Phenylaminopyrimidine-Derived Compounds, Method for Obtaining, Using Said Compounds in the Treatment of Cancer, and Treatment Methods

Abstract

The present invention relates to novel phenylaminopyrimidine(FAP)-derived compounds of general formulas I and II:

##STR00001##

Where, in formula I, R.sub.1 is:

##STR00002##

Where, in formula II, X.sup.+ is selected among one of the compounds below:

##STR00003##

Where, in formula II, Y is

##STR00004##

The compounds of the present invention are powerful and nonspecific tyrosine kinase inhibitors, and the use of these compounds in the treatment.

Claims

1. A compound derived from phenylaminopyrimidine selected from the group consisting of formula I and formula II: ##STR00019## wherein, in formula I, R.sub.1 is ##STR00020## and wherein, in formula II, X.sup.+ is selected from the group consisting of: ##STR00021## and wherein Y.sup.− is: ##STR00022##

2. The compound of claim 1, wherein the compound is of formula I and is: (3R,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyldecahydro-3H-3-,12-epoxy[1,2]dioxopyne[4,3-yl]isochromen10-yl-4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)amino)-4-oxobutanoate.

3. The compound of claim 1, wherein the compounds is of formula II and is selected from the group consisting of: N-(2-methyl-5-(4-((4-methylpiperazine-1-yl)methyl)benzamide)phenyl)-4-(pyridin-3-yl)pyrimidin-2-aminium-4-oxo-4-(((3R,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin[4,3-yl]isochromen-10-yl)oxy)butanoate and 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzenaminium-4-oxo-4-(((3R,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin[4,3-yl]isochromen-10-yl)oxy)butanoate.

4. A process for preparing a compound of formula I, as defined in claim 1, comprising a single step of stirring a mixture of artesunic acid and phenylaminopyrimidine in the presence of a coupling agent, at room temperature for 24 hours.

5. The process of claim 4, wherein the coupling agent is 1-hydroxybenzotriazole hydrate (EDC) and 1-ethyl-3(3-dimethylaminopropyl)carbodiimide) (HOBT).

6. A process for preparing a compound of formula II, as defined in claim 1, comprising a single step of reacting artesunic acid and one base selected from the group consisting of imatinib and phenylaminopyrimidine in the presence of an alcohol, under stirring, at room temperature for 24 hours.

7. The process, according to claim 6, wherein the alcohol is methanol.

8. (canceled)

9. (canceled)

10. A pharmaceutical composition comprising a compound of claim 1.

11. A method of treating chronic myelogenous leukemia comprising administering the pharmaceutical composition of claim 10.

12. A method for treating cancer comprising administering a therapeutically effective amount of at least one compound of formulas I or formula II, as defined in claim 1.

13. The method of claim 12, wherein the cancer is chronic myelogenous leukemia.

14. The method of claim 12, comprising inhibiting tyrosine kinase enzyme.

15. (canceled)

16. The method of claim 12, comprising inducing apoptosis of cancerous cells.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0026] FIG. 1 shows first, second and third generation drugs used in CML chemotherapy.

[0027] FIGS. 2A and 2B show a comparison of the action of the compounds of the invention in reducing the cell viability of K562 and K562 Lucena lineages.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The main object of the present invention is to provide novel substances derived from formulations I and II shown herein which, in addition of being active, do not induce the same resistance observed in the drugs already used in current therapy of the disease.

[0029] The compounds of the present invention are derived from phenylaminopyrimidine (FAP) of general formulas I and II:

##STR00013##

Where, in formula I, R.sub.1 is:

##STR00014##

Where, in formula II X.sup.+ is selected among one of the compounds below:

##STR00015##

Where, in formula II, Y.sup.−

##STR00016##

[0030] According to IUPAC, the compounds of formula I are called (3R,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxopyne[4,3-yl]isochromen-10-i1-4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)amino)-4-oxobutanoate. According to IUPAC, the compounds of formula II are called N-(2-methyl-5-(4-((4-methylpiperazine-1-yl)methyl)benzamide)phenyl)-4-(pyridin-3-yl)pyrimidin-2-aminium-4-oxo-4-(((3R,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyldecahydro-3H-3, 12-epoxy[1,2]dioxepin[4,3-yl]isochromen-10-yl)oxy)butanoate and 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzenaminium-4-oxo-4-(((3R,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin[4,3-yl]isochromen-10-yl)oxy)butanoate.

[0031] According to the present invention, the compounds 1-3, shown below, where obtained, said compounds being powerful nonspecific tyrosine kinase inhibitors, based on hybrid structures between artesunate with imatinib and with phenylaminopyrimidine (FAP) backbones, which may be salts or amides thereof.

