ES2303444A1 - (2,3-dihydro-5h-1,4-benzodiheteroepin-3-il) purines with antitumoral activity. (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

(2,3-dihydro-5h-1,4-bezodiheteroepin-3-yl) purines with antitumor activity that find application in the treatment of tumors in animals and humans, as well as a method for the preparation of the compounds of the invention . (Machine-translation by Google Translate, not legally binding)

Description

(2,3-dihydro-5 H -1,4-benzodiheteroepin-3-yl) purines with antitumor activity.

Field of the Invention

The invention relates to compounds with antitumor properties against breast, lung, colorectal, pancreas and myeloproliferative syndromes in animals and human beings, as well as with a method for the preparation of compounds of the invention.

Background of the invention

In 2004 in Europe, there was an estimate of 2,886,800 cases of diagnosed cancers and 1,711.00 of deaths caused by cancer. The type of cancer with the highest incidence was lung cancer (13.3% of all cancers), followed by colorectal (13.2%) and breast cancer (13%). Lung cancer was the one that produced the highest number of deaths (341,800), followed by colorectal (203,700), stomach (137,900) and breast (129,900). With an estimate of 2.9 million new cases (54% in men and 46% in women) and 1.7 million deaths (56% in men, 44% in women) each year, cancer remains a problem of First-rate public health in Europe. On the other hand, the aging of the European population will make these figures even increase, even if the percentages by age groups remain constant [Boyle, P .; Ferlay, J. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2005 , 16 , 481-488].

Currently, research on therapy anti-cancer includes, in a very general way, the following strategies for pharmacological suppression of cell phenotypes malignant:

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Inhibition therapies in DNA synthesis: They cause cell death due to arrest of cell metabolism, growth and proliferation (therapies cytotoxic).

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Therapies that cause injuries in DNA, capable of activating the physiological processes that They lead to apoptosis.

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Therapies that act at the level of cell cycle, on regulatory or effector proteins: This approach seeks to stop the cycle, mainly in its phase G_ {1}, from where the cell can proceed to its differentiation. It is not about producing cell death but the Reversal of the malignant phenotype.

Antimetabolites belong to the first group of drugs. Its mission is to block DNA synthesis by inhibiting enzymes involved in its replication [Gómez-Vidal, JA; Campos, J .; Marchal, JA; Boulaiz, H .; Gallo, MA; Carrillo, E .; Espinosa, A .; Aranega, A. Curr. Topics Med. Chem . 2004 , 4 , 175-202]. Among them, 5-fluorouracil (5-FU) is used in the treatment of solid tumors, especially in those of the gastrointestinal tract. However, 5-FU causes serious toxic effects derived from its distribution in bone marrow, gastrointestinal tract, central nervous system and skin. In order to increase the selectivity of this drug by tumor tissues and thus reduce its side effects, numerous derivatives have been designed in which it joins structural fragments that act as transporters to the site of action. These derivatives include ftorafur [1- (2-tetrahydrofuranyl) -5-fluorouracil], which is twice as potent and five times less toxic than 5-FU. However, an improvement in its selectivity was still necessary.

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one

In 1996, the synthesis and antiproliferative properties of O, N- acetals of acylonucleoside nature with a general structure of 1- [3- (2-hydroxyethylhetero) -1-alkoxypropyl] -5-fluorouracils were published (see compounds 1 and 2 ) [Campos, J .; Pineda, MJ; Gómez, JA; Train, A .; Trujillo, MA; Gallo, MA; Espinosa, A. Tetrahedron 1996 , 52 , 8907-8924].

Compounds 1 and 2 had an in vitro activity superior to that of 5-FU against certain tumor lines. The first of these, with an IC 50 of about 22 µM, against human carcinoma cells of the larynx HEp-2 (approximately twice lower than that of 5-FU). The second one, with IC 50 of 9.4, 3.9 and 5.8 µM against the tumor lines CX-1 (human colon carcinoma), MX-1 (human breast carcinoma) and LZ -1 (human lung carcinoma).

Compounds with the hydroxyl group blocked, and therefore not phosphorylable, they were designed to act as 5-FU prodrugs. Its hydrolysis in tissues Tumor releases two cytotoxic substances, 5-FU and acrolein Cytotoxic activity tests of these compounds on HT-29 cells (human colon carcinoma) showed compound 10 as more interesting (IC 50 = 70 µM) which, even so, is eight times less active than the 5-FU. In a study on capacity differentiator in cultures of RD cells (human rhabdomyosarcoma), both 10 and 5-FU produced an increase of certain differentiation markers (such as demining, a-actinin and tropomyosin) more pronounced in 10 than, In addition, it showed lower cellular toxicity than 5-FU.

A subsequent approach consisted of increasing lipophilicity by incorporating aromatic rings in certain positions of these structures [Saniger, E .; Campos, JM; Train, A .; Marchal, JA; Suárez, I .; Aranega, A .; Choquesillo, D .; Niclós, J .; Gallo, MA; Espinosa, A. Tetrahedron 2003 , 59 , 5457-5467; Saniger, E .; Campos, JM; Train, A .; Marchal, JA; Boulaiz, H .; Aranega, A .; Gallo, MA; Espinosa, A. Tetrahedron 2003 , 59 , 8017-8026]. Thus, several families of O, N- acetal compounds were prepared.

The increase in lipophilicity, had as consequently a decrease in the IC 50 values versus MCF-7 human breast carcinoma cells, as it follows from the comparison between the activity of compound 1, with an IC 50 greater than 70 µM, and that of the compounds 13a-d.

2

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3

On these products, they were carried out capacity studies to induce apoptosis. Paclitaxel (Taxol®), with 43% induction in cancer cell cultures of breast, is one of the few known examples of inductors of apoptosis since most cytotoxic drugs cause it only in a small fraction of the tumor cells. Fits highlight that, among the developed compounds, there are some that exceeded the induction value of apoptosis in cultures paclitaxel breast cancer cells at concentrations equal to those of its IC 50s. The most powerful inductors of apoptosis against the tumor line MCF-7 cancer of breast were compounds 12 (54.33 and 35.49% at 24 and 48 h respectively), 13a (59.90% at 24 h), 14d (40.08 and 46.73%), and 15 (57.33 and 51.37%).

Another very important fact in the activity of these compounds, which indicates the progress of research in the group towards non-cytotoxic therapies, is their ability to accumulate cells in phases of the cell cycle other than 5-FU and its prodrug ftorafur. The latter retain the S-phase cells, where thymidylate synthase enzyme is inhibited, while compounds 12, 14a-d, and 15 do so in the G0 / G1 and 13b or 13c phase in the G_ { 2} / M (to the detriment of the population in phase S). This indicates the ability of said compounds to be drugs per se (with the exception of 13d, with a pattern similar to 5-FU in cell cycle arrest).

