, 4-carboxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 3,4-ethoxyphenyl, 4- (dimethylamino) phenyl, 3-isopropylphenyl, 3-chlorophenyl, 3,4,5-trimethoxyphenyl,
4-phenoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2-thiazolyl, 2,2'-bipyridinyl and 2-pyridinyl.

In an even more preferred embodiment, the compounds of formula (I) of the present invention are those where R 1 is selected from the group consisting of 3-isoproproxyphenyl, 3-chlorophenyl, 4-ethylphenyl, 4-ethoxycarbonylphenyl,
4-methoxyphenyl and 3,4-dimethoxyphenyl.

In another preferred embodiment, the compounds of formula (I) are those where R_ {1} and R2 have the same meaning. In another preferred embodiment, the compounds of formula (I) are those where R2 is H.

In another preferred embodiment, the compounds of formula (I) are those where R_ {3} and R_ {4} are H. In another even more preferred embodiment, the compounds of formula (I) are those where R_ {3} and R_ {4} are F.

The most preferred compounds of formula (I) such as defined above are those of the following Table one:

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TABLE 1

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The compounds of the present invention are can conveniently prepare from commercial reagents through a variety of procedures. They can be prepared from Simple and flexible way. The synthetic sequence is direct, allowing the synthesis of different structural analogues.

The compounds of the present invention are they can prepare by a procedure comprising Suzuki couplings. Scheme I illustrates an embodiment Particular of the procedure.

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Scheme I

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According to the previous scheme, the 2,2'-bistiazole of formula (I) where R 3 and R 4 are H can be obtained directly by the homocoupling ("homocoupling") of 2-bromothiazole using a palladium catalyst, such as Pd (OAc) 2, a base such as diisopropylethylamine and an appropriate solvent such as toluene. Other 2-halothiazoles can be used as starting products 2,2'-Bistiazole can be selectively lithiated with lithium diisopropylamide ("lithium diisopropylamide ", LDA) and the organometallic derivative that gets can be doubly halogenated with a source of iodine, such as molecular iodine obtaining the compound 5,5'-diiodo-2,2'-bistiazole.

The preparation of non-symmetric compounds of formula (I) is carried out by performing, sequentially, two Suzuki couplings. The first coupling is done with a boronic acid of formula R 1 B (OH) 2 and then the second coupling is made with an acid boronic of formula R 2 B (OH) 2. In the formula previous R_ {1} and R_ {2} have the same meaning as for compounds of formula (I). How palladium catalysts can used, for example, Pd (OAc) 2, tetrakis (triphenylphosphine) -palladium (0) or tris (dibenzylidenacetone) dipaladium (0). Examples of Suitable bases include potassium phosphate or sodium carbonate. In In general, the reaction is heated to an approximate temperature of 80 ° C

The preparation of symmetric compounds of formula (I) can be carried out as illustrated in the scheme previous, but subjecting the iodinated derivative to a single coupling of Suzuki, usually using two equivalents of the acid arylboronic of formula R 1 B (OH) 2.

In a preferred embodiment, the preparation of the symmetric compounds of formula (I) where R 1 = R 2 and R 3 =
R 4 = H is carried out using as a ligand the 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (S-Phos).

The non-symmetrical diarylbistiazole compounds of formula (I) where R 2 = R 3 = R 4 = H can be prepare as indicated in scheme II:

Scheme II

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According to the previous scheme, the 5-iodine-2,2'-bistiazole can be obtained by monolithing the corresponding derivative diiodized and subsequent water treatment. Next, the 5-iodine-2,2'-bistiazole can undergo a Suzuki coupling with a boronic acid of formula R 1 B (OH) 2, to obtain with good yields the compounds of formula (I) with R2 = R3 = R 4 = H.

The compounds of the present invention also They can be prepared by Stille couplings. In the next Scheme III illustrates a particular embodiment of the process.

Scheme III

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In the previous scheme, X represents an atom of halogen, preferably X is Br. According to the above scheme, they can obtain both non-symmetrical diarylbistiazoles and symmetric diarylbistiazoles in which R 1 = R 2 and R 3 = R4 = H.

The preparation of diarylbistiazoles does not Symmetric of formula (I) includes two Stille couplings sequential from 5,5'-bis (trimethylstannil) -2,2'-bistiazole, first with a halogenated derivative of formula R1 X and a then with a second halo derivative of formula R2 X, where R_ {1} and R2 can vary in the same way they do in the formula (I). Preferably, this coupling is performed in presence of a palladium catalyst. A preferred catalyst is tetrakis (triphenylphosphine) palladium (0). Generally, to obtain derivatives 5,5'-bisaryl-2,2'-bistiazole 10 mol% of the palladium catalyst is used. The coupling is carried out in a suitable solvent such as dimethylformamide. In general, the reaction is heated to an approximate temperature of 100 ° C The reaction can be carried out in the presence of silver oxide (I) as an additive.

The compounds of formula (I) where R2 = R 3 = R 4 = H can also be prepared by Stille couplings. The following Scheme IV shows a particular realization of this procedure.

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Scheme IV

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According to the previous scheme, the 5-iodine-2,2'-bistiazole undergoes a Stille coupling with a trimethylstannaryl suitable for providing the compounds of formula (I) where R 2 = R 3 = R 4 = H with good yields.

The compounds of the present invention can also prepare by a C-H procedure activation. This procedure is useful for the preparation of compounds of formula (I) where R 3 = R 4 = H. Scheme V illustrates a particular embodiment of this procedure.

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Scheme V

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According to the previous scheme, the 2,2'-bistiazole can undergo a reaction of oxidative coupling with a suitable compound of formula R_ {1} I. This reaction is carried out in the presence of a suitable palladium catalyst. A preferred catalyst is the tetrakis (triphenylphosphine) palladium (0). Usually 10 mol% palladium catalyst should be used. The coupling usually carried out in a suitable solvent such as dimethylformamide and in the presence of a base such as carbonate of cesium. In a particular embodiment, the reaction is carried out at an approximate temperature of 150ºC.

In another particular embodiment, it is used triphenylphosphine (20 mol%) as ligand. In another embodiment In particular, copper iodide (I) is used as an additive.

