BR102012021717B1 - Ionically labeled metallic catalysts for multicomponent reactions, their process of obtaining and application of the same in obtaining bioactive substances - Google Patents

Abstract

IONICALLY MARKED METALLIC CATALYSTS FOR MULTI-COMPONENT REACTIONS, THEIR PROCESS OF OBTAINING BIOACTIVE SUBSTANCES. Originally proposed by Pietro Biginelli, the model multicomponent reaction used in this invention involves the combination of an aldehyde, a (Beta)-ketoester and urea under acid catalysis providing a DHPM. The great interest in DHPMs lies in their pharmacological potential. The classic Biginelli reaction requires high reaction times and often low yields. The present invention relates to ionically labeled catalysts for multicomponent reactions. More specifically, the invention relates to labeled catalysts in Biginelli reactions. Another aspect of the invention deals with the process of obtaining ionically labeled catalysts based on imidazolium ionic liquids comprising transition metals. More particularly, of obtaining iron-containing ionically labeled catalysts. The catalytic viability of the developed catalysts was verified both in terms of reaction time and the amount of catalyst used. Additionally, the catalysts obtained are used in the synthesis of dihydropyrimidinones or dihydropyrimidinthiones with outstanding antitumor activity.

Description

FIELD OF THE INVENTION

The present invention relates to ionically labeled catalysts for multicomponent reactions. More specifically, the invention relates to ionically labeled catalysts for Biginelli reactions.

Another aspect of the invention concerns the process of obtaining ionically labeled catalysts based on imidazolium ionic liquids comprising transition metals. More particularly, obtaining iron-containing ionically labeled catalysts. In addition, the catalytic viability of the developed catalysts was verified both in terms of reaction time and the amount of catalysts used.

Additionally, the catalysts obtained are used in multicomponent Biginelli-type reactions providing compounds with antitumor activity already described, as well as a family of derivatives of these compounds, namely, the dihydropyrimidinones (DHPMs).

STATUS OF THE TECHNIQUE

Divergent and convergent synthetic routes are useful tools for obtaining new compounds. In this context, a very attractive type of reaction is the class of reactions called multicomponent reactions (MCR), which by definition comprises reactions with more than two raw materials that participate in the reaction and where, at the same time, the atoms are incorporated into the product. formed.

Multicomponent reactions (MCRs) are of increasing importance in the fields of Organic and Medicinal Chemistry and applied as synthetic alternatives in numerous syntheses of bioactive substances. The diversity and efficiency in the drug discovery process widely described in the literature have made RMCs an effective synthetic alternative, as they offer significant advantages over traditional linear synthesis (Domling, A.; Wang, W.; Wang, K. Chem. Rev. . 2012, 112, 3083.)

RMCs have numerous advantages over classical syntheses (linear or divergent synthesis). The main one is the fact that they are highly convergent. The advantage of convergence over a divergent synthetic approach is the considerable time reduction in the synthetic methodology and better yields. Furthermore, RMCs are a one-pof procedure, which increases the efficiency of the process (Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083). Thus, RMCs present synthetic efficiency due to the following 5 factors: selectivity, atom economy, convergence and reduction in the number of steps and purification processes.

The prior art comprises several examples of RMCs represented in Scheme 1 in chronological order of findings: Strecker (1850), Hantzsch (1882), Biginelli (1891), Mannich (1912), Passerini (1921) and the Ugi Reaction (1959). ) 10 (Ganem, B. Acc. Chem. Res. 2009, 42, 463).

The Biginelli reaction is one of the most important reactions for the synthesis of dihydropyrimidinones (DHPMs). DPHMs are known to have a wide variety of biological activities such as: antifungal, antitumor, calcium channel modulators, antioxidant and antibacterial. This broad spectrum of biological activity makes DHPMs targets of synthetic interest (Kappe, CO Acc. Chem. Res. 2000, 33, 879). The classic Biginelli reaction requires high reaction times and often low yields. Originally proposed by Pietro Biginelli, this reaction (Scheme 2) involves the combination of a urea or thiourea 1, an aldehyde 2 and a /3-ketoester 3 under acid catalysis providing a DHPM 4 (Narahari, SR; Reguri, BR; Gudaparthi, O.; Mukkanti, K. Tetrahedron Lett. 2012, 53, 1543).