The authors of the present invention have discovered, after laborious investigation, that certain modifications in the structure of the compounds described in the background of this invention, show a significant improvement of antiproliferative activity

Brief Description of the Invention

The invention provides in its first objective a family of compounds that are represented, depending on its hemiaminal junction, by formulas I and / or II:

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where the R group can be an electron-donor group (OH, OR, OMe, NH2, NHCOR '), electronically neutral (H, alkyl) or an electron-attractant group (NO2, CF3) , COR ') in positions 7' and / or 9 '. The structures are characterized by presenting a seven-member cycle, fused to a benzene ring, with two heteroatoms in relative positions 1.4 and attached through their position 3 to the nitrogen atom in position 9 '(type I compound) or through position 7 '(compound type II) of a pubic base. Compounds in this family have very low levels of
toxicity.

In a second objective, the invention provides the use of compounds of formula I and II in clinical trials About cancer patients.

A further objective of the invention is in providing pharmaceutical formulations that comprise at least a compound of formula I and / or II.

The invention provides, in another object, a method for the preparation of the compounds of formula I and / or II.

Detailed description of the invention

In its first objective the invention provides a family of compounds that respond, depending on their binding hemiaminal, to the general formula I and / or II:

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6

where,

X

It represents oxygen atom, sulfur atom or a sulfonyl group, an bencensulfanilamino group substituted ortho, meta or para by a nitro or amino group, or a fluorenylmethyl group carbamate (FMOC-N {tertiary});

Y

represents a radical selected from the group formed by benzyl (mono- or disubstituted), benzyloxy (mono- or di-substituted), phenoxy (mono- or di-substituted), phenylthio (mono- or di-substituted), cyclohexylmethyloxy, allyloxy, allyl, chlorine, bromine or iodine;

Z

represents a hydrogen or an atom of chlorine;

R

well represents a radical selected from the group formed by H, alkyl, an electron donor group as hydroxyl, alkoxy, amino, acylamino, or a group electron-attractant like a halogen, trifluoromethyl, acyl, at positions 7 'and / or 9' of the ring benzene fused to the seven-member heterocycle.

Compounds belonging to family I and II, in addition to acting as antiproliferative agents against various strains of cancers, are characterized by presenting minimum toxicity levels against healthy cell lines [normal breast epithelial line (MCF-10A) e intestinal bowel (IEC-6)].

Type I compounds of the invention are shown in Table 1:

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TABLE 1

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Type II compounds of the invention are shown in Table 2:

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TABLE 2

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In a second objective, the invention provides the use of the compounds of formula I and / or II in medicine. Specifically, the compounds of formula I and / or II are claimed For use in medicine. In a particular embodiment, the invention provides the compounds of formula I and / or II for the cancer treatment, preferably breast cancers, lung, colorectal, pancreas and myeloproliferative syndromes.

On the other hand, the use of a compound of formula I and / or II in the preparation of a medicament. In a particular embodiment, the compounds of formula I and / or II they are used in the development of a cancer medicine, preferably breast, lung, colorectal cancers, pancreas and myeloproliferative syndromes.

In its third objective, the invention provides pharmaceutical formulations comprising as active ingredient at least one compound of formula I and / or II. These formulations Pharmaceuticals may contain one or more excipients and / or substances Conveyors Furthermore said formulations may contain any other active ingredient that has properties anti-cancer

Excipients, transport substances and auxiliary substances have to be pharmaceutical and pharmacologically tolerable, so that they can be combined with other components of the formulation or preparation and do not exert adverse effects on the treated organism. The compositions Pharmaceuticals or formulations include those that are suitable for oral or parenteral administration (including subcutaneous, intradermal, intramuscular and intravenous), although the best route of Administration depends on the patient's condition. Formulations They can be in the form of single doses. The formulations are prepared according to known methods in the field of pharmacology. The quantities of active substances for administered may vary depending on the particularities of the therapy.

The invention also provides a method for the preparation of the compounds of formula I and II: the process comprises mixing the derivative ( RS ) -3-methoxy-2,3-dihydro-5 H -1,4-benzodiheteroepinic with the pyric base , Lewis acid, trimethylchlorosilane, 1,1,1,3,3,3-hexamethyldisilazane in dry acetonitrile at a temperature between -5 and 5 ° C under argon, and after allowing the suspension to reach room temperature, it is heated the suspension at a temperature between 40 and 45 ° C for 16-24 h. In the process for obtaining ( RS ) -9- or 7- (1,1-dioxo-2,3-dihydro-5 H -4,1-benzoxatiepin-3-yl) -9 H - or -7 Substituted H -purines can be carried out in the following two ways: (a) by condensation between ( RS ) -3-methoxy-2,3-dihydro-5 H -4,1-benzoxatiepine and the substituted purine , according to the procedure specified above, and subsequent oxidation of the sulfur atom in the compound condensed with Oxone®, as detailed in the synthesis of compound ( RS ) -1,1-dioxo-2,3-dihydro-5 H -4,1-benzoxatiepine or compound 22, code MN / 92B; and (b) by condensation between the previously oxidized compound such as ( RS ) -1,1-dioxo-3-methoxy-2,3-dihydro-5 H -4,1-benzoxatiepine and the substituted purine.

Cell cultures Cellphone line

The human cell line derived from cancer Breast MCF-7 was provided by Dr. N. Olea of Institute of Tumoral Biology Sánchez Mora del Hospital University of Granada.

Growing conditions

Cell cultures were performed in the cabin laminar flow (Micro-V, Telstar, Spain) under sterility conditions The sterile culture jars (Falcons of 25 or 80 cm 2 of useful surface) were maintained in stove at 37 ° C, atmosphere at 5% CO2 and 90% humidity. During cell culture, the cells had to be reseeded in new Falcons as saturation was reached, peeling them off the surface of the culture jars by a solution of PBS-EDTA (0.02%) or Trypsin (10x). They were then centrifuged at 600 g for 5 minutes and washed twice with PBS, resuspending them in culture medium.