The subsequent fluorination of the compound (I) in the thiazole ring with a fluorinating agent such as bis- (tetrafluoro-
borate) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane (Selectfluor®), gives rise to compounds of formula (I) with R 3 and / or R 4 = F With good yields. The fluorination is carried out in a suitable solvent such as, for example, acetonitrile, generally at high temperatures, in particular, it is usually carried out at the reflux temperature of the solvent used.

The bromination of compound (I) in the ring of thiazole can be made with bromine, to give compounds of formula (I) with R 3 and / or R 4 = Br with good yields. The bromination is carried out in a suitable solvent such as acetonitrile, chloroform or mixtures thereof.

The preparation procedures described previously, they can be modified to obtain compounds enantiopuros as well as mixtures of stereoisomers. it's possible synthesize specific stereoisomeric compounds or mixtures specific by various methods, including the use of reagents stereospecific or by the introduction of chiral centers in the compounds during synthesis. In addition, it is possible to separate stereoisomers once the compound has been synthesized by standard resolution techniques well known to the person subject matter expert

The preparation of salts pharmaceutically acceptable can be carried out by methods known in the art previous. For example, they can be prepared from the compounds primitives which contain a basic or acid reactive center, by conventional chemical methods. Generally, said salts they are prepared by reacting the acid or free base with the stoichiometric amount of a base or an acid in water, in a organic solvent or in a mixture thereof. The compounds of the present invention can be found in crystalline form, both Solvated solvent-free compounds such as solvates (for example, hydrates) and it is understood that both forms are within the scope of protection of the present invention. Solvation methods are generally known in the literature.

An important feature of the compounds of the present invention is its bioactivity by inhibiting the cell growth of the tumor cell lines tested, and in particular its cytotoxic activity promoting apoptosis.

As illustrated in the Examples, the compounds of the present invention show antitumor properties (proapoptotic properties) against several cell lines carcinogenic The best results have been obtained for compounds (Is) and (It), the (Is) having an IC 50 of less than 1 at 6 µM. Both promote apoptosis of tumor cells regardless of the p53 protein.

Thus, another aspect of the present invention is related to providing compounds of formula (I), or their pharmaceutically acceptable salts, or their solvates for use in the therapeutic treatment of cancer in a mammal, including being human,

8

where: R1 is selected from the group consisting of: phenyl, optionally mono-, di-, or tri-substituted by a radical independently selected from the group consisting of: F, Cl, Br, I, (C_ { 1} C4) -alkyl, N, N- (C1C4) -alkylamino, hldroxyl, (C1C4) -alkoxy, phenoxy, methylenedioxy, trifluoromethoxy, trifluoromethyl, carboxl, 2- (2-methoxyethoxy) ethoxy, and (C 1 C 4) -alkoxycarbonll; 2-thiazolyl; 2-plridlnll; 2,2'-bipyridinyl;2,2'-bistiazole;naphthyl; 4-phenoxyphenyl and isoquinolyl; R 2 is selected from the same group as R 1 and also independent of H and I; and R 3 and R 4 are independently selected from
H, Br and F.

Preferably, the types of cancer against which the compounds of the present invention are active are the following: leukemias, lymphomas, cervical carcinoma, colon cancer and neuroblastoma. More preferably, the cancer is leukemia or lymphomas. Even more preferably, the type of lymphoma or leukemia is neoplasms of
B cells.

This aspect can also be formulated as the use of the compounds of formula (I) as defined above, for the preparation of a medicine for the therapeutic treatment of cancer in a mammal, including being human.

The invention also relates to a method of cancer treatment in a mammal, including humans, which suffer from cancer, in particular to the types of cancer and mentioned, said method comprises administration to said patient of a therapeutically effective amount of a compound of formula (I), as defined above, together with pharmaceutically acceptable carriers or excipients.

The compounds of the present invention can be used in the same way as other agents chemotherapeutics already known. They can be used alone or in combination with other suitable bioactive compounds.

Another aspect of the present invention is related to a pharmaceutical composition containing a therapeutically effective amount of the compounds herein invention, together with appropriate amounts of excipients or pharmaceutically acceptable carriers.

The chemotherapeutic treatment that is derived of the present invention is a new approach to the therapy of cancer and has the advantage of being useful for the treatment of several types of cancer.

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 following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. In addition, the present invention covers all possible combinations of particular and preferred embodiments indicated herein.

Brief description of the figures

Fig. 1A shows the dose-response of compound (I t) from 5 µM to 40 µM in Jurkat cells (T lymphocytes from a type T leukemia) at 24 h of incubation. He cell growth (CG) was measured with the MTT assay and is expressed as the percentage with respect to the control cells at treatment principle (100%). The results are shown as the mean ± the standard deviation (SD) of the tripled

Fig. 1B shows the dose-response of compound (I t) from 5 µM up to 40 µM in Jurkat cells at 24 h of incubation. Viability (V) was measured by flow cytometry and is expressed as the percentage of cells non-apoptotic

Fig. 2A shows the dose-response of compound (I s) from 5 µM up to 40 µM in Jurkat cells at 24 h of incubation. Cell growth (CG) was measured with the MTT test and is expressed as the percentage with respect to control cells at the beginning of treatment (100%). The results they are shown as the mean ± SD of triplicates.

Fig. 2B shows the dose-response of compound (I s) from 5 µM up to 40 µM in Jurkat cells at 24 h of incubation. Viability (V) was measured by flow cytometry and is expressed as the percentage of cells non-apoptotic

Fig. 3A shows the dose-response of compound (I t) from 5 µM to 40 µM in TK6 cells (B lymphoblasts from hereditary spherocytosis) at 24 h of incubation. Cell growth (CG) was measured with the assay of MTT and is expressed as the percentage with respect to control cells at the beginning of the treatment (100%). The results are shown as the mean ± SD of triplicates.

Fig. 3B shows the effect of the compound (I t) at 20 µM and 40 µM in TK6 cells at 24 h of incubation. Viability (V) was measured by flow cytometry and is expressed as the percentage of cells non-apoptotic

Fig. 4A shows the effect of the compound (I t) at 20 µM and 40 µM in Ramos cells (B lymphocytes from Burkitt lymphoma) at 24 h of incubation. He cell growth (CG) was measured with the MTT assay and is expressed as the percentage with respect to the control cells at treatment principle (100%). The results are shown as the mean ± SD of triplicates.