##STR00017##

[0032] The reaction beginning with artesunate was proposed because the literature describes the growing importance of these derivatives for the treatment of several types of cancer, including CML. Furthermore, in the last few years, a wide variety of these biologically active derivatives have been synthesized and evaluated.

[0033] The method for obtaining compounds 1 to 3 of the present invention is a one-step process and the achieved yield is 84-88%, and is detailed in Example 1, below.

[0034] The invention will now be described on the basis of the examples, which are not to be construed as limiting the scope of protection.

Organic Synthesis

[0035] The synthesis strategy for the preparation of the compound of formula I (derivative 02) was initiated with the reaction between artesunic acid and PAF using EDC (1-hydroxybenzotriazole hydrate) and HOBT (1-ethyl-3 (3-dimethylaminopropyl) carbodiimide) as coupling agents. After 24 hours under stirring at room temperature, the desired product was formed with good reaction yields (Scheme 1).

[0036] The preparation of the novel hybrids of artesunate with imatinib and FAP, formula II (compound 03 and 04), was carried out by means of an acidic-base reaction between artesunic acid, imanitib bases and FAP, respectively (Scheme 1).

##STR00018##

[0037] All the novel compounds were characterized by RMN .sup.1H and .sup.13C, infrared and mass spectrometry.

[0038] Moreover, the compounds of the invention obtained according to Example 1 were evaluated for antineoplastic activity, cytotoxicity, and for the impact of the novel compounds on the cell cycle phases and induction of DNA fragmentation.

Antineoplastic Evaluation

[0039] The novel compounds of formula I-II, tyrosine kinase inhibitors (TKIs), have been tested on human cell lineages K562 and K562-Lucena 1, developed from K562, by continuous and increasing exposure to the chemotherapeutic vincristine. This lineage shows multidrug resistance (MDR) phenotype and exhibits the expression and activity of P-glycoprotein (Pgp) efflux pump. Both lineages K562 and K562-Lucena 1 express the BCR-ABL chimeric protein, constitutively activated, and derive from CML. Cell viability was evaluated through the MTT method, after 72 hours of incubation with TKIs. MTT is a colorimetric method which measures mitochondrial dehydrogenase activity, based on the ability of living cells to reduce the salt, 3-(4,5-dimethylazole-2-yl)-2,5-diphenyltetrazolium bromide in the product formazan.

Analysis of Spontaneous and Induced Apoptosis Foster by Novel Compounds in Leukemic Cells

[0040] The cytotoxicity assay, through annexin V labeling and flow cytometric analysis, was performed to determine the cytotoxic action of the novel compounds in K562 and K562-Lucena 1 lineages. Cells were incubated for 24 hours with or without addition of the novel compounds. The index of apoptosis induced by the novel compounds was obtained as follows: percentage of cells in induced apoptosis (treated with the drugs) minus the percentage of cells in spontaneous apoptosis (not treated with the drugs) (Vasconcelos et aL, 2007; Vasconcelos et al., 2011).

Cell Cycle and DNA Fragmentation Analysis

[0041] The analysis of the impact of the new compounds on the phases of the cell cycle and on the induction of DNA fragmentation were carried out by DNA labeling with the fluorochrome propidium iodide. The assays were analyzed by flow cytometry and the results were analyzed in relation to the control (cells without treatment).

Example 1—Synthesis of Compounds of Formula I—(Compound 02)

[0042] Amide 02 was obtained using 1 mol of artesunic acid, 1.8 mol of FAP, 0.5 mol of triethylamine, 1.5 mol of EDC coupling reagents and HOBT in 50 ml of dichloromethane. The medium was stirred at room temperature for 24 hours. At the end of the reaction, the organic phase was washed three times with a H.sub.3PO.sub.4 solution (5%), Na.sub.2CO.sub.3 saturated solution and water. The organic phase was dried with anhydrous sodium sulfate and evaporated, leading to the formation of the desired product.

Compound 02

ESI-EM (3.00 Kv; 50 V), m/z (%): 643 (100)

Example 2—Synthesis of Compounds of Formula II—(Compounds 03-04)

[0043] The salts of the artesunic acid with imatinib (03) and FAP (04) were obtained using 1 mol of the respective free bases, which were solubilized in 10 ml of methanol. Artesunic acid (1 mol) in methanol (16 mL) was added to this solution. The reaction mixture was kept under stirring at room temperature for about 24 hours. After evaporation of the methanol and addition of pentane there was formation of a solid, which was dried under high vacuum.