Dubelcco's medium was used for cultivation Modified Eagle (DMEM) (Gibco, USA) (13.37 g of base medium), supplemented with 10% inactivated bovine fetal serum (Flow, Kingdom United) in moist heat between 50 and 60 ° C for 30 minutes. The middle it was buffered with NaHCO3 and 1M Hepes (Flow) buffer pH 7.2 and was supplemented with 40 mg / L of gentamicin (S.A. Antibiotics), 500 mg / L of ampicillin (Antibiotics S.A.), 20 mL of 200 mM L-glutamine (Flow) and double distilled water, c.s.p.  up to 1000 mL. Once the culture medium was prepared, it was filtered with 0.22 µM sterile Millex filters (Millipore, France) and se He added to the jars.

Cell freezing method

For cell freezing, the cells are they took off from the surface of the Falcons by a solution of PBS-EDTA (0.02%) or Trypsin (10x), centrifuged at 600 g for five minutes and washed twice with PBS. Pellet  cell was resuspended in freezing medium at a rate of 0.5 x 10 6 cells per mL being immediately introduced into cryotubes and these in the freezer at -80ºC for 24 h, being definitely stored in liquid nitrogen after this period.

Freezing medium : fetal bovine serum (Sigma, SL), inactivated in humid heat for 30 minutes, and dimethylsulfoxide (DMSO).

Cell defrosting method

The MCF-7 cell line Cryopreserved in liquid nitrogen was thawed in moist heat. Immediately after, the cells were resuspended in PBS sterile, being centrifuged at 1500 rpm for five minutes, Repeating the process twice to remove the remains of DMSO. The pellet was resuspended in previously filtered culture medium and The cells were deposited in culture bottles.

Modes of realization

The following examples are presented as illustration of the present invention:

Compounds 16 [code MB-90A, ( RS ) -6-chloro-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine] and 23 [code MB- 90B, ( RS ) -6-chloro-7- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -7 H -purine] : SnCl 4 / CH 2 Cl_ { 2} (6.66 mL, 3.63 mmol) in dry acetonitrile (6 mL) is added with syringe, under argon atmosphere, to a suspension of ( RS ) -3-methoxy-2,3-dihydro-5 H -1,4-benzodioxepino [Saniger, E .; Campos, JM; Train, A .; Marchal, JA; Suárez, I .; Aranega, A .; Choquesillo, D .; Niclós, J .; Gallo, MA; Espinosa, A. Tetrahedron 2003 , 59 , 5457-5467] (1 g, 5.55 mmol), 6-chloropurine (857 mg, 5.54 mmol), containing trimethylchlorosilane (0.55 mL, 4.35 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (0.88 mL, 4.22 mmol) in dry acetonitrile (22 mL) at 0 ° C. After 10 min. at 0 ° C, the suspension was allowed to reach room temperature and heated at 45 ° C for 16 h. After cooling, the reaction mixture was diluted with water (20 mL), and NaHCO3 was added until the pH was neutral. The aqueous phase was extracted with ethyl acetate (2 x 10 mL) and the organic phase was dried (Na2SO4). After filtration, the solvent was removed on a rotary evaporator and the residue was purified by flash chromatography using a mixture of EtOAc / hexane: 6/4 as eluent. The first fraction weighed 380 mg (22.6%) with the appearance of white amorphous powder and was identified as 16, code MB-90A; mp .: 133-134 ° C. R f (EtOAc): 0.42. 1 H NMR (400 MHz, CDCl 3) δ 8.78 (s, 1H, H pur); 8.44 (s, 1H, H pur); 7.31 (dt, 1H, J = 1.4, 7.5 Hz, H arom); 7.22 (d, 1H, J = 7.5 Hz, H arom); 7.12 (d, 1H, J = 8.6 Hz, H arom); 7.11 (t, 1H, J = 7.5 Hz, H arom); 6.32 (dt, 1H, J = 2.2, 6.2 Hz, H-3); 4.89 (s, 2H, H-5); 4.62 (dd, 1H, J = 2.2, 13.0 Hz, H-2); 4.43 (dd, 1H, J = 6.2, 13.0 Hz, H-2). 13 C NMR (100 MHz, CDCl 3) δ 158.79; 154.67; 152.44; 151.58; 143.88; 137.41; 132.75; 124.38; 129.36; 130.13; 129.36; 84.17; 73.57; 69.10. HR LSIMS (NOBA matrix) calculated for C 14 H 11 ClN 4 O 2 Na (M + Na) +:
325.0468; Found: 325.0468. Analysis for C 14 H 11 ClN 4 O 2: Calculated: C 55.55; H 3.66; N 18.51. Found: C 55.63; H 3.80; N, 18.46.

The second fraction weighed 290 mg (17.3%) with the appearance of amorphous white powder and was identified as 23, code MB-90B; mp .: 138-139 ° C. R f (EtOAc): 0.17. 1 H NMR (400 MHz, CDCl 3) δ 8.90 (s, 1H, H pur); 8.70 (s, 1H, H pur); 7.31 (dt, 1H, J = 1.6, 7.7 Hz, H arom); 7.22 (d, 1H, J = 7.2 Hz, H arom); 7.13 (d, 1H, J = 8.1 Hz, H arom); 7.10 (t, 1H, J = 7.5 Hz, H arom); 6.55 (dd, 1H, J = 2.2, 5.2 Hz, H-3); 4.80 (dd, J = 9.0, 14.0 Hz, 2H, H-5); 4.66 (dd, 1H, J = 2.2, 13.1 Hz, H-2); 4.40 (dd, 1H, J = 5.3, 13.0 Hz, H-2). 13 C NMR (100 MHz, CDCl 3) δ 162.07; 158.72; 152.98; 147.61; 143.26; 130.32; 130.26; 129.45; 124.66; 120.80; 85.08; 74.09; 68.42. HR LSIMS (NOBA matrix) calculated for C 14 H 11 ClN 4 O 2 Na (M + Na) +: 325.0468; Found: 325.0468. Analysis for C 14 H 11 ClN 4 O 2: Calculated: C 55.55; H 3.66; N 18.51. Found: C 55.43; H 3.90; N 18.86.