Fig. 4B shows the dose-response of compound (I t) from 5 µM to 40 µM in Ramos cells at 24h incubation. Viability (V) was measured by flow cytometry and is expressed as the percentage of non-apoptotic cells.

Fig. 5A shows the dose-response of compound (I t) from 5 µM up to 40 µM in cells from patients with chronic lymphocytic leukemia (CLL) at 24 h of incubation. Be shows a representative patient. Viability (V) was measured by flow cytometry and is expressed as the percentage of cells non-apoptotic

Fig. 5B shows the dose-response of compound (I s) from 5 µM up to 40 µM in cells from patients with chronic lymphocytic leukemia (CLL) at 24 h of incubation. Be shows a representative patient. Viability (V) was measured by flow cytometry and is expressed as the percentage of cells non-apoptotic

Fig. 5C shows the dose-response of compound (I t) from 5 µM up to 40 µM in normal lymphocytes (non-tumor) B and T from healthy donors to 24 h incubation The results are shown as the average ± SD. Viability (V) was measured by flow cytometry and is expressed as the percentage of cells non-apoptotic

Examples

Unless otherwise indicated, all reactions they were carried out under argon atmosphere. Reagents Commercial were used without further purification. The reaction temperatures were controlled by a modulator of the IKA temperature. Thin layer chromatography is performed in 60 F 254 silica gel chromatopholios (Merck) and development is performed by visualization with UV light or with a solution of KMnO_ {4}. For flash chromatographic column purification, uses 35-70 silica gel as stationary phase \ mum of particle size. Phase columns were used Reverse Symmetry C_ {18} of dimensions 4.6 mm x 150 mm, 5 um (column A) of HPLC. HPLC analyzes were performed in an apparatus composed of two solvent supply pumps, a automatic injector and a variable wavelength detector and a system controller (Breeze V3.20). The analyzes by MALDI-TOF were performed using the ACH matrix. IR spectra are obtained with a Thermo spectrophotometer Nicolet Nexus and absorption bands are indicated in cm -1. The melting points were performed on a Büchi Melting Point apparatus B-540

Example 1 Preparation of 5,5'-bis (3-isopropoxyphenyl) -2,2'-bistiazole (compound (Ic))

To a glass flask (oven drying) provided with a condenser and kept under nitrogen atmosphere, was added 5,5'-diiodo-2,2'-bitiazole (190 mg, 0.45 mmol) and the tetrakis (triphenylphosphine) palladium (0) (31.2 mg, 0.027 mmol). The flask was purged three times with nitrogen and then added toluene (20 mL). To the orange solution was added a aqueous solution of 2M Na2CO3 (1.37 mL) and the acid 3-isopropoxyphenylboronic (178 mg, 0.99 mmol). The The reaction mixture was stirred at 80 ° C for 12 h. When the reaction completed, inorganic solids were filtered on a diatomaceous earth bed (Celite®) and the residue obtained was washed several times with dichloromethane, then filtered and evaporated. The residue was purified by type chromatographic column. flash (SiO2, hexane: AcOEt, 8: 2). Next, a crystallization in toluene to yield the product 5,5'-bis (3-isopropoxyphenyl) -2,2'-bistiazole as a yellow solid (95% yield). IR (NaCl), \ nu (cm -1): 3073, 2969, 2924, 1581, 1255, 1116. MS (IE) m / z, (%): 437 (M +, 100). HRMS (ESI): Calculated for C 24 H 25 N 2 O 2 S 2: 437.1351; found: 437.1347. Melting point: 202.6-203.8 ° C.

Example 2 Preparation of 4- (5'-iodo-2,2'-bistiazol-5-yl) -2-methoxyphenol (compound (Ij))

To a glass flask (oven dried) equipped with a condenser and kept under a nitrogen atmosphere, 5,5'-diiodo-2,2'-bitiazole (190 mg, 0.45 mmol) and tetrakis (triphenylphosphine) palladium were added (0) (15.6 mg, 0.013 mmol). The flask was purged three times with nitrogen and then toluene (20 mL) was added. To the yellow solution was added an aqueous solution of 2M Na2CO3 (680 µL) and 4-hydroxy-3-methoxyphenylboronic acid pinacol ester
(123 mg, 0.49 mmol). The reaction mixture was stirred at 80 ° C for 12 h. When the reaction was complete, the inorganic solids were filtered over Celite®. The obtained residue was washed several times with dichloromethane, then filtered and evaporated. The residue was purified by flash chromatographic column (SiO2, hexane: AcOEt, 8: 2). Next, a crystallization in toluene was performed to yield the product 4- (5'-iodo-2,2'-bistiazol-5-yl) -2-methoxyphenol as a yellow solid (88% yield). IR (NaCl), ν (cm -1): 3079, 2922, 2851, 1596, 1533, 1378, 1268, 917. MS (IE) m / z, (%): 416 (M + }, 100). HRMS (ESI): Calculated for C 13 H 10 N 2 O 2 S 2 I: 416.9226; Found: 416.9229. Melting point: 213.5-214.7 ° C.

Example 3 Preparation of 4- [5 '(3,4-dimethoxyphenyl) -2,2'-bistiazolyl-5-yl] -benzoate ethyl (compound (Iq))

To a glass flask (oven dried) provided with a condenser and maintained under a nitrogen atmosphere, ethyl 4- (5'-iodo-2,2'-bistiazol-5-yl) -benzoate (162 mg, 0.37 mmol) and tetrakis (triphenylphosphine) palladium (0) (15.6 mg, 0.013 mmol). The flask was purged three times with nitrogen and then toluene (20 mL) was added. To the yellow solution was added an aqueous solution of 2M Na 2 CO 3 (680 µL) and 3,4-dimethoxyphenylboronic acid
(74 mg, 0.40 mmol). The reaction mixture was stirred at 80 ° C for 12 h. When the reaction was complete, the inorganic solids were filtered over Celite®. The obtained residue was washed several times with dichloromethane, then filtered and evaporated. The residue was purified by flash chromatographic column (SiO2, hexane: AcOEt, 8: 2). Next, a crystallization was carried out in toluene to yield the product 4- [5 '(3,4-dimethoxyphenyl) -2,2'-bistiazolyl-5-yl] -benzoate as a beige solid (98% yield) . MS (IE) m / z, (%): 452 (M, 100). IR (NaCl), ν (cm -1): 3045, 2942, 2893, 1705. HRMS (IE): Calculated for C 23 H 20 O 2 N 2 S 2 }: 452.0864; Found: 452.0852. Melting point: 164.8-165.2 ° C.