Compound 03

ESI-EM (3.00 Kv; 50 V), m/z (%): 877 (100)

Compound 04

ESI-EM (3.00 Kv; 50 V), m/z (%): 661 (100)

Example 3—Antineoplastic Evaluation

[0044] Cells were cultured in plates of 96 wells at the concentration of 1×10.sup.4 cells/well in 200 μl of RPMI supplemented with 10% fetal bovine serum. 10 μl of each of the novel TKIs, or imatinib, previously diluted in RPMI medium, were added in different concentrations, and no molecule or imatinib was added in the control group. The plates were kept in a humid atmosphere containing 5% CO.sub.2 at 37° C. for 72 hours. Four hours before completion of the established time (72 hours), 20 μl of MTT (Sigma) (final concentration of 10 μg/ml) were added. The plates were kept in the oven for the remaining four hours. 180 μl of the supernatant were removed from each well, and then 150 μl of dimethylsulfoxide (DMSO; Sigma) were added, homogenizing thoroughly for complete dissolution of the salt crystals formed by mitochondrial metabolism, thus resulting in a coloration. The obtained coloration has different apoptical densities, according to the mitochondrial metabolism treatment applications of the cells with the different concentrations of novel TKIs, or in the absence of these. The 96-well plate was read by the spectrophotometer (Spectramax Plus 384), using a wavelength of 570 nm. The results were analyzed through the absorbance of each well. The viability percentage was obtained through the following formula: [(Absorbance of cells treated with TKIs or imatinib/Absorbance of untreated cells)×100]. All the tests were performed in three different occasions. Three experiments, at least, independent, were carried out and triplicates were made for each concentration. By means of this method, we detected the cell inhibition percentage of each new molecule and we compared it with the percentage of viability reduction caused by imatinib.

[0045] The results showed that the novel compounds had similar or better activities when compared with imatinib. Moreover, the novel compounds did not exhibit cytotoxic activity. The results are described in Table 1.

TABLE-US-00001 TABLE 1 Examples of biological evaluation of the novel compounds. Cell viability percentage after treating K562 lineage with different tyrosine kinase inhibitors. The results represent the average of three independent experiments. 3% 4% Imatinib % 0.05 μM  77.68 97.54 93.52 0.1 μM 82.43 86.68 63.44 0.25 μM  43.45 87.20 54.53 0.5 μM 20.16 79.53 20.08 1.0 μM 18.11 85.68 16.34 1.5 μM 16.73 69.52 14.33 2.0 μM 15.12 56.13 19.79  2.5 μM. 17.89 53.28 19.43 3.0 μM 16.69 48.95 14.75 4.0 μM 16.51 48.17 13.53 5.0 μM 15.76 47.69 15.01

[0046] Among the evaluated compounds, some had the same effect as that of imatinib. Compound 03 promoted a reduction in cell viability of about 50%, at a concentration of 0.25 μM. The maximum reduction induced by these compounds was reached at the concentration of 1.0 μM, where approximately 20% of viable cells remained (Table 1). This percentage of viability remained constant despite the increase in the concentration of KIs molecules to the concentration of 5 μM (Table 1).

[0047] Compound 04 could induce a 50% reduction of viability, but to achieve this, a concentration of 2.5 μM had to be used (Table 1). Although it is less effective than imatinib in reducing cell viability in K562 lineage, studies with this compound have continued to better evaluate its effect using other methodologies.

Effects on the Novel Compounds on K562-Lucena Cell Lineage

[0048] To investigate whether the novel compounds would be able to inhibit viability in a multidrug resistance (MDR) phenotype, with overexpression of the P-glycoprotein (Pgp), we initiated trials in the Lucena cell lineage. The compounds were tested for their cytotoxicity in this lineage. The action of these compounds was also compared with the action of imatinib.

[0049] The viability of the Lucena cell lineage was evaluated after 72 h of incubation with the novel compounds, through the MTT assay.

[0050] Compound 03 was cytotoxic for at least 50% of the cells at a concentration of 0.25 μM, while, 1.0 μM of compound 04 were needed to attain a similar effect. However, the analyzed compounds were capable of reducing the viability of the Lucena cell lineage, in a dosage-dependent manner. These results suggest that such compounds have the propriety of overcoming the resistance barrier mediated by Pgp.

[0051] Upon incubation with imatinib, the viability reduction occurred in a concentration-dependent manner, until a plateau was reached, from a concentration of 1.5 μM. The incubation of 0.25 μM of imatinib led to approximately a 60% reduction in the viability of Lucena lineage. The novel TKIs compounds exhibit a cytotoxic effect similar to the one of imatinib.