Compound 17 [BDM-69C code, ( RS ) -6-bromo-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine] : SnCl 4 /
CH 2 Cl 2 (1.16 mL, 1.11 mmol) in dry acetonitrile (3 mL) is added with syringe, under argon atmosphere, to a suspension of ( RS ) -3-methoxy-2, 3-dihydro-5 H -1,4-benzodioxepino [Saniger, E .; Campos, JM; Train, A .; Marchal, JA; Suárez, I .; Aranega, A .; Choquesillo, D .; Niclós, J .; Gallo, MA; Espinosa, A. Tetrahedron 2003 , 59 , 5457-5467] (0.200 g, 1.11 mmol), 6-bromopurine (0.221 g, 1.11 mmol), containing trimethylchlorosilane (143 µL, 1.11 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (233 µL, 1.11 mmol) in dry acetonitrile (3 mL) at 0 ° C. After 10 min. at 0 ° C, the suspension was allowed to reach room temperature and was heated at 45 ° C for 24 h. After cooling, the reaction mixture was neutralized with a 5% aqueous solution of NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 20 mL) and the organic phase dried (Na2SO4). After filtration, the solvent was removed on a rotary evaporator and the residue was purified by flash chromatography using a mixture of CH2Cl2 / MeOH: 9.8 / 0.2 as eluent. The fraction weighed 0.063 mg (16.4%) with the appearance of white amorphous powder and was identified as 17, code BMD-69C; mp: 153-154 ° C. R f (CH 2 Cl 2 / MeOH: 9.5 / 0.5): 0.56. 1 H NMR (300 MHz, CDCl 3) δ 8.72 (s, 1H, H pur); 8.45 (s, 1H, H pur); 7.31 (dt, 1H, J = 1.8, 7.2 Hz, H arom); 7.21 (dd, 1H, J = 1.8, 7.2 Hz, H arom); 7.12 (d, 1H, J = 7.2 Hz, H arom); 7.08 (dt, 1H, J = 1.2, 7.2 Hz, H arom); 6.31 (dd, 1H, J = 2.4, 6.2 Hz, H-3); 4.89 (s, 2H, H-5); 4.63 (dd, 1H, J = 2.4, 13.0 Hz, H-2); 4.43 (dd, 1H, J = 6.2, 13.0 Hz, H-2). 13 C NMR (75 MHz, CDCl 3) δ 158.56; 153.20; 153.13; 150.77; 144.53; 144.40; 135.05; 130.90; 130.13; 125.15; 121.54; 84.97; 74.33; 69.88. HR LSIMS (NOBA matrix) calculated for C 14 H 11 BrN 4 O 2 Na (M + Na) +: 368.9963; Found: 368.9962. Analysis for C 14 H 11 BrN 4 O 2: Calculated: C 48.43; H 3.19; N 16.14. Found: C 48.54; H 3.13; N, 16.46.

Compounds 18 [code BDM-185A, ( RS ) -6-iodo-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine] and 24 [code KS- 193B, ( RS ) -6-iodo-7- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -7 H -purine] : SnCl 4 / CH 2 Cl_ { 2} (4.4 mL, 4.25 mmol) are added with syringe, under argon, to a suspension of ( RS ) -3-methoxy-2,3-dihydro-5 H -1,4-benzodioxepino [ Saniger, E .; Campos, JM; Train, A .; Marchal, JA; Suárez, I .; Aranega, A .; Choquesillo, D .; Niclós, J .; Gallo, MA; Espinosa, A. Tetrahedron 2003 , 59 , 5457-5467] (0.3 g, 1.7 mmol), 6-iodopurine [Elion, GB; Hitchings, GH J. Am. Chem. Soc . 1956 , 78 , 3508-3510]. (420 mg, 1.7 mmol), containing trimethylchlorosilane (218 µL, 1.7 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (350 µL, 1.7 mmol) in dry acetonitrile (5 mL) at 0 ° C. After 10 min. at 0 ° C, the suspension was allowed to reach room temperature and heated at 45 ° C for 20 h. After cooling, the reaction mixture was diluted with water (20 mL), and a 5% aqueous solution of NaHCO3 was added until the pH was neutral. The aqueous phase was extracted with ethyl acetate (4 x 20 mL) and the organic phase was dried (Na2SO4). After filtration, the solvent was removed on a rotary evaporator and the residue was purified by flash chromatography using a gradient mixture of EtOAc / hexane (2/8 → 4/6 → 6/4) as eluent. The first fraction weighed 54.5 mg (8.5%) with the appearance of white amorphous powder and was identified as 18, BDM-185A code; mp: 137-138 ° C. R f (EtOAc / hexane: 6/4): 0.41. 1 H NMR (300 MHz, CDCl 3) δ 8.65 (s, 1H, H pur); 8.44 (s, 1H, H pur); 7.30 (dt, 1H, J = 1.8, 7.0 Hz, H arom); 7.21 (d, 1H, J = 7.0 Hz, H arom); 7.12 (d, 1H, J = 7.5 Hz, H arom); 7.10 (dt, 1H, J = 1.1, 8.3 Hz, H arom); 6.28 (dd, 1H, J = 2.3, 6.3 Hz, H-3); 4.88 (s, 2H, H-5); 4.61 (dd, 1H, J = 2.3, 13.0 Hz, H-2); 4.41 (dd, 1H, J = 6.3, 13.0 Hz, H-2). 13 C NMR (75 MHz, CDCl 3) δ 158.72; 152.33; 147.39; 143.14; 138.56; 130.11; 130.06; 129.31; 124.30; 122.47; 120.72; 84.11; 73.49; 69.06. Analysis for C 14 H 11 IN 4 O 2: Calculated: C 42.66; H 2.81; N, 14.21. Found: C 42.63; H 2.80; N, 14.48.

The second fraction weighed 95.7 mg (15%) with the appearance of amorphous white powder and was identified as 24, code KS-193B; mp: 133-134 ° C. R f (EtOAc / hexane: 6/4): 0.17. 1 H NMR (400 MHz, CDCl 3) δ 8.90 (s, 1H, H pur); 8.70 (s, 1H, H pur); 7.30 (m, 1H, H arom); 7.20 (d, 1H, J = 7.2 Hz, H arom); 7.10 (m, 2H, H arom); 6.54 (dd, 1H, J = 2.3, 5.3 Hz, H-3); 4.82 (d, 14.0 Hz, 1H, H-5); 4.77 (d, 14.0 Hz, 1H, H-5); 4.66 (dd, 1H, J = 2.2, 13.2 Hz, H-2); 4.42 (dd, 1H, J = 5.3, 13.2 Hz, H-2). Analysis for C 14 H 11 IN 4 O 2: Calculated: C 42.66; H 2.81; N, 14.21. Found: C 42.55; H 2.69; N 14.03.