Example 4 Preparation of 5- (3-Fluoro-4-methoxyphenyl) -2,2'-bistiazole (compound (Ie))

To a glass flask (oven drying) provided with a condenser and kept under nitrogen atmosphere, was added 5-iodine-2,2'-bistiazole (132 mg, 0.45 mmol) and the tetrakis (triphenylphosphine) palladium (0) (15.6 mg, 0.013 mmol). The flask was purged three times with nitrogen and then added toluene (20 mL). A yellow solution was added aqueous solution of 2M Na2CO3 (680 µL) and the acid 3-fluoro-4-methoxyphenylboronic (84 mg, 0.49 mmol). The reaction mixture was stirred at 80 ° C for 12 h When the reaction was complete, inorganic solids were filtered on Celite®. The residue obtained was washed several times with dichloromethane, then filtered and evaporated. The residue purified by flash type chromatographic column (SiO2, hexane: AcOEt, 8: 2). Then, crystallization was performed in toluene to yield the product 5- (3-Fluoro-4-methoxyphenyl) -2,2'-bistiazole as a yellow solid (42% yield). IR (NaCl), \ nu (cm -1): 3121, 2924, 1485, 1276. HRMS (ESI): Calculated for C 13 H 10 N 2 OFS 2: 293.0213; Found: 293.0221. Melting point: 171.9-172.3 ° C.

Example 5 Preparation of 4- (5'-iodo-2,2'-bistiazol-5-yl) -benzoate ethyl (compound (Ih))

Obtaining analogously to example 4 a start from 5,5'-diiodo-2,2'-bistiazole and 4-ethoxycarbonylphenylboronic acid (81% of performance). IR (NaCl), ν (cm -1): 3400, 3074, 2976, 2923, 2852, 1712, 1275, 1107, 912, 767, 692. MS (IE) m / z, (%): 442 (M +, 100). HRMS (ESI): Calculated for C 15 H 12 N 2 O 2 S 2 I: 442.9379; found: 442.9385. Melting point: 134.1-134.7 ° C.

Example 6 Preparation of 5,5'-bis [3,4- (methylenedioxy) phenyl] -2,2'-bistiazole

To a glass flask (oven dried) equipped with a condenser and kept under a nitrogen atmosphere, 5,5'-diiodo-2,2'-bistiazole (336 mg, 0.8 mmol), S-Phos (197 mg) , 0.48 mmol), tris (dibenzylidene ketone) dipaladium (0) or Pd 2 (dba) 3 (146.5 mg, 0.16 mmol), K 3 PO 4 (1.05 g, 4.97 mmol) and the 3,4- (methylenedioxy) phenylboronic acid (531 mg, 3.2 mmol). The flask was purged three times with nitrogen and then anhydrous toluene was added
(20 mL). The reaction mixture was stirred at 100 ° C for 12 h. When the reaction was complete, the inorganic solids were filtered over Celite®. The obtained residue was washed several times with dichloromethane, then filtered and evaporated. The residue was purified by flash chromatographic column (SiO2, hexane: AcOEt, 8: 2). Next, a crystallization was carried out in toluene to yield the product 5,5'-bis (3-isopropoxyphenyl) -2,2'-bistiazole as a yellow solid (67% yield). IR (NaCl), ν (cm -1): 2922, 1469, 1444, 1249. MS (IE) m / z, (%): 408 (M, 100). HRMS (EI): Calculated for C 20 H 12 N 2 O 4 S 2: 408.023893; Found: 408.023851. Melting point: 234.1-234.9 ° C.

Example 7 Preparation of 5- (2-pyridinyl) -2,2'-bistiazole (compound (Im))

To a glass flask (oven drying) provided with a condenser and kept under nitrogen atmosphere, 2-bromopyridine (58 µL, 0.61 mmol) was added, 2-trimethylstanylpyridine (0.30 mmol), and tetrakis (triphenylphosphine) -palladium (0) (116 mg, 0.1 mmol, 10 mol%). The flask was purged three times with nitrogen and then anhydrous dimethylformamide (5 mL) was added. The The reaction mixture was stirred at 80 ° C for 12 h. When the reaction was completed, inorganic solids were filtered over Celite® The obtained residue was washed several times with dichloromethane, It was then filtered and evaporated. The residue was purified by Flash type chromatographic column (SiO2, hexane: AcOEt, 9: 1, + 1% NEt_ {3}). Then, crystallization was performed in AcOEt-hexane to yield the product 5- (2-pyridinyl) -2,2'-bistiazole as a yellow solid (15% yield). IR (NaCl), \ nu (cm -1): 3104, 3077, 1581, 1463. MS (IE) m / z, (%): 245 (M +, 100), 135 (61). HRMS (ESI): Calculated for C 11 H 8 N 3 S 2: 246.0154; Found: 246.0162. Calculated for C 11 H 7 N 3 S 2 Na: 267.9974; Found: 267.9969. Melting point: 208.8-209.5 ° C.