Comparison of the Effects of the Novel Compounds in the Reduction of Cell Viability of K562 and K562-Lucena Lineages

[0052] The action of the novel compounds was compared between the K562 lineage and the Lucena lineage. Compound 03 reduced the viability in the two lineages in a similar way. However, compound 04 was more effective in the Lucena lineage, where viability reduction was considerably higher than in the K562 lineage, after 72 hours of incubation, as shown in FIG. 2A.

[0053] The action of these compounds was independent of the presence of Pgp, suggesting that they are not substrate for this carrier. On the other hand, the greater susceptibility of Lucena to compound 04 can suggest that this molecule enters the cell through an influx carrier, such as the OCT1 (FIG. 2B). It was observed that this carrier is enhanced in the Lucena lineage when compared with the K562 lineage (Correa, 2012).

Cell Death Induced by Imatinib and by the Novel Compounds

[0054] To analyze the apoptosis induction potential by the new imatinib derivatives, annexin V/propidium iodide assay was used by flow cytometry.

[0055] To analyze death by apoptosis, the cells were incubated for 24 hours instead of 72 hours. Moreover, low concentrations of the compounds of the invention were chosen to proceed with the experiments (0.25 μM, 0.5 μM and 1.0 μM).

[0056] Cells without addition of any drug were used for the evaluation of spontaneous death. Cells incubated with DMSO (used to solubilize the compounds derived from imatinib) were used to discard the effect of this substance on cell death induction. None of the novel compounds induced the lineages to death via necrosis (cells labeled only with propidium iodide). Compounds 03 and 04 induced cell death, probably by apoptosis (annexin-positive cells and annexin and propidium iodide-positive cells), in both lineages. Compound 04 induced death in a way similar to imatinib.

[0057] Upon incubation with compound 03, the Lucena lineage showed a greater cell death rate than the K562 lineage. The Lucena lineage was more sensitive to compound 03 than the K562 lineage, differently from what has been observed in the MTT assay. In the present assay, the cells were incubated for 24 hours and cell death was analyzed. In the MTT assay, cell viability was verified after 72 hours of incubation. A plausible explanation for this divergence is that the response to compound 03 occurs immediately in the Lucena lineage and later in the K562 lineage. Regardless of the mechanism responsible for the cellular response to this compound, it is of undeniable importance because it induced death in cells of the K562-Lucena lineage, which have the MDR phenotype that is known to reduce the efficacy of imatinib, both in vitro and in clinical practice (Nestal de Moraes, 2012).

[0058] The treatment with compound 04 developed the opposite effect. Upon 24 hours of incubation with compound 04, cell death rate did not reach the average of 20%, independently of the concentration and of the analyzed lineage. However, upon 72 h of incubation, the Lucena lineage showed greater percentage of reduction of cell viability than the K562 lineage. It looks like compound 04 took more time to act and that it was capable to induce cell death only in the most resistant lineage. Cell death rate was higher with compound 04 than with imatinib in the Lucena lineage.

Influence of Imatinib and of the Novel Compounds on Cell Cycle and DNA Fragmentation

[0059] The induction of DNA fragmentation by the new compounds and by imatinib was assessed by flow cytometry. The analysis of cell cycle and DNA fragmentation was carried out upon 24 hours of incubation with the compounds.

[0060] In the K562 lineage, imatinib and compound 03 fostered a halt in the G0/G1 phase of the cell cycle, characterized by an increase of about 10% in the number of cells in that phase. In this lineage, compound 04 did not foster alterations in the cell cycle. Only imatinib induced DNA fragmentation in the K562 lineage.

[0061] Despite the low rate of cell death detected by the annexin/PI method, compound 03 induced DNA fragmentation in the Lucena lineage. Both assays were performed after 24 hours of incubation. Compound 03 probably induced DNA fragmentation by a path other than apoptosis. All the compounds induced halts at the G0/G1 phase. Cell increase at the G0/G1 phase fluctuated from 10 to 25%.

[0062] In combination, our data proved the effectiveness of molecules 03 and 04 in the induction of death in cells of CML which have different resistance mechanisms, such as BCR-ABL amplification and Pgp overexpression.

[0063] Considering the results presented herein, it is shown that the compounds of the present invention are capable of overcoming the resistance mediated by the drug-efflux carrier Pgp in chronic myelogenous leukemia cells. The novel compounds of the invention exhibit antineoplastic activity in resistant cells, which overexpress Pgp, more than the drugs used in the therapy of patients with CML, in addition to the fact that they do not exhibit cytotoxicity.

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