Another method for obtaining 18 [BDM-185A code, ( RS ) -6-iodo-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine] . The ( RS ) -6-chloro- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine (16, code MB-90A, 0.25 g, 0 was dissolved. , 88 mmol), sodium iodide (2.64 g, 17.6 mmol) and trifluoroacetic acid (0.34 mL, 4.4 mmol) in butanone (20 mL) and this solution was left under stirring in the range -40 ° C and -50 ° C for 5 h. The solution was then neutralized with NaHCO 3 and extracted with CH 2 Cl 2. The iodine was reduced with a saturated aqueous solution of Na 2 SO 3 and the organic phase was washed with Na 2 SO 4. The crude was purified by flash chromatography (gradient elution with EtOAc / hexane: 1/9? 2/8? 3/7? 7/3). Finally, product 16, MB-90A ethanol code (0.104 g, 30% yield) was recrystallized.

Another method for obtaining 24 [code KS-193B, ( RS ) -6-iodo-7- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -7 H -purine] . The ( RS ) -6-chloro- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine (23, code MB-90B, 0.3 g, 1 was dissolved) , 06 mmol), sodium iodide (3.17 g, 21.1 mmol) and trifluoroacetic acid (0.4 mL, 5.3 mmol) in butanone (24 mL) and this solution was left under stirring in the range -40 ° C and -50 ° C for 5 h. The solution was then neutralized with NaHCO 3 and extracted with CH 2 Cl 2. The iodine was reduced with a saturated aqueous solution of Na 2 SO 3 and the organic phase was washed with Na 2 SO 4. The crude was purified by flash chromatography (gradient elution with EtOAc / hexane: 4/6? 6/4? 7/3). Finally, product 24, code KS-193B of ethanol (0.117 g, 28% yield) was recrystallized.

Compounds 19 [code KS-171C, ( RS ) -6-trifluoromethyl-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine] and 25 [code KS- 171 D, ( RS ) -6-trifluoromethyl-7- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -7 H -purine] obtained from 18, BDM-185A code : A mixture of 18, code BDM-185A, ( RS ) -6-iodo-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine (0.188 g, 0 , 5 mmol), trifluoromethyl-trimethylsilane (0.1 mL, 0.7 mmol), potassium fluoride (0.041 g, 0.7 mmol), copper (I) iodide (0.152 g, 0.8 mmol), dimethylformamide ( 0.5 mL) and N- methylpyrrolidone (0.5 mL) was stirred at 60 ° C for 24 h. After cooling to room temperature of the mixture, the solvents were removed by rotary evaporation and the reaction crude was purified by flash chromatography (gradient elution with EtOAc / hexane: 2/8 → 3/7). The first fraction weighed 80.3 mg (49%) with the appearance of white amorphous powder and was identified as 19; mp: 70-71 ° C. R f (EtOAc / hexane = 6/4): 0.43. 1 H NMR (300 MHz, CDCl 3): 9.10 (s, 1H, H pur); 8.60 (s, 1H, H pur); 7.31 (m, 1H, H arom); 7.23 (m, 1H, H arom); 7.12 (m, 2H, H arom); 6.39 (dd, 1H, J = 2.3, 6.2, H-3); 4.93 (d, 1H, J = 17.7, H-5); 4.90 (s, 2H, H-5); 4.66 (dd, 1H, J = 2.4, 13.0, H-2); 4.44 (dd, 1H, J = 6.2, 13.0, H-2). 13 C NMR (75 MHz, CDCl 3): 158.74; 153.20; 152.36; 145.97; 145.50; 130.14; 130.02; 129.34; 124.39; 122.53; 120.75; 84.09; 73.48; 69.17. Analysis for C 15 H 11 F 3 N 4 O 2: Calculated: C 53.58; H 3.30; N 16.66. Found: C 53.42; H 3.59; N 16.42.

The second fraction weighed 32.5 mg (20%) with the appearance of white amorphous powder and was identified as 25, code KS-171D; mp: 126-127 ° C. R f (EtOAc / hexane = 6/4): 0.34. 1 H NMR (300 MHz, CDCl 3): 9.10 (s, 1H, H pur); 8.60 (s, 1H, H pur); 7.33 (m, 1H, H arom); 7.23 (m, 1H, H arom); 7.13 (m, 2H, H arom); 6.40 (dd, 1H, J = 2.3, 6.2, H-3); 4.91 (dd, 1H, J = 3.7, 14.1, H-5); 4.66 (dd, 1H, J = 2.3, 13.0, H-2); 4.44 (dd, 1H, J = 6.2, 13.0, H-2). 13 C NMR (75 MHz, CDCl 3): 158.78; 153.22; 152.39; 145.95; 145.46; 130.18; 130.06; 129.37; 124.43; 122.55; 120.79; 84.12; 73.54; 69.22. Analysis for C 15 H 11 F 3 N 4 O 2: Calculated: C 53.58; H 3.30; N 16.66. Found: C 53.31; H 3.71; N 16.68.

Compounds 19 [code KS-171C, ( RS ) -6-trifluoromethyl-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine] and 25 [code KS- 171 D, ( RS ) -6-trifluoromethyl-7- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -7 H -purine] obtained from 24, BDM-193B code : A mixture of 24, code BDM-193B, ( RS ) -6-iodo-7- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -7 H -purine (0.188 g, 0 , 5 mmol), trifluoromethyl-trimethylsilane (0.1 mL, 0.7 mmol), potassium fluoride (0.041 g, 0.7 mmol), copper (I) iodide (0.152 g, 0.8 mmol), dimethylformamide ( 0.5 mL) and N- methylpyrrolidone (0.5 mL) was stirred at 60 ° C for 24 h. After cooling to room temperature of the mixture, the solvents were removed by rotary evaporation and the reaction crude was purified by flash chromatography (gradient elution with EtOAc / hexane: 2/8 → 3/7). The first fraction weighed 8 mg (4%) with the appearance of white amorphous powder and was identified as 19.

The second fraction weighed 24 mg (14%) with appearance of white amorphous powder and was identified as 25, code KS-171 D.