Example 8 Preparation of 5,5'-diphenyl-2,2'-bistiazole

To a glass flask (oven drying) provided with a condenser and kept under a nitrogen atmosphere, tetrakis (triphenylphosphine) palladium (0) (130 mg, 0.12 mmol, 20 mol%) and triphenylphosphine (63 mg, 0.24 mmol) were added ,
10 mol%). The flask was purged three times with nitrogen and then anhydrous dimethylformamide (5 mL) was added. After stirring for 10 minutes at room temperature, copper (I) iodide (907 mg, 4.76 mmol), cesium carbonate (931 mg, 2.86 mmol), 2,2'-bistiazole (200) were slowly added (about 15 minutes) mg, 1.19 mmol) and iodobenzene (318 µL, 2.85 mmol). The reaction mixture was stirred at 150 ° C for 12 h. When the reaction was complete, the inorganic solids were filtered over Celite®. The obtained residue was washed several times with dichloromethane, then filtered and evaporated. The residue was purified by flash chromatographic column (SiO2, hexane: AcOEt, 9: 1). Next, a crystallization was carried out in toluene to yield the product 5,5'-diphenyl-2,2'-bistiazole as an orange-yellow solid (60% yield). IR (NaCl), ν (cm -1): 3064, 1477, 1442, 1394, 1332. MS (IE) m / z, (%): 320 (M +, 100). HRMS (ESI): Calculated for C 18 H 13 N 2 S 2: 321.0515; Found: 321.0518. Melting point: 237.4-239.0 ° C.

Example 9 Preparation of 4,4'-difluoro-5,5'-diphenyl-2,2'-bistiazole (compound (Is))

To a solution of 5,5'-diphenyl-2,2'-bitiazole (125 mg, 0.39 mmol) in acetonitrile (10 mL), Selectfluor® (276.8 mg, 0.78 mmol) was added. The reaction was stirred for 12 h at reflux temperature. The reaction was monitored by TLC (1: 4 ethyl acetate / hexane). Then, 15 mL of EtOAc was added and extracted with H2O (3x15 mL) and a saturated aqueous solution of NaHCO3 (3x15 mL). The organic extracts were dried with Na2S04, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography (SiO {2}, hexane: AcOEt, 8: 2) type to give the product 4,4'-difluoro-5,5'-diphenyl-2,2, -bistiazol as a yellow solid (100% yield, with 92% purity). MS (IE) m / z, (%): 356.9 (M +, 100). IR (NaCl), ν (cm -1): 2924, 1530, 1450, 1370, 1210, 1154, 1125, 1021. HRMS (ESI): Calculated for C 18 H 10 N 2 } S2F2: 356.0253; Found: 356.0252. Melting point: 119.5-119.9 ° C. HPLC (Column A, R t 16.553 min).

Example 10 Preparation of 4,4'-dibromo-5,5'-diphenyl-2,2'-bistiazole (compound (Ig))

To a solution of 5,5'-diphenyl-2,2'-bitiazole (60 mg, 0.18 mmol) in 1 mL of chloroform and 1.5 mL of acetonitrile is slowly added Br2 (40 µL, 0.75 mmol). The reaction is stirred for 12 h at room temperature. After this time, The mixture was filtered. A solution was added to the filtrate saturated aqueous Na 2 S 2 O 4 (10%) and the mixture is extracted with ether (3 x 25mL). The organic extracts were dried with Na 2 SO 4, filtered and evaporated under reduced pressure, obtaining a crystalline compound. The solid product is recrystallized from methylene chloride to yield the product 4,4'-dibromo-5,5'-diphenyl-2,2'-bistiazole as a yellow solid (99% yield). IR (NaCl), \ nu (cm -1): 3369, 2923. MS (IE) m / z, (%): 478 (M, 100), 480 (55), 476 (49). HRMS (ESI): Calculated for C 18 H 11 N 2 S 2 Br 2: 478.8724; found: 478.8715. Calculated for C 18 H 12 N 2 S 2 Br: 398.9619; Found: 398.9636. Melting point: 213.1-213.8 ° C.

Example 11 Preparation of 5- (3,4-dimethoxyphenyl) -5'-iodo-2,2'-bistiazole (compound (It))

Pd (PPh3) 4 (31.2 mg, 0.027 mmol), an aqueous solution of Na2CO3 (2M, 1.37 mL) and 3,4-dimethoxyphenylboronic acid (179 mg , 0.99 mmol) were added to a solution of 5,5'-diiodo-2,2'-bistiazole (190 mg, 0.45 mmol) in anhydrous toluene (20 mL). The reaction mixture was stirred at 80 ° C for 12 h, then filtered on a thin layer of Celite® and the filtrates were evaporated under reduced pressure. The residue was purified by flash column chromatography (SiO {2}, hexane: AcOEt, 8: 2) type. Next, a crystallization was carried out in toluene to yield the desired product (165 mg, 95% yield). IR (NaCl): 29 2989, 2928, 2829, 1598, 1513, 1476, 1443, 1382, 1258, 1144, 1024, 916, 836 cm -1. Melting point: 170.5-170.7 ° C. MS (EI): m / z (%): 431 (M +, 100). HRMS (ESI): Calculated for C 14 H 12 N 2 O 2 S 2 I: 430.9376; Found: 430.9373.

Example 12 Biological tests for the detection of activity antitumor

An activity exploration was carried out antitumor of compounds with formula (I) in Jurkat cells and a study of the most active compounds in the cells was performed Ramos, TK6 cells, cells from patients with leukemia chronic lymphocytic (LLC), and B and T lymphocytes from healthy donors.

Patients with LLC or healthy donors and cell isolation

Peripheral blood lymphocytes were obtained from patients with CLL or from healthy donors of the Unit of Hematology at IDIBELL- Hospital de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain. LLC was diagnosed according to standard clinical and laboratory criteria. The informed consent of all patients, according to the Bellvitge Hospital Ethics Committee. Purification was performed of the mononucleated leukocytes by a gradient of Ficoll-Hypaque (Seromed, Berlin, Germany). Purity of the LLC samples was evaluated by flow cytometry with allophycocyanin-conjugated anti-CD3 (allophycocyanin, APC) and anti-CD19 conjugated with phycoerythrin (phycoerythrin, PE) (Becton Dickinson, Frankiln Lakes, NJ, USA). The results were analyzed with a FACSCalibur and the analysis was carried out with the CellQuest program (Becton Dickinson, Mountain View, CA, USA).

Cell culture

Jurkat human cell lines (lymphocytes T from acute T-cell leukemia), Ramos (lymphocytes B of a Burkitt lymphoma) and TK6 (B lymphoblasts from hereditary spherocytosis) were obtained from the European Collection of Cell cultures.