Over the years, catalytic processes have not only diversified, but yields have also improved. Increasingly differentiated synthetic methodologies in which catalysis combined with ultrasound are used (Shaabani, A.; Rahmati, A. Catai. Lett. 2005, 100, 177.; — Dadhania, A. N.; Patel, V. K.; Raval, D. K. J. Braz. Chem. Soc. 2010, 22, 511) and Lewis 10 or Bronsted acids (Cepanec, I.; Litvic', M.; Litvic', M. F.; Grungold, I. Tetrahedron 2007, 63, 11822) were gradually increasing being highlight: — Cu(NH2SO3)2 (Liu, C.J.; Wang, J.D. Molecules 2009, 14, 763.) — CuCl2.2H2O (Dadhania, A.N.; Patel, V.K.; Raval, D.K.J. Braz. Chem. Soc. 2010, 22, 511) — C2H8O7P2 (Savant, M.M.; Pansuriya, A.M.; Bhuva, C.V.; Kapuriya, N.P.; Naliapara, Y.T. Catal Lett. 2009, 132, 281) —Zr-PILC (Singhl, V.; Sapehiyia, V.; Srivastava, V.; Kaur, S. Catal.Commun. 2006, 7, 571) — HBF4 (Chen, W. Y.; Qin, S. D.; Jin, J. R. Catal. Commun. 2007, 8, 123) — CU(BF4)2.XH2O ( Kamal, A.; Krishnaji, T.; Azhar, M. A. Catal. Commun. 2007, 8, 1929) — Fe(CF3CO2)3 and Fe(CF3SO3)3 (Adibi, H.; Samimi, H.A.; Beygzadeh , M. Catal. common 2007, 8, 2119) — SrCI2.6H2O (Chitra, S.;Devanathan, D.; Pandiarajan, K. Eur. J. Med. Chem. 2010, 45, 367) — FeCl3.6H2O (Xu, L.W.; Wang, Z.T.; Xia, C.G.; Li, L; Zhao, P.Q. Helv Chim Acta. 2004, 87, 2608) — [Fe2CuO(CCI3COO)6(THF)3] (Prodius, D.; Macaev, F.; Mereacre, V. ; Shova, S.; Lutsenco, Y.; Styngach, E.; Ruiz, P.; Muraviev, D.; Lipkowski, J.; Simonov, Y. A.; Turta, C. Inorg. Chem. Commun. 2009, 12, 642 ) — Yb(OTf)3 (Wannberg, J.; Dallinger, D.; Kappe, C. O.; Larhed. M. J. Comb. Chem. 2005, 7, 574) — Pd(PPh3)2CI2 (Kamal, A.; Krishnaji, T. .; Azhar, M. A. Catal. Commun. 2007, 8, 1929) — BF3.OEt2 (Hu, H. E.; Sidler, D. R.; Dolling. U. J. Org. Chem. 1998, 63, 3454) — InCl3 (Ranu, B. C.; Hajra, A.; Jana, U.J. Org. Chem. 2000, 65, 6270 ), — Yb(OTf)3 (Huang, Y.; Yang, F.; Zhu. C. J. Am. Chem. Soc. 2005, 127, 16386) — SnCI2.2H2O (Russowsky D.; Lopes, F.A.; Silva V.S.S.; Canto, K.F.S.; D'Ocab, M.M.G.; Godoi, M.N.J. Braz. Chem. Soc. 2004, 15, 165) — Cu(NH2SO3)2 (Liu, C.J. ;Wang, J.D.; Molecules 2009, 14, 763) - Sn(CIO4)3 (Liu, C.J.; Wang, J.D. Molecules 2010, 15, 2087), SbCl3 (Cepanec, I.; Litvic', M.; Litvic', M.F.; Grungold, I. Tetrahedron 2007, 63, 1182) — [AI(H2O)6(BF4) 3-3H2O] (Litvic, M.; Vecenaj, I.; Ladisic, Z. M.; Lovric, ML; Vinkovic, V.; Filipan-Litvic, M. Tetrahedron 2010, 66, 3463) — ZrCI4 (Reddy, C. V.; Mahesh , M.; Raju, P. V. K.; Babu, T. R.; Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657) — CaF2 (Chitra, S.; Pandiaraja, N, K. Tetrahedron Lett. 2009, 50, 2222), — Cu (OTf)2 (Paraskar, A.S.; Dewkar, G.K.; Sudalai, A. Tetrahedron Lett. 2003, 44, 3305) - NbCl5 (Cai, Y.F.; Yang, H.M.; Li, L.; Jiang, K.Z.; Lai, G.Q.; Jiang, J.X.; Xu, L.W. Eur. J. Org. Chem. 2010, 26, 4986) — CeCl37H2O (Zych, A.J.; Wang, H.J.; Sakwa, S.A. Tetrahedron Lett. 2010, 51, 5103) — Cu(NO3)2 3H2O (Wang, D.C.; Guo, H.M.; Qu, G.R. Synth. Commun. 2010, 40, 1115) — TFA (Xin, J.; Chang, L.; Hou, Z.; Shang, D.; Liu, X. ; Feng, X. Chem. Eur. J. 2008, 14, 3177) among others. Furthermore, recent literature reports many methodological studies involving Biginelli reactions employing ionic liquids (Lys). The established protocols are quite broad and the conditions employed are diverse (Yadav, J. S.; Antony, A. ; Reddy, B. V. S. Curr. Org. Synth. 2011, 8, 787; — Panda, S. S.; Khanna, P ; Khanna, L. Curr. Org. Chem. 2012, 16, 507; — Suresh, S.; Sandhu, J. S. Arkivoc 2012, 1.66).

By obeying some principles of green chemistry, the use of LI has become a synthetic alternative. The negligible vapor pressure is one of the most important benefits of using Lys, which offers lower toxicity in relation to the boiling point of solvents. Lys have a series of physical and chemical properties that are determined by the combination of cations and anions, which allows to modulate the desired properties (Dadhania, A. N; Patel, V. K.; Raval, D. K. J. Braz. Chem. Soc. 2011 , 22, 511; —Yamamoto, Y.J. Org. Chem. 2007, 72, 7817; —Plechkova, N.V.; Seddon, K.R. Chem. Soc. Rev. 2008, 37, 123).

The development of new efficient, sustainable, selective and inexpensive catalytic systems is a fundamental objective in modern chemistry. The use of non-toxic metals and recyclable reaction media is a major challenge in many research groups around the world. In this sense, the use of non-toxic and biocompatible metals can become a viable alternative to expensive and rare catalytic systems that use precious and economically expensive metals such as palladium, platinum, rhodium, ruthenium, iridium and others.