Compounds 20 [code KS-47A, ( RS ) -2,6-dichloro-9- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -9 H -purine] and 26 [code KS-47B, ( RS ) -2,6-dichloro-7- (2,3-dihydro-5 H -1,4-benzodioxepin-3-yl) -7 H -purine] : SnCl4 / CH_ { 2 Cl2 (2.3 mL,
2.22 mmol) is added with syringe, under argon atmosphere, to a suspension of ( RS ) -3-methoxy-2,3-dihydro-5 H -1,4-benzodioxepino [Saniger, E .; Campos, JM; Train, A .; Marchal, JA; Suárez, I .; Aranega, A .; Choquesillo, D .; Niclós, J .; Gallo, MA; Espinosa, A. Tetrahedron 2003 , 59 , 5457-5467] (0.200 g, 1.11 mmol), 2,6-dichloropurine (210 mg, 1.11 mmol), containing trimethylchlorosilane (143 µL, 1.11 mmol ) and 1,1,1,3,3,3-hexamethyldisilazane (2.33 µL, 1.11 mmol) in dry acetonitrile (3 mL) at 0 ° C. After 10 min. at 0 ° C, the suspension was allowed to reach room temperature and heated at 45 ° C for 26 h. After cooling, the reaction mixture was diluted with water (20 mL), and NaHCO3 was added until the pH was neutral. The aqueous phase was extracted with methylene chloride (3 x 20 mL) and the organic phase was dried (Na2SO4). After filtration, the solvent was removed on a rotary evaporator and the residue was purified by flash chromatography using a mixture of CH2Cl2 / MeOH: 9.8 / 0.2 as eluent. The first fraction weighed 50 mg (13.4%) with the appearance of white amorphous powder and was identified as 20, code KS-47A; mp: 154-156 ° C. Rf (CH 2 Cl 2 / MeOH = 9.8 / 0.2): 0.42. 1 H NMR (300 MHz, CDCl 3): 8.43 (s, 1H, H pur); 7.31 (m, 1H, H arom); 7.23 (m, 1H, H arom); 7.12 (m, 2H, H arom); 6.29 (dd, 1H, J = 2.3, 6.1, H-3); 4.95 (d, 1H, J = 14.1, H-5); 4.95 (d, 1H, J = 14.1, H-5); 4.86 (d, 1H, J = 14.1, H-5); 4.63 (dd, 1H, J = 2.3, 13.1, H-2); 4.34 (dd, 1H, J = 6.1, 13.1, H-2). 13 C NMR (75 MHz, CDCl 3): 158.67; 153.51; 152.29; 144.42; 130.78; 130.15; 129.87; 129.32; 124.39; 120.76; 84.11; 73.46; 69.21. Analysis for C 14 H 10 Cl 2 N 4 O 2: Calculated: C 49.87; H 2.99; N 16.62. Found: C 49.93; H 3.11; N 16.67.

The second fraction weighed 26 mg (7%) with the appearance of white amorphous powder and was identified as 26, code KS-47B; mp: 178-180 ° C. R f (CH 2 Cl 2 / MeOH = 9.8 / 0.2): 0.27. 1 H NMR (300 MHz, CDCl 3): 8.74 (s, 1H, H pur); 7.33 (m, 1H, H pur); 7.23 (m, 1H, H arom); 7.13 (m, 2H, H arom); 6.50 (dd, 1H, J = 2.2, 5.0, H-3); 4.81 (d, 1H, J = 14.1, H-5); 4.76 (d, 1H, J = 14.1, H-5); 4.65 (dd, 1H, J = 2.2, 13.2, H-2); 4.44 (dd, 1H, J = 5.0, 13.2, H-2). 13 C NMR (75 MHz, CDCl 3): 163.78; 158.68; 153.83; 149.09; 144.04; 130.34; 130.12; 129.48; 124.75; 120.79; 84.98; 73.85; 68.26. Analysis for C 14 H 10 Cl 2 N 4 O 2: Calculated: C 49.87; H 2.99; N 16.62. Found: C 50.03; H 2.89; N 16.72.

Compound 21, [code MN-84D, ( RS ) -6-chloro-9- (2,3-dihydro-5 H -4,1-benzoxatiepin-3-yl) -9 H -purine] . In a flask under argon, they are added at room temperature ( RS ) -3-methoxy-2,3-dihydro-5 H -4,1-benzoxatiepine [Núñez, MC; Train, A .; Rodríguez-Serrano, F .; Marchal, JA; Aranega, A .; Gallo, MA; Espinosa, A .; Campos, JM Tetrahedron , 2005 , 61 , 10363-10369] (0.5 g, 2.55 mmol), 6-chloropurine (0.394 g, 2.55 mmol), 1,1,1,3,3,3- hexamethyldisilazane (0.53 ml, 2.55 mmol), trimethylchlorosilane (0.33 mL, 2.55 mmol) and scandium triflate (1.25 g, 2.55 mmol) in anhydrous acetonitrile (20 mL) and heat the suspension at 45 ° C for 24 h. Once the resulting solution reaches room temperature, it is neutralized (NaHCO3), concentrated, extracted (CH2Cl2) and once the solvent is removed it is purified by flash chromatography (eluent CH_ { 2 Cl2 / MeOH: 9.8 / 0.2) yielding 21, code MN-84D with the appearance of amorphous white solid (0.456 g, 56%); mp: 185-187 ° C. 1 H NMR (CDCl 3, 300 MHz): δ (ppm) 8.76 (s, 1H, H pur); 8.28 (s, 1H, H pur); 7.65 (m, 1H, H arom); 7.36 (m, 3H, H arom); 6.29 (dd, J = 3.3, 8.1 Hz, 1H, H-3); 5.18 (d, J = 13.3 Hz, 1H, H-5); 5; 01 (d, J = 13.3 Hz, 1H, H-5); 3.27 (m, J = 6.1 Hz, 2H, H-2). 13 C NMR (CDCl 3, 75 MHz): δ (ppm) 152.23; 151.42; 150.60; 142.79; 141.75; 135.82; 132.84; 131.77; 130.18; 129.20; 128.75; 87.77; 73.93;
39.19. Analysis for C 14 H 11 ClN 4 OS: Calculated: C 52.75; H 3.48; N 17.58. Found: C 52.81; H 3.21; N, 17.79.