All cell types were grown in medium RPMI 1640 containing 10% inactivated fetal serum (from veal), 1% glutamine, and 1% penicillin-streptomycin at 37 ° C in atmosphere moistened and with 5% carbon dioxide.

Reagents

The bromide of 3- (4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazole (MTT) and dimethyl sulfoxide (DMSO) from Sigma Chemicals Co. (St Louis, MO, USA). Annexin V-FITC and iodide propidium (propidium iodine, PI) were obtained from Bender MedSystems (Vienna, Austria).

Analysis of cell viability by MTT assay

Cell viability was determined using the MTT assay. Cells (0.25-0.3 * 10 5 cells / well) were incubated in a 96-well plate in the absence or in the presence of the compound of interest, in a final volume of 100 µl. 10 µL of MTT (3- (4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazole bromide) (Sigma Chemicals Co, St Louis, MO, USA) (5 mg / ml in phosphate buffered saline) , phosphate-buffered saline, PBS) to the control well at 0 h of incubation and all wells at 24 h and an additional 4 h was left. The blue MTT formazan precipitate dissolved with
100 µl of isopropanol: 1M HCl (24: 1) and optical density (OD) values were measured at 550 nm in a multiwell plate reader.

100% growth has been given cell (cell growth, CG) at the OD of the control well at 0 h of incubation. The percentage increase / decrease of the DO in the 24-hour wells were calculated by comparison with the control well from 0 h. An increase in OD correlates with an increase in cell proliferation while a decrease in OD is indicative of induction of apoptosis.

The MTT test offers a convenient and quantitative to assess the response of a cell population to external factors, which may be an increase in growth cellular, no effect, or a decrease in growth due to necrosis or apoptosis. The yellow MTT (bromide of 3- (4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazole) It is reduced to formazan blue in the mitochondria of living cells. A solubilization solution is added to dissolve the product Insoluble blue formazan to a colored solution. Absorbance of this colored solution can be quantified by measuring it at a certain wavelength with a spectrophotometer. These reductions take place only when reductase enzymes mitochondrials are active, and therefore their conversion is used frequently as a measure of viable (live) cells. When the amount of formazan blue produced by cells treated with the agent is compared to the amount produced by the control cells (untreated), the effectiveness of the agent in causing cell death is deduced through a dose-response curve. For each cell type, a linear relationship between the number is established of cells and absorbance, allowing direct quantification and exact changes in proliferation.

Analysis of apoptosis by flow cytometry

0.25-0.3 * 10 6 was washed cells in phosphate buffered saline saline, PBS), were resuspended in 100 µl of binding buffer of annexin and incubated with 1 µl of annexin V-Fluorescein-5-isothiocyanate (FITC). After a 20 min incubation in the dark to room temperature, 100 µl of binding buffer of annexin with 5 µl of propidium iodide (propidium iodide, PI) (20 µg / ml) just before analysis by flow cytometry. The data were analyzed with the Cell Quest software program (Becton Dickinson) In the case of the compound (I t), the cell viability through exposure analysis of the phosphatidylserine and the PI input, and is expressed as the percentage of annexin-V and double PI cells negative In the case of the compound (I s), the apoptosis through a reduction in cell size ("cell forward scatter ", FSC) and an increase in cellular complexity ("cell side scatter", SSC).

Apoptosis, or programmed cell death, is a general mechanism of the immune system for cell removal unwished. It is characterized by the condensation of chromatin, a reduction in cell volume, and a cut of the DNA carried out by endonucleases that results in length fragments oligonucleosomal Apoptosis is also accompanied by a loss. of the asymmetry of the phospholipid membrane, resulting in the phosphatidylserine exposure on the cell surface. The Phosphatidylserine expression on the cell surface plays a important role in the recognition and elimination of cells apoptotics that macrophages carry out. This is one of the earliest events of the apoptotic process. The method for apoptotic cell detection by flow cytometry uses annexin V binding to fluorescein isothiocyanate (or other fluorochromes) to phosphatidylserine.

In addition, the plasma membrane is disturbed during late apoptosis but also during necrosis, since It becomes permeable to substances such as PI. The PI is sandwiched between double stranded nucleic acids and is a molecule fluorescent with a molecular weight of 668.4 Da that can be used to dye the DNA. PI is excluded by viable cells but can penetrate the cell membranes of dying cells and dead.

Therefore, viable cells are Annexin-V and PI negative double, apoptotic Early are annexin-V positive and PI negative while late apoptotic cells are annexin-V and double positive PI. These three populations are indicative of apoptosis. A fourth population of Positive PI cells correlates with necrotic cells.

Results 1. Exploratory test in Jurkat cells

An exploration of the effect of the compounds from (I_ {a}) to (I_ {v}) at 20 µM during an incubation 24 h was performed on Jurkat cells (T lymphocytes from of an acute T-cell leukemia). The cells were chosen Jurkat among other leukemic tumor cell lines because They have the mutated p53 protein.

Compounds from (I_ {a}) to (I_ {v}) were dissolved in the minimum amount of DMSO necessary for They will be completely dissolved. Cell viability was measured with the MTT methodology. It was verified that DMSO alone did not decrease cell viability In this way, all the observed effects in cell viability they were due to the activity of these compounds.

Cell viability is expressed as the percentage with respect to the control cells at the beginning of the incubation (0 h).

The results obtained are summarized in the Table 2 and were calculated with the formula:

(MTT compound (I) at 24 h - MTT Control at 0 h) / (MTT control at 24 h - MTT Control at 0 h) x 100

The term MTT in the above formula means the OD of the sample minus the OD of the blank (culture medium).

A value of 100% is indicative of non-effect, neither in cell proliferation nor apoptosis Values between 100 and 0% are indicative of inhibition of cell proliferation while negative values indicate apoptosis

The compounds (Ia) - (It) have the structure indicated in Table 1. The compound (Iu) is a compound of formula (I) where R 1 = R 2 = 2-naphthyl and R 3 = R 4 = H. The compound (Iv) is a compound of formula (I) where R 1 = R 2 = phenyl and R 3 = R 4 = H.