In catalytic systems, ionic liquids (Lys) can also be used as reaction media. These, especially the imidazoliums, are excellent media for organometallic catalysis, in particular, biphasic liquid-liquid catalysis involving two immiscible phases. Furthermore, they appear as ecologically friendly alternative reaction media with numerous attractive properties for their use in industrial reactions (Plechkova, NV; Seddon, KR Chem. Soc. Rev. 2008, 37, 123). Some of the imidazolium ionic liquids commonly used in biphasic catalysis are shown in Table 1, presented below.TABLE 1

The potential of Lys for multiphase catalysis makes them a very attractive and efficient medium for supporting different organometallic catalysts, since their unique characteristics and properties make these compounds a very interesting alternative to classic organic solvents and water, providing the application in several areas.

The use of Lys in biphasic catalysis has been introduced in order to facilitate the separation between the catalyst and the product after the end of the reaction and to enable the reuse of this catalytic system. Different applications of these systems have been described in topics as diverse as polymerization, oligomerization, metathesis and hydrogenation reactions of unsaturated substrates. The use of Lys in two-phase catalytic systems using complexes of transition and representative metals, as well as the role of these liquids in catalytic systems, were described in several review articles published recently, such as publications: Welton., T.; Chem. Rev. 1999, 99, 2071; —Dupont, J.; Consorti, C.S.; Spencer, J.J. Braz. Chem. social 2000, 11, 337; —Dupont, J.; de Souza, R.F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667; — Welton, T. Coord. Chem. Rev. 2004, 248, 2459; —Dupont J.J. Braz. Chem. social 2004, 15, 341; and — Dupont, J.; Suarez, P. A. Z. Phys. Chem. Chem. Phys. 2006, 8, 2441.

Whenever a catalyst is adsorbed on Lys, there is a high decrease in its activity after some reactions. The main cause of this effect is usually the leaching process of the catalyst during the extraction of the product from the reaction mixture or during the purification of the ionic phase for the recycle. The use of modified catalysts, with physicochemical properties more similar to those of Lis, may be a possible solution to the problem of catalyst leaching, with the incorporation of an ionic moiety in the catalyst structure being a direct strategy (Sebesta, R .; Kmentová, I.; Toma, S. Green. Chem. 2008, 10, 484). An important premise is that the ionic moiety must be inert under reaction conditions, but this is not always the case. As a result, rational development and optimization of the catalyst structure is seen as crucial for success.

Ionic labeling is undoubtedly an interesting option, and has been successfully employed for stoichiometric reagents. The association between metals and ionically charged ligands characterizes a new and promising class of catalysts, called ionically labeled catalysts. They can also be used in classical organic solvents, and due to their insolubility or immiscibility with such solvents, they can be easily recovered and reused. The use of ionically labeled catalysts with charged groups (i.e. imidazoliums, pyridiniums, phosphoniums, ammoniums) allows for a more efficient support on Lys, normally observing a greater activity, stability and possibility of recycling it (Huo, C.; Chan, T.H. Chem. Soc. Rev. 2010, 39, 2977 ).

Although the state of the art brings together a range of variations in the reaction conditions used in the Biginelli reactions, even using LI, some reaction conditions are severe, such as: high reaction temperature, long reaction time and reflux in a very acidic medium.

Patent document CN102225910 describes an ionic liquid containing substituted isonicotinic acid as a cation (Formula I). The ionic liquid with Bronsted acid characteristics was used to catalyze Biginelli reactions, providing the advantages of good catalytic activity, mild reaction conditions, short reaction times, simple operations and high yield.

Chinese patent application CN102153525 employs benzothiazole-derived ionic liquids (Formula II) as highly efficient catalysts for benzoin and Biginelli condensation reactions. The process has the following advantages: simple procedures, high yields and low cost.

R. Zheng et al., in 2006, described the use of 3-carboxymethyl-1-methylimidazolium bisulfate (Formula III) in the synthesis of 3,4-dihydropyrimidin-2-(1 /-/)-ones and 3,4- dihydropyrimidin-2-(1/-/)-thiones. The catalyst was recovered and reused without loss of activity (Zheng, R.; Wang, X.; Xu, H.; Du, J. Synth. Commun. 2006, 36, 1503).

In 2007, A. Barba and colleagues reported studies related to the Biginelli reaction in medium comprising a free carboxy-imidazole salt as a Bronsted catalyst (Makaev, F.; Styngach, E.; Shargarovskii, V.; Bets, L.; Vlad, L; Barba, A. Russian Journal of Organic Chemistry, 2010, 46, 610; — Makaev, V.; Styngach, E.; Muntyanu, V.; Pogrebnoi, S.; Rybkovskaya, Z.; Barba, A. Russian Journal of Organic Chemistry, 2007, 43, 1512/ The Biginelli reaction employing the catalysts described in Scheme 3 gave yields of 50-78% at 100-125°C.

X. Chen et al., in 2008, used Lys with Lewis acid ion characteristics in the Biginelli reactions (Scheme 4). The experimental conditions employed were: 71-90°C, 2-3 hours of reaction and 10 mol% catalyst (Chen, X.; Peng, Y. Catai Lett, 2008, 122, 310).

Patent document CN101260082 discloses a process for the preparation of 3,4-dihydropyrimidin-2-(1H)-ones comprising the following 15 reagents: an aromatic aldehyde, a urea and ethyl acetoacetate in a molar ratio of 1:1.5 :1, and the 1-butyl-3-imidazolium bisulfate catalyst (Scheme 5). The reaction is carried out in a temperature range between 60 and 70 °C for a period of 2 to 6 hours. The Biginelli adduct is obtained in yields between 80 and 90%, with the catalyst being recovered and reused.

In 2009, J. Gui and co-authors also reported the use of Bronsted acid-character Lis to catalyze Biginelli-type reactions (Gui, J.; Liu, D., Wang, C.; Lu, F.; Lian , J., Jiang, H.; and Sun, Z. Synth. Commun. 2009, 39, 3436). The 3,4-dihydropyrimidin-2-(1/7)-ones are obtained in good yields and under solvent-free conditions, the catalytic activity being maintained even after five recycles.

Chinese document CN102010374 describes a method of synthesizing 3,4-dihydropyrimidin-2-(1/-/)-ones catalyzed by the ionic liquid of Formula IV. The process has the following advantages: — the use of a biodegradable ionic liquid as a catalyst — the use of water as a solvent — the reaction conditions are mild — the reaction time is short — and the yield obtained was of the order of 82% to 94%. Such a synthetic process adds high efficiency and favors large-scale production.

Recently DK Raval and colleagues described the preparation of 3,4-dihydropyrimidin-2-(1H)-ones via multicomponent reactions catalyzed by ionic liquids (Formula V). The reaction was carried out using ultrasound, at a temperature in the range of 30°C and reaction times ranging from 30 to 70 min. The authors postulated a mechanism based on catalytic promotion by ionic liquids and also performed at least six recycle reactions with good conservation of activity (Dadhania, A. N; Patel, VK; Raval, DKJ Braz. Chem. Soc. 2011, 22, 511).

It should be noted that, to date, no ionically labeled catalyst has presented a double activation mechanism in Biginelli reactions, that is, no previously described catalyst presents the mechanism of action and the efficiency described in the present invention. Furthermore, the catalysts already reported in the state of the art, show a significant loss of activity in recycle reactions, a problem that was fully resolved with the use of an ionically labeled and Lys-supported double activation catalyst. Other labeled catalysts already disclosed contained strong Bronsted acids, thus presenting a potential impediment for industrial application, as strong acids can corrode equipment. Lewis acids, however, have been little explored for double activation and Lys support as in the present invention.

In view of the aforementioned problems and, in order to overcome them, the present invention describes the obtainment and application of a new ionically labeled catalyst containing transition metals for multicomponent reactions, more particularly Biginelli-type reactions.

Notably, the catalysts presented in this invention present excellent conditions for the reuse of the catalytic systems used, generating little amount of waste and competitive results compared to the techniques currently used to obtain adducts from the Biginelli reaction. In addition to having numerous advantages in operational and ecological terms for the preparation of DPHMs, such as: - Use of a sustainable catalytic system, due to the possibility of using iron-based catalysts, with low environmental impact and low costs; - Use of reduced amounts of catalytic system when compared to the promoters described in the state of the art; - The catalyst presented by the present invention promotes the RMC's reactions efficiently and allows the recycling of the system without loss of catalytic activity; - It does not generate a large amount of waste, being, therefore, an ecologically viable process and/or alternative to cleaner production processes; - Obtaining DPHMs under mild conditions and reduced reaction times; - Possibility of using ionic liquids (ILs) as a solvent, avoiding the use of traditional solvents and the concomitant emission of volatile organic compounds (VOCs); - The catalyst with high reactivity guarantees that the Biginelli reactions are conducted under reaction conditions similar to those adopted in industrial environments, presenting a performance compatible with those observed in industrial processes, which use classical catalytic systems, whose molar proportions are significantly higher than those used in the present invention .

SUMMARY OF THE INVENTION

The present invention relates to ionically labeled catalysts for multicomponent reactions. More specifically, the invention relates to ionically labeled catalysts in Biginelli reactions.

Another aspect of the invention deals with the process of obtaining ionically labeled catalysts based on imidazolium ionic liquids comprising transition metals. More particularly, of obtaining iron-containing ionically labeled catalysts. The catalytic viability of the developed catalysts was verified both in terms of reaction time and the amount of catalyst used.

Additionally, the catalysts obtained are used in the synthesis of dihydropyrimidinones or dihydropyrimidinthiones with outstanding antitumor activity.

BRIEF DESCRIPTION OF THE FIGURES

The invention can be better understood based on Figures 1 to 10, whose description follows below:

Figure 1 shows the suggested mechanism using the MAI.Fe2CI? (Note that the new catalyst has a dual mode of activating the reactants, one being Lewis catalysis and the other Bronsted).

Figure 2 shows the ES1-QTion-product spectrum in (+) and (-) mode of reactive species derived from the MAI.Fe2Cl7 catalyst.

Figure 3 shows the spectrum of pure 13C-{1H}-NMR (A) benzaldehyde (0.8 mL). (B) Mixture of (benzaldehyde (0.8 mL), MAI.CI (≥ 50 mg) and BMI.BF4 (0.8 mL). (C) Expansion from (A). (D) Expansion from of (B) (E) Expansion of the DMSO-dβ solvent.

Figure 4 shows the effect of temperature on the reaction medium promoted by the catalyst MAI.Fe2CI? during the period of one hour

Figure 5 shows the effect of MAI.Fe2Clz catalyst concentration on the Biginelli reaction (1h).

Figure 6 shows the results referring to the analysis of the yields of the recycle reactions of the Biginelli reaction of β-dicarbonyl (3.00 mmol), aldehyde (9.00 mmol), urea (3.00 mmol) with 5 mol% of MAI.Fe2CI7 in 1 mL of BMI.BF4 (LI) using the catalyst supported on the BMI.BF4 itself, for 2 h at 80 °C temperature.

Figure 7 indicates the effect of DHPMs derivatives on MCF-7 tumor cells (A-G) MCF-7 cells were treated with different concentrations of each tested compound (0.5 μM - 1 mM) for 24 h and cell viability was determined in assays of MTT. data represented by mean ± SEM of independent experiments in triplicate. *P<0.05, **P<0.01 and ***P<0.001 vs untreated control group. Figure 7A comprises derivatives of DHPMs with piperonal; Figure 7B comprises derivatives of DHPMs with benzaldehyde; Figure 7C comprises derivatives of DHPMs with 3-hydroxy-benzaldehyde; Figure 7D comprises derivatives of DHPMs with 2 or 3-nitro-benzaldehyde; Figure 7E comprises derivatives of DHPMs with 2-hydroxy or 4-hydroxy-3-methoxy-benzaldehyde; Figure 7F comprises derivatives of DHPMs with formaldehyde or acetaldehyde; 7G comprises derivatives of DHPMs with furfuraldehyde or 4-chloro-benzaldehyde

Figure 8 shows the effects of DHPMs derivatives on MCF-7 tumor cells (A-G) MCF-7 cells were treated with different concentrations of test compounds (0.50 µM - 1.00 mM) for 48 h and cell viability determined by MTT® assays (Sigma-Aldrich, USA). Data represented by mean ± SEM from three independent and triplicate trials. *P<0.05, **P<0.01 and ***P<0.001 vs control group without treatment. Figure 8A comprises derivatives of DHPMs with piperonal; Figure 8B comprises derivatives of DHPMs with benzaldehyde; Figure 8C comprises derivatives of DHPMs with 3-hydroxy-benzaldehyde; Figure 8D comprises derivatives of DHPMs with 2 or 3-nitro-benzaldehyde; Figure 8E comprises derivatives of DHPMs with 2-hydroxy or 4-hydroxy-3-methoxy-benzaldehyde; Figure 8F comprises derivatives of DHPMs with formaldehyde or acetaldehyde; 8G comprises derivatives of DHPMs with furfuraldehyde or 4-chloro-benzaldehyde.

Figure 9 demonstrates the effects of DHPMS derivatives on MCF-7 tumor cells (A-G) MCF-7 cells treated with different concentrations of each tested compound (0.50 µM - 1.00 mM) for 72 h and cell viability tested by MTT assays ® (Sigma-Aldrich, USA). Data represented by mean ± SEM of three independent and triplicate trials. *P<0.05, **P<0.01 and ***P<0.001 vs control group without treatment. Figure 9A comprises derivatives of DHPMs with piperonal; Figure 9B comprises derivatives of DHPMs with benzaldehyde; Figure 9C comprises derivatives of DHPMs with 3-hydroxy-benzaldehyde; Figure 9D comprises derivatives of DHPMs with 2 or 3-nitro-benzaldehyde; Figure 9E comprises derivatives of DHPMs with 2-hydroxy or 4-hydroxy-3-methoxy-benzaldehyde; Figure 9F comprises derivatives of DHPMs with formaldehyde or acetaldehyde; 9G comprises derivatives of DHPMs with furfuraldehyde or 4-chloro-benzaldehyde

Figure 10 shows the morphological changes caused by the treatment of MCF-7 tumor cells with the derivatives of DHPMs: MCF-7 cells untreated (A) or treated for 72 h with 1 mM monastrol (B), 800 μM of the 4bt derivative - (C), 1 mM of 4m (D), 800 μM of 4x (E), 400 μM of 4p (F) and 1 mM of 4bc (G) were analyzed with the aid of the inverted optical microscope Axiovert 100 (ZEISS - Germany ). Morphological changes such as decrease, rounding and loss of cell adhesion due to cell death caused by the treatments can be seen in figures B-G. Bar: 20 μM.

DETAILED DESCRIPTION

The main object of the present invention is to obtain ionically labeled catalysts based on imidazolium salts for metal catalysis reactions, such as multicomponent reactions. Related catalysts in the present invention comprise association of metals and ionically labeled ligands. Ionic labeling is well known in the art and is extremely useful, since ionic liquids act as an immobilization solvent and also as a catalyst binder.

For a better understanding of the present invention some previous definitions are necessary.

The term "imidazoles" refers to a 5-membered cyclic fragment with nitrogens at positions 1 and 3, with a delocalized positive charge;

The term “Lys” refers to Ionic Liquids;

The term “ionic labeling” refers to the use of a permanently charged group through a covalent bond, such as the imidazolium group in the case of the MAL cation

The term "β-dicarbonyl compound" comprises acyclic or cyclic β-diketones and acyclic β-ketoesters.

The term “dual activatio” refers to the protonation of benzaldehyde by Bronsted acid (MAI) and the formation of the Acac system by Lewis acid (Fe2Cl7) in the β-dicarbonyl compound, having both the cation and the anion a key role for catalysis.

The term “leaching process” refers to the loss of catalyst from the ionic phase to the organic phase during the purification of the same or in the extraction of the product;

The term “RMC's” refers to multicomponent reactions.

One of the embodiments of the present invention describes the production of ionically labeled catalysts based on imidazolium, pyridinium, phosphonium and ammonium groups containing a functionalization of the carboxylic acid type. Thus the first step of forming the catalysts of this invention involves the preparation of an ionically labeled Bronsted acid. The 1,3-dialkylimidazolium ligand, comprising a Bronsted acid, was rationalized as ideal for the catalyst, due to the high thermal stability of ionic liquid derivatives based on the 1,3-imidazolium ion and its almost universal solubility. A preferred embodiment of this embodiment involves the reaction of 1-methylimidazole with chloroacetic acid providing the 3-carboxymethyl-1-methyl-imidazolium chloride, hereafter denoted as MAI.Cl, as per Scheme 6.

In the synthetic sequence, the MAI.CI is converted into the ionically labeled catalyst containing transition metal. In preparing these catalysts, the transition metal chloride comprises a cation selected from the group consisting of iron, zinc, tin, nickel, palladium, platinum, copper, cobalt, titanium, chromium, vanadium, and other transition metals, FeCh being a transition metal chloride with very promising results in obtaining the catalyst of the present invention. Thus, in a preferred embodiment, MAI.CI is associated with iron trichloride as illustrated in Scheme 7.

In general, the process for obtaining the catalyst of the present invention comprises the following steps: i) Adding the transition metal chloride to the ionically labeled Bronsted acid; ii) Stirring the mixture obtained in step i for a period.

In step (i) the selected reagents were previously described for the catalyst of interest in Biginelli reactions, being exemplified by FeCh and the Bronsted acid ionically labeled by MAI.CI.

The resulting catalyst is according to the starting reagents and their initial proportions used, as in the case of compound formation: BMI.MxChx+i (x = 1 or 2).

In step (ii) the temperature range for the reaction medium between 0 and 170°C, preferably between 50 and 80°C, under magnetic or mechanical agitation for a reaction time between 2 and 4 hours.

In one of its preferred embodiments, the present invention relates to obtaining iron-containing ionic catalysts. The process for obtaining such a catalyst comprises the following steps: I) Adding FeCh to MAI.CI in different molar proportions; II) Stir the mixture obtained in step I.

In step (I) the molar ratio of FeChiMAI.CI around 1:1 provides 3-carboxymethyl-1-methylimidazolium tetrachloride ferrate (MAI.FeCU) in quantitative yield. Also, the molar ratio of FeCh:LI around 2:1 provides 3-carboxymethyl-1-methylimidazolium heptachloride-bisferrate (MAI.Fe2Cl7) in quantitative yield.

Another embodiment of the present invention is related to the use of the catalysts of the present invention in RMCs. An embodiment of this embodiment of the invention comprises the use of ionically labeled catalysts in the Biginelli reaction (Scheme 8).

In general, the process used in the Biginelli reactions comprises the following steps: a) Prepare the catalytic system by mixing the ionically labeled catalyst with at least one ionic liquid; b) Then, adding to the mixture obtained in step (a) a β-dicarbonyl compound, an aldehyde and a urea or a thiourea; c) Stirring the resulting mixture at a controlled temperature; d) After the end of the reaction time, cool the system and remove the final product from the catalytic system of step (a) by washing the solid formed with solvent; e) Then the solid obtained in step (d) is filtered and dried, the supernatant containing the reserved catalytic system; f) Optionally, the reaction mixture is separated from the catalytic system by column chromatography; g) Additionally, the supernatant reserved in step (e), or the fraction containing the catalytic system in step (f), is evaporated to recover the catalytic system, which is reused for a new reaction cycle through the addition of the reagents from step ( B).

In step a, the ionic liquids used are preferably BMI.NTf2, BMI.BF4 and BMI.PFθ.

In step (a), the catalysts used are preferably MAI.Fe2Cl7 and MAI.FeCU.

In step (b), the β-dicarbonyl compound is preferably selected from ethyl acetoacetate, acetyl ketone, 1,3-cyclohexanedione and 5,5-dimethyl-1,3-cyclohexanedione.

Also in step (b), the aldehyde is preferably selected from benzaldehyde, 2-nitro-benzaldehyde, 3-nitro-benzaldehyde, 2-hydroxy-benzaldehyde, 3-hydroxy-benzaldehyde, 4-hydroxy-3-methoxy-benzaldehyde, 4 -chloro-benzaldehyde, piperonaldehyde, acetaldehyde, p-formaldehyde and furfuraldehyde.

In step (d) the solvent is preferably selected from ethanol, acetone, acetonitrile and water.

The conditions of the reaction systems highlighted in this process involve the temperature range for the reaction medium comprising 25 to 180°C, preferably between 60 and 90°C. The reaction times are very promising technologically, ranging from about 1 min to about 720 minutes, preferably between 1 to 180 minutes.

The molar ratios between the urea (or thiourea), the β-dicarbonyl compound, the aldehyde and the catalyst are in the range between 1.00:0.20:0.20:0.01 and 1.00:5, 00:5.00:0.10. The ratio between volume (ml_) of ionic liquid and the molar amount (mmol) of urea (or thiourea) is between 0.10 and 1.00.

In step (e) obtaining the Biginelli product and recovering the components of the catalytic system, ionically labeled catalyst and isolated ionic liquids, occurs mainly by filtration, followed by consecutive washing of the solid with appropriate solvents. Then, the solvent is removed through procedures comprised in the state of the art, step (q).

The reuse of components recovered from the catalytic system in step (a) occurs after filtering the product, followed by washing the components with ethanol, followed by vacuum removal of the washing solvent.

In steps (f) and (g), in cases where there was no precipitation of the final product, the separation of the product obtained is preferably performed by column chromatography using organic solvents selected from acetone, ethyl acetate, hexane, ethyl ether, ethanol. The catalytic system recovered at the end of the chromatographic column shows good stability during the next Biginelli reaction cycles, guaranteeing a good degree of reuse.