Compound 22, [code MN-92B, ( RS ) -6-chloro-9- (1,1-dioxo-2,3-dihydro-5 H -4,1-benzoxatiepin-3-yl) -9 H -purine ] : To a solution of compound 21, code MN-84D (0.15 g, 0.47 mmol) in methanol (7 mL), a solution of Oxone® (2KHSO_5 \ cdotKHSO_ {4) is added dropwise } K 2 SO 4, 0.58 g, 0.94 mmol) in water (3 mL) and left at room temperature for 2 h. After this time, it is neutralized with NaHCO 3, concentrated, suspended in 15 ml of water and extracted with CH 2 Cl 2. Once the solvent is removed, it is purified by flash chromatography (eluent CH2Cl2 / MeOH: 9.8 / 0.2) to obtain 22, code MN-92B with white solid appearance (0.165 g, 100%) ; mp: 230-232 ° C. 1 H NMR (CDCl 3, 400 MHz): or (ppm) 8.77 (s, 1H, H pur); 8.27 (s, 1H, H pur); 8.18 (dd, J = 1.0, 7.6 Hz, 1H, H arom); 7.56 (dt, J = 1.2, 7.6 Hz, 1H, H arom); 7.64 (dt, J = 1.0, 7.6 Hz, 1H, H arom); 7.46 (d, J = 7.6 Hz, 1H, H arom); 6.66 (dd, J = 1.5, 10.5 Hz, 1H, H-3); 5.58 (d, J = 14.0 Hz, 1H, H-5); 5.01 (d, J = 14.0 Hz, 1H, H-5); 4.31 (dd, J = 10.5, 14.0 Hz, 1H, H-2); 3.98 (dd, J = 1.5, 14.0 Hz, 1H, H-2). 13 C NMR (CDCl 3, 100 MHz): or (ppm) 152.55; 151.85; 150.76; 143.01; 139.32; 135.58; 134.63; 131.95; 131.32; 129.65; 128.43; 83.69; 72.09; 59.97. Analysis for C 14 H 11 ClN 4 O 3 S: Calculated: C 47.94; H 3.16; N 15.97. Found: C 48.05; H 3.24; N 15.80.

Compound 27 [code MN-116B, 6-chloro-7- (2,3-dihydro-5 H -1,4-benzoxatiepin-3-yl) -7 H -purine] . In a flask under argon, add at room temperature ( RS ) -3-methoxy-2,3-dihydro-5 H -4,1-benzoxatiepine [Núñez, MC; Train, A .; Rodríguez-Serrano, F .; Marchal, JA; Aranega, A .; Gallo, MA; Espinosa, A .; Campos, JM Tetrahedron , 2005 , 61 , 10363-10369] (0.25 g, 1.28 mmol), 6-chloropurine (0.22 g, 1.40 mmol), 1,1,1,3,3, 3-hexamethyldisilazane (0.27 ml, 1.28 mmol) and trimethylchlorosilane (0.16 mL, 1.28 mmol) in anhydrous acetonitrile (4 mL); This suspension is cooled to -25 ° C and tin tetrachloride in CH 2 Cl 2 (1 M, 1.53 mL, 1.28 mmol) dissolved in 3 mL of acetonitrile is added dropwise. The resulting suspension is heated at 45 ° C for 24 h. After this time and after cooling to room temperature, the resulting solution is neutralized with NaHCO 3, concentrated, extracted (CH 2 Cl 2) and once removed the solvent is purified by flash chromatography (eluent CH_ {2} Cl2 / MeOH: 9.9 / 0.1) yielding 27, code MN-116B with a syrup appearance (0.032 g, 8%). 1 H NMR (CDCl 3, 300 MHz): δ (ppm) 8.89 (s, 1H, H pur); 8.43 (s, 1H, H pur); 7.66 (m, 1H, H arom); 7.35 (m, 3H, H arom); 6.55 (dd, J = 1.8, 9.4 Hz, 1H, H-3); 5.18 (d, J = 13.4 Hz, 1H, H-5); 5.02 (d, J = 13.4 Hz, 1H, H-5); 3.33 (dd, J = 1.8, 14.0 Hz, 1H, H-2); 3.18 (dd, J = 9.4, 14.0 Hz, 1H, H-2). 13 C NMR (CDCl 3, 75 MHz): δ (ppm) 162.11; 152.83; 145.97; 142.91; 141.71; 135.42; 133.01; 130.19; 129.25; 128.90; 121.50; 89.36; 73.95; 39.80. Calculated: C 52.75; H 3.48; N 17.58. Found: C 52.59; H 3.78; N 17.41.

Compound 28 [code MN-80C, ( RS ) -6-chloro-7- (1,1-dioxo-2,3-dihydro-5 H -4,1-benzoxatiepin-3-yl) -7 H -purine] . In a flask under argon, add at room temperature ( RS ) -1,1-dioxide-3-methoxy-2,3-dihydro-5 H -4,1-benzoxatiepine (0.137 g, 0.60 mmol), 6-chloropurine (0.101 g, 0.65 mmol), 1,1,1,3,3,3-hexamethyldisilazane (0.125 mL, 0.60 mmol) and trimethylchlorosilane (0.08 mL, 0.60 mmol) in anhydrous acetonitrile ( 2 mL) This suspension is cooled to -25 ° C and tin tetrachloride in CH 2 Cl 2 (1 M, 0.72 mL, 0.72 mmol) dissolved in acetonitrile (2 mL) is added dropwise. The suspension is heated at 45 ° C for 24 h. After this time, the resulting solution is neutralized (NaHCO 3), concentrated, extracted (CH 2 Cl 2, 3 x 20 mL)) and once the solvent is removed it is purified by flash chromatography (eluent , CH 2 Cl 2 / MeOH: 9.8 / 0.2) yielding 28, code MN-80C with the appearance of amorphous white solid (0.018 g, 9%); mp: 196-197 ° C. 1 H NMR (CDCl 3, 400 MHz): δ (ppm) 8.89 (s, 1H, H pur); 8.41 (s, 1H, H pur); 8.13 (d, J = 7.7 Hz, 1H, H arom); 7.67 (t, J = 7.4 Hz, 1H, H arom); 7.61 (t, J = 7.7 Hz, 1H, H arom); 7.43 (d, J = 7.4 Hz, 1H, H arom); 6.97 (t, J = 6.0 Hz, 1H, H-3); 5.55 (d, J = 14.0 Hz, 1H, H-5); 4.99 (d, J = 14.0 Hz, 1H, H-5); 3.98 (d, J = 6.0 Hz, 2H, H-2). 13 C NMR (CDCl 3, 100 MHz): δ (ppm) 161.81; 153.16; 145.89; 143.36; 138.93; 135.53; 134.79; 131.28; 129.68; 128.46; 121.50; 84.41; 71.81; 60.60. Analysis for C 14 H 11 ClN 4 OS: Calculated: C 47.94; H 3.16; N 15.97. Found: C 48.04; H 3.11; N 15.77.

Treatment of the MCF-7 cell line with drugs

The following protocol was followed: the cells were detached from the surface of the culture jars with PBS-EDTA (0.02%) or PBS-trypsin (10x) at 37 ° C, and washed twice with PBS at a temperature between 0 and 10 ° C by centrifugation at 600 g for 5 minutes. TO then diluted in medium supplemented Dubelcco's Eagle with fetal bovine serum until obtaining cultures of 5 x 10 6 cells. From this moment the induction was carried out with the drugs by adding the desired concentrations of each of them, remaining in contact with the cells for six days. Parallel cultures were used as control in each experiment of MCF-7 cells without drugs. The middle of both cultures, control and those treated with drugs, was replaced every 48 h.