In the table: "+" means activity normal; "++" means good activity and "+++" means very good activity

TABLE 2

9

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2. Study of cell viability in cells Jurkat, Ramos, TK6 and LLC

The most active compounds were studied subsequently in Jurkat cells and other B cell lines leukemia such as Ramos cells (with mutated p53) and cells TK6 (with wild, non-mutated p53). In addition, the effect of these compounds was tested in primary cells of patients with chronic lymphocytic leukemia (CLL).

These different cell types were incubated with these compounds at 20 µM for 24 h and the viability Cellular was measured with the MTT assay and by flow cytometry.

The results of the MTT method are summarized in Table 3 and were calculated as in Table 2.

The results of flow cytometry are express as the effect of each compound at 20 µM with respect to untreated cells (control). Cell viability is expressed as the percentage of double negative cells for annexin-V and PI. In the case of the compound (I_ {s}), cell viability is expressed as the percentage of high size cellular (FSC) and low cellular complexity (SSC).

A MTT value of 100% is indicative of non-effect, neither in cell proliferation nor apoptosis MTT values between 100 and 0% are indicative of inhibition of cell proliferation while values Negatives indicate apoptosis.

Cytometry values below 100% They are indicative of apoptosis.

In Table 3, citom. It means cytometry.

TABLE 3

10

Therefore, the results show that these compounds induce inhibition of cell proliferation and that some of them induce apoptosis in these same cells.

3. Dose-response study of compounds (Is) and (It)

The effect of the two proapoptotic compounds (Is) and (It) were determined in several tumor lines. The study of dose-response was performed using cancer cells with wild p53, such as leukemic lines (TK6), of neck cancer uterine (HeLa) and neuroblastoma (SH-SY-5Y). In addition, it also they used tumor cells with mutated p53, as leukemic lines (Jurkat and Ramos) and colon cancer cells (HT-29). The study was completed using cells primary patients of CLL patients and donor cells healthy.

Cell viability was measured with two methodologies:

-

He MTT test and is expressed as the percentage with respect to control cells at the beginning of incubation.

-

Flow cytometry and is expressed as the percentage of non-apoptotic cells with respect to the cells control.

Jurkat cells (which are T lymphocytes with p53 mutated were incubated with a dose range from 5 to 40 µM of both compounds for 24 hours. The compounds (It) and (Is) induced apoptosis in a dose-dependent manner measured by MTT (cf. Fig. 1A and 2A respectively) and by cytometry of flow (cf. Fig. 1B and 2B respectively).

TK6 cells (which are B lymphoblasts with p53 wild) were incubated with a dose range from 5 to 40 µM of compound (It) for 24 hours. A trial of flow cytometry with doses of 20 and 40 µM while The entire dose-response curve was studied with the MTT test. The compound induced apoptosis in a way dose-dependent measured by MTT (cf. Fig. 3A) and by flow cytometry (cf. Fig. 3B).

Ramos cells (which are B lymphocytes with mutated p53) were incubated with a dose range from 5 to
40 µM of compound (It) for 24 hours. An MTT assay with doses of 20 and 40 µM was performed while the dose-response curve was studied by flow cytometry. Compound (It) induced apoptosis measured by MTT (cf. Fig. 4A) and by flow cytometry (cf. Fig. 4B), especially at high doses.

LLC cells (from 4 patients different) were incubated with a dose range from 5 to 40 µM of compound (It) for 24 hours. The compound (Is) was tested on LLC cells (from a patient) using the same range of dose. The compound (It) (cf. Fig. 5A) and the compound (Is) (cf. Fig. 5B) induced apoptosis measured by flow cytometry.

B and T lymphocytes from healthy donors (n = 2) are incubated with a dose range of 5 to 40 µM of the compound (It) for 24 hours. The compound induced apoptosis in the cells B but not in T cells (cf. Fig. 5C). These results indicate that B cells are much more sensitive than T cells to the compound-induced apoptosis (It). This differential effect is of great interest in B cell neoplasms.

The IC 50 at 24 hours was calculated for compound (Is) and (It) using the MTT method and by cytometry of flow and results are expressed in Table 4. ND indicates undetermined. N indicates the number of experiments made.

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TABLE 4

eleven

These results show that apoptosis induced by these bistiazoles is independent of p53, a important difference from most drugs used in cancer therapy, which induce cell cycle arrest and Apoptosis through the activation of p53.

Claims (16)

1. Compound of formula (I) or a salt pharmaceutically acceptable thereof, or a solvate thereof,

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12

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where: R_ {1} is selected from the group consisting of: phenyl, optionally mono-, di-, or tri-substituted by a radical independently selected from the group that It consists of: F, Cl, Br, I, (C 1 -C 4) -alkyl, N, N- (C 1 -C 4) -alkylamino, hydroxyl, (C 1 -C 4) -alkoxy, phenoxy, methylenedioxy, trifluoromethoxy, trifluoromethyl, carboxy, 2- (2-methoxyethoxy) ethoxy, and (C 1 -C 4) -alkoxycarbonyl; 2-thiazolyl; 2-pyridinyl; 2,2'-bipyridinyl; 2,2'-bistiazole; naphthyl; 4-phenoxyphenyl and isoquinolyl. R2 is selected from the same group of R2 and also independent of H and I; Y R_ {3} and R_ {4} are selected regardless of the group consisting of H, Br and F; with the proviso that the compound (I) is not one of the following compounds: Compound (I) with R 1 = R 2 = phenyl, and R 3 = R 4 = H; Compound (I) with R1 = R2 = 2-naphthyl, and R 3 = R 4 = H; Compound (I) with R1 = R2 = 4-trifluoromethylphenyl, and R 3 = R 4 = H; Compound (I) with R1 = R2 = 4-butoxyphenyl, and R 3 = R 4 = H; or Compound (I) with R1 = R2 = 4-ethoxyphenyl, and R 3 = R 4 = H.