The Lys used as a solvent for the Biginelli reactions comprise the general formula A+X", where A+ represents a quaternary ammonium cation or a quaternary phosphonium cation and X" represents all anions capable of forming a liquid salt with these cations at the reaction temperature . Anions are selected from the group comprising chloride, bromide, tetrachloroindate, perchlorate, nitrate, tetrafluoroborate, tetrachloroborate, hexafluorophosphate, hexafluoroantimonate, fluoroarsenate, hexafluorotantalate, trifluoromethyl sulfate, fluorosulfonate, tetrachloroaluminate and dichlorocuprate among others. It is further predicted that cations are selected from 1,3-dialkylimidazolium, tetraalkylammonium, alkylpyridinium, tetraalkylphosphonium. Thus, the use of 1-n-butyl-3-methylimidazolium hexafluorophosphate (BMI.PFe), 1-butyl-3-methyl-imidazolium bis-tetrafluoroborate (BMI.BF4) and 1-n- butyl-3-methylimidazolium (BMI.NTf2) as examples of reaction media does not limit the scope of the present invention.

In one of its embodiments, the present invention also comprises the use of other ionically labeled catalysts, containing transition metals, selected from iron, zinc, tin, nickel, palladium, platinum, copper, cobalt, titanium, chromium, vanadium, as active species to promote multicomponent reactions, especially Biginelli reactions. Thus, the use of iron as an active species in Biginelli reactions does not limit the scope of the present invention.

In addition, this reaction system for the Biginelli reaction is used in batches, in a continuous or semi-continuous manner.

em que: X denota enxofre ou oxigênio R1 denota alquila ou arila ou heteroarila R2 denota alquila ou arila ou heteroarila ou OAlquila ou OArila ou OHeteroarila, R3 denota alquila ou arila ou heteroarila Opcionalmente: R2 e R3 denotam -CH2C(R4)2CH2- R4 denota H ou metilaThe aforementioned process for multicomponent Biginelli-type reactions allowed the preparation of 3,4-dihydropyrimidin-2-('l/-/)-ones and 3,4-dihydropyrimidin-2-(1/-/)-thiones with outstanding activity. antiproliferative. Thus, the present invention further relates to the use of compounds comprising the chemical formula (VI):

wherein: X denotes sulfur or oxygen R1 denotes alkyl or aryl or heteroaryl R2 denotes alkyl or aryl or heteroaryl or OAlkyl or OAryl or OHeteroaryl, R3 denotes alkyl or aryl or heteroaryl Optionally: R2 and R3 denote -CH2C(R4)2CH2-R4 denotes H or methyl

In this context, cytotoxic assays were performed on MCF-7 mammalian cancer cell lines (human cells). Significant differences in treated and untreated cells were observed in cell viability assays, with several of the compounds having an inhibitory activity on cell proliferation in dose and time dependence. Within 24 hours some have already exhibited activity and the distribution of cell viability according to treatment and time is shown in Figures 7-9 (Example 7).

In another embodiment the present invention provides for obtaining and characterizing a novel 3,4-dihydropyrimidin-2-(1/-/)-one 4bs and a novel 3,4-dihydropyrimidin-2-(1/7)-thione 4bp (Formula VII and Formula VIII respectively) from the established process for the Biginelli reaction employing the catalysts of the present invention.

The 4bs derivative showed significant activity in MCF-7 cells (breast adenocarcinoma) after 72 hours with cytotoxic activity greater than 50% in tumor cells. It does not show relevant cytotoxic activity against these normal cells, making it a potential candidate in the treatment of cancer.

The mechanistic rationalism for the Biginelli reaction using the catalyst of the present invention indicates that the Bnansted acid of the MAI structure is responsible for the activation (Figure 1) of the carbonyl group of the aldehyde. While the anion Lewis acid (Fe2Cl7) is responsible for the in situ formation of Fe(acac)3 complex reacting with the activated aldehyde. This iron complex formed is a strong nucleophile when compared to ethyl acetoacetate.

In the proposal presented (Figure 1) the catalyst behaves as a dual activation type, one part being responsible for the Lewis (anion) catalysis and the other for the Bnansted (cation) catalysis. The formation of these intermediates was verified by ESl-QTof mass spectrometry, where the species of interest were intercepted and characterized (Figure 2).

In this procedure, only the iminium mechanism intermediates were detected and no enamine or Knoevenagel mechanistic pathway intermediates were observed.

From experimental data from kinetic procedures and mass spectrometry, our results agree with the observations of K. Folkers and T. B. Johnson (Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1993, 55, 3784) and explored later by Kappe (Kappe, C.O.J. Org. Chem. 1997, 62, 7201), being the first attack of urea on benzaldehyde.

Experiments carried out in NMR also identified the role of the proton MAI.Cl in the activation by the cation in benzaldehyde. A sealed capillary tube containing DMSO-c/6 was placed in an NMR tube to adjust the scale (external standard). Initially benzaldehyde was added, then benzaldehyde and MAI.Cl and later benzaldehyde, MAI.CI and BMI.BF4, the displacements of the analyzed species were identified as shown in the spectra below (Figure 3). The deshielding effect of the aldehyde C=O from 191.1 ppm (C) to 192.0 ppm (D) with mixing of the reagents. Also note the low intensity of MAI.CI signals in (B) due to its low concentration relative to aldehyde and liquid ionic concentrations (Figure 3).

Note that the carbonyl (C=O) of the aldehyde undergoes deshielding, with shifting at a higher frequency in the presence of MAI.CI. This demonstrates that in the presence of Bronsted acid, the electrophilic carbon becomes more prone to nucleophilic attack (Figure 3). As in mass experiments, NMR analysis confirms the reaction kinetics.

The catalyst presented by the present invention promotes the RMC's reactions efficiently and allows the recycling of the system without loss of catalytic activity. Catalyst and LI recycles were also evaluated and at least eight recycles (Figure 6) were performed without any loss of activity. Demonstrating the efficiency of the dual activation catalyst in Biginelli reactions. As there is no leaching of the catalyst from the ionic phase, the catalytic activity is kept constant, even after several recycle reactions.

The catalytic system developed is quite versatile, being able to carry out the Biginelli reactions with the use of reduced amounts of catalytic system when compared to the promoters described in the state of the art. In addition, by employing iron as a metallic center and by being reused several times without loss of catalytic activity, this catalyst proves to be extremely promising both from an economic and environmental point of view.

The examples below are represented in order to further illustrate certain embodiments of the invention. It is important to note that the present invention is not limited to the examples cited, and can be used in all the applications described or in any other equivalent variations.

EXAMPLES EXAMPLE 1: SYNTHESIS OF IRON-LABELED IRON (III) BASED CATALYST. Example 1.1: Obtaining 3-carboxymethyl-1-methyl-imidazolium chloride (MAI.CI)

In a two-neck flask, 1 equivalent of chloroacetic and acetonitrile were added, and methyl imidazole (1 equivalent) was slowly dripped, under reflux and continuous stirring in an inert atmosphere for 48 h at 80°C. The product was washed with acetonitrile and vacuum dried. IR (KBr, cm -1 ): 3158, 3095, 2984, 2884, 1735, 1578, 1439, 1395, 1201, 1191, 772. H NMR (HOD, 300 MHz, δ in ppm): 8.83 (s, 1H), 7.52 (s, 2H), 5.15 (s, 1H) and 3.94 (s, 3H). 13C NMR (HOD, 75 MHz, δ in ppm): 170.8, 138.1, 124.2, 50.8 and 36.6.

Example 1.2: Production of MAI.Fe2CI7 Catalyst

1 equivalent of MAI.CF and 2 equivalents of Fe2Cl3 were added to a flask, under continuous stirring and in an inert atmosphere. The product was preserved in the flask and used afterwards. IR (KBr, cm -1 ): 3156, 1728, 1644, 1457, 1393, 1164, 625.

EXAMPLE 2: BIGINELLI REACTION EMPLOYING THE IONICALLY LABELED CATALYST.

The traditional Biginelli reaction involved 1 equivalent of benzaldehyde, 1 equivalent of ethyl acetoacetate, 1 equivalent of urea and stringent reaction conditions: acid catalysis (HCI) for 18 h in the presence of ethanol (Kappe, C. O. Tetrahedron 1993, 49, 6937).

The reactions were conducted by varying the concentrations of each reagent, initially using 3 mmol of each reagent, according to the model reaction described above.

From the concentration of 9 mmol of urea, there is no further increase in the reaction rate, which indicates an apparent relative reaction order of zero for this reagent, since increasing its concentration will not increase the reaction rate. Another important fact observed was that only the presence in excess of benzaldehyde led to higher yields. With 9 mmol of aldehyde in the reaction medium, the yield was quantitative in 2 h of reaction.

EXAMPLE 3: EVALUATION OF THE EFFECT OF TEMPERATURE ON THE BIGINELLI REACTION.

The effect of temperature on the reaction, in order to evaluate the entropic effect on the formation of the Biginelli adduct, was also investigated by varying the temperature from 20-120°C, obtaining yield variations from 0 to 46% using 3 mmol β- dicarbonyl, 3 mmol aldehyde, 3 mmol urea (Figure 4).

From 80 °C, it is observed that there is a drop in yield due to the instability resulting from the increase in temperature in the formation of transition and intermediate states of the Biginelli reaction.

EXAMPLE 4: EVALUATION OF THE EFFECT OF CATALYST CONCENTRATION ON THE BIGINELLI REACTION.

To analyze the catalytic effect of MAI.Fe2Cl7, eleven reactions were carried out varying the amount of catalyst in the reaction medium: a reaction without catalyst and variations of 1-10 mol% of MAI.Fe2Cl7 (Figure 5). After 5 mol%, an aggregation of the ionically labeled catalyst occurs, a common characteristic of imidazolium derivatives and, therefore, the concentration of the active species in the reaction medium decreased. As a result, there is a drop in income.

EXAMPLE 5: OBTAINING BIGINELLI ADDUCTS ACCORDING TO THE BEST ESTABLISHED REACTIONAL CONDITIONS.

As evidenced in the previous examples many reaction conditions were evaluated to achieve the desired adduct. The best condition was obtained at 80 °C using 5 mol % of catalyst, 9.00 mmol of benzaldehyde, 3.00 mmol of ethyl acetoacetate, 3.00 mmol of urea, 1.0 mL of BMI.BF4 in 2 h of reaction. Other Lys derived from imidazolium, pyridinium, ammonium and phosphonium cations are also efficiently used. Concentrations above and below 5 mol% also promote the formation of the desired DHPM, but in lower yields and longer times.

After performing all the reaction kinetics and establishing all the reaction conditions for the Biginelli reaction in LI and an ionically labeled catalyst, substrate variations were performed in order to synthesize compounds that possibly have a pronounced biological activity (Table 2).

When compared with other state-of-the-art protocols for Biginelli reactions, which also employ Lys catalysis, we observed that the catalyst of the present invention presents significant advantages and satisfactory yields: short reaction time (2 h), low temperatures (80° C), small amount of catalyst (5 mol%). Table 2

Example 5.1: OBTAINING 7,7-DIMETHYL-4