Calculation of 50 inhibitory concentrations (IC 50)

After induction for 6 days with the drugs, at the concentrations of 0.5, 1, 3, 5, 10 and 20 µM, of the cultured cell line, and after carrying out a colorimetric test with sulforrodamine-B (SRB) to be specified later, the absorbance was measured for an optical density of 492 nm. The graphs of optical density (OD) (ordinate axis) and concentration (abcissa axis) of each drug were constructed, and on the graphs it was calculated by interpolating the value of the IC 50 by plotting the vertical of the curve of the value obtained on average between the two extreme values of the OD Two values were determined for each point of the curve, the
This was repeated two or three times and the average values were estimated. The results are summarized in Tables 3 and 4.

Colorimetric test

After periods of 6 days of culture, the cells They were colored with SRB using the following protocol:

one.

The cell tapestry was washed with 1% PBS and incubated with glutaraldehyde for 15-30 minutes at a temperature between 0 and 4 ° C, then washed with PBS and letting it dry.

2.

The cells thus fixed were stained for 15 minutes with SRB in acetic acid.

3.

Later the tapestry was washed with acetic acid and the plates were allowed to dry again.

Four.

The dye fixed on the cells was solubilized with a Tris-base solution with stirring soft.

5.

100 µL aliquots were transferred to plates of 96 wells and were read on a Titertek colorimeter multiscan

Tables 3 and 4 summarize the results obtained in the tests carried out.

TABLE 3

9

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TABLE 4

10

In summary, the present invention relates to a family of compounds that respond, depending on their binding Hemiaminal, to general formulas I and II:

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eleven

where,

X

represents an oxygen atom, sulfur or sulfonyl group (SO {2}), an bencensulfanilamino group substituted in ortho, meta or para by a nitro or amino, or fluorenylmethyl group carbamate (FMOC-N {tertiary}) positions;

Y

represents a radical selected from the group formed by benzyl (mono- or disubstituted), benzyloxy (mono- or di-substituted), phenoxy (mono- or di-substituted), phenylthio (mono- or di-substituted), cyclohexylmethyloxy, allyloxy, allyl, chlorine, bromine or iodine;

Z

represents a hydrogen or an atom of chlorine;

R

well represents a radical selected from the group formed by H, alkyl, electron-donor groups as hydroxyl, alkoxy, amino, acylamino, or groups electron-attractants such as halogens, trifluoromethyl, acyls, at positions 7 and / or 9 of the benzene ring fused to seven-member heterocycle.

These compounds can be active components of a pharmaceutical formulation and used for treatment of breast, lung, colorectal, pancreas and syndromes cancers myeloproliferative in animals and humans or for the Preparation of medications for these treatments.

These compounds would be produced according to the described procedure comprising the following phases:

-

mixture of derivative ( RS ) -3-methoxy-2,3-dihydro-5 H -1,4-benzo-diheteroepinic with the pyric base, Lewis acid, trimethylchlorosilane, 1,1,1,3,3,3- hexamethyldisilazane in dry acetonitrile at a temperature between -5 and 5 ° C under argon,

-

After allowing the suspension to reach room temperature, the suspension is heated to a temperature between 40-50 ° C for 16-24 h. In the procedure for obtaining ( RS ) -9- or 7- (1,1-dioxo-2,3-dihydro-5 H -4,1-benzoxatiepin-3-yl) -9 H - or -7 Substituted H -purines can be carried out in the following two ways: (a) by condensation between ( RS ) -3-methoxy-2,3-dihydro-5 H -4,1-benzoxatiepine and the substituted purine , according to the procedure specified above, and subsequent oxidation of the sulfur atom in the compound condensed with Oxone® and (b) by condensation between the previously oxidized compound, such as ( RS ) -1,1-dioxo-3-methoxy -2,3-dihydro-5 H -4,1-benzoxatiepine and substituted purine.

Claims (5)

1. A family of compounds that respond, in function of its hemiaminal union, to the general formulas I or II: 12 where,

X

represents an oxygen atom, sulfur or a sulfonyl group, a benzenesulfanylamino group substituted in ortho positions, or stops by a nitro or amino group, or a fluorenylmethyl carbamate (FMOC-N tertiary) group,

Y

represents a radical selected from the group formed by benzyl (mono- or disubstituted), benzyloxy (mono- or di-substituted), phenoxy (mono- or disubstituted), phenylthio (mono- or di-substituted), cyclohexylmethyloxy, allyloxy, allyl, chlorine, bromine or iodine;

Z

represents a hydrogen or an atom of chlorine;

R

well represents a radical selected from the group formed by H, alkyl, an electron donor group such as hydroxyl, alkoxy, amino, acylamino, or a group electron-attractant such as a halogen atom, a trifluoromethyl, acyl group, at positions 7 'and / or 9' of the benzene ring fused to heterocycle seven members.

2. A pharmaceutical formulation comprising as active ingredient at least one compound defined in the claim 1. 3. A compound according to claim 1 for the treatment of breast, lung, colorectal cancers, pancreas and myeloproliferative syndromes in animals and beings humans. 4. Use of a compound according to claim 1 in the preparation of a medicament for the treatment of breast, lung, colorectal, pancreas cancers and myeloproliferative syndromes in animals and humans. 5. Procedure for the preparation of a compound according to claim 1 comprising the following phases: - mixing the derivative ( RS ) -3-methoxy-2,3-dihydro-5 H -1,4-benzo-diheteroepinic with the pubic base, Lewis acid, trimethylchlorosilane, 1,1,1,3,3,3 -hexamethyldisilazane in dry acetonitrile at a temperature between -5 and 5 ° C under argon, - After letting the suspension reach the room temperature, the suspension is heated to a temperature between 40-50ºC during 16-24 h. In the procedure for obtaining ( RS ) -9- or 7- (1,1-dioxo-2,3-dihydro-5 H -4,1-benzoxatiepin-3-yl) -9 H - or -7 Substituted H -purines can be carried out in the following two ways: (a) by condensation between ( RS ) -3-methoxy-2,3-dihydro-5 H -4,1-benzoxatiepine and the substituted purine , according to the procedure specified above, and subsequent oxidation of the sulfur atom in the compound condensed with Oxone® and (b) by condensation between the previously oxidized compound, such as ( RS ) -1,1-dioxo-3-methoxy -2,3-dihydro-5 H -4,1-benzoxatiepine and substituted purine.