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2. Compound according to claim 1, wherein R1 is selected from the group consisting of: phenyl, optionally mono-, di-, or tri-substituted by a radical independently selected from the group consisting of: F, Cl, Br , I, (C 1 C 4) -alkyl, N, N-dimethylamino, methoxy, ethoxy, isopropoxy, phenoxy, methylenedioxy, carboxy, and ethoxycarbonyl;
2-thiazolyl; 2-pyridinyl; 2,2'-bipyridinyl and 2,2'-bistiazole; and R2 is selected from the same group of R2 or is H. 3. Compound according to claim 2, wherein R_ {1} and R2_ are independently selected from the group that consists of: 3-isoproproxyphenyl, 3-chlorophenyl, 4-ethoxycarbonylphenyl, 4-ethylphenyl, 4-carboxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 3,4-ethoxyphenyl, 4- (dimethylamino) phenyl, 3-isopropylphenyl, 3-chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4- (methylenedioxy) phenyl, 4-phenoxyphenyl, 3,4-dimethoxyphenyl, 2,4-difluorophenyl, 2-thiazolyl, 2,2'-bipyridinyl, and 2-pyridinyl. 4. Compound according to claim 3, wherein R1 is selected from the group consisting of: 3-isoproproxyphenyl,
3-chlorophenyl, 4-ethylphenyl, 4-ethoxycarbonylphenyl, 4-methoxyphenyl and 3,4-dimethoxyphenyl. 5. Compound according to any of the claims 1-4, wherein R1 and R2 are same. 6. Compound according to any of the claims 1-4, wherein R2 is H. 7. Compound according to any of the claims 1-6, wherein R 3 and R 4 are H. 8. Compound according to any of the claims 1-6, wherein R 3 and R 4 is F.

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9. Compound according to claim 1, which is select from the following table: 13 10. Compound of formula (I), or a salt pharmaceutically acceptable thereof, or a solvate thereof, to its use in the therapeutic treatment of cancer in a mammal, including the human being. fifteen where: R_ {1} is selected from the group consisting of: phenyl, optionally mono-, di-, or tri-substituted by a radical independently selected from the group that consists of: F, Cl, Br, I, (C 1 C 4) -alkyl, N, N- (C 1 C 4) -alkylamino, (C 1 C 4) -alkoxy, phenoxy, methylenedioxy, trifluoromethoxy, trifluoromethyl, hydroxy, carboxy, 4-phenoxyphenyl, and (C 1 C 4) -alkoxycarbonyl; 2-thiazolyl; 2-pyridinyl; 2,2'-bipyridinyl; 2,2'-bistiazole; naphthyl; 4-phenoxyphenyl and isoquinolyl; R2 is selected from the same group as R1 and also independently of H and I; Y R_ {3} and R_ {4} are selected regardless of the group consisting of H, Br and F. 11. Compound according to claim 10, for use in therapeutic treatment against a cancer selected from group consisting of: leukemia, lymphoma, neck carcinoma uterine, colon cancer and neuroblastoma. 12. Compound according to claim 11, for use in the therapeutic treatment of leukemia or lymphoma. 13. Compounds according to claim 12, for use in the therapeutic treatment of leukemia or lymphoma, which are B cell neoplasms 14. Use of the compound as defined in any of claims 1-9, for the preparation of a medication for the therapeutic treatment of cancer in a mammal, including the human being. 15. Pharmaceutical composition comprising a therapeutically effective amount of the compound as defined in any of claims 1-9, together with appropriate amounts of pharmaceutically excipients or carriers acceptable. 16. Procedure for preparing a compound of formula (I) as defined in any of the claims 1-9, which includes: a) submit a compound of formula (II) 16 to a Suzuki coupling with a compound of formula R 1 B (OH) 2, in the presence of a palladium catalyst to give a compound of formula (I) with R 1 = R 2 and R 3 = R 4 = H; or, alternatively, b) subjecting a compound of formula (II) to a Suzuki coupling first with a compound of formula R 1 B (OH) 2, in the presence of a catalyst of palladium, and subsequently with a compound of formula R2 B (OH) 2, in the presence of a catalyst of palladium, to provide a compound of formula (I) with R1 different from R2 and R3 = R4 = H; or, alternatively, c) subject to a compound of formula (III) 17 to a Suzuki coupling with a compound of formula R 1 B (OH) 2, in the presence of a palladium catalyst, to give a compound of formula (I) with R2 = R3 = R4 = H; or, alternatively, d) subject to a compound of formula (IV) 18 to a Stille coupling with a compound of formula R 1 X, in the presence of a catalyst of palladium, to give a compound of formula (I) with R 1 = R 2 and R 3 = R 4 = H; or, alternatively, e) subjecting a compound of formula (IV) to a Stille coupling first with a compound of formula R 1 X, in the presence of a palladium catalyst, and subsequently with a compound of formula R2 X, in the presence of a palladium catalyst, to provide a compound of formula (I) with R 1 different from R 2 and R 3 = R 4 = H; or, alternatively, f) subject to a compound of formula (V) 19 to a Stille coupling with a compound of formula R 1 Sn (CH 3) 3, in presence of a palladium catalyst, to give a compound of formula (I) with R2 = R3 = R4 = H; or, alternatively, g) subject to a compound of formula (VI) twenty to an oxidative coupling with a compound of formula R 1 I, in the presence of a catalyst of palladium, to give a compound of formula (I) with R2 = R3 = R4 = H; or, alternatively, h) subjecting a compound of formula (VI) to a oxidative coupling first with a compound of formula R1I, presence of a palladium catalyst, and subsequently with a compound of formula R 2 I, in the presence of a catalyst of palladium, to provide a compound of formula (I) with R1 different from R2 and R3 = R4 = H; Y i) optionally submit the compounds obtained in any of the previous procedures from a) to h) to a fluorination reaction with a fluorinating agent or to a bromination reaction with a brominating agent to provide compounds of formula (I) wherein R 3 and / or R 4 are F or Br; Y j) optionally, convert the compounds obtained in any of the procedures a) to i) in a salt pharmaceutically acceptable by reacting compound (I) with a appropriate pharmaceutically acceptable acid or with a base pharmaceutically acceptable appropriate to render the corresponding pharmaceutically acceptable salt; where: R 1, R 2, R 3, and R 4 have the same meaning as in claim 1; Y X is a halogen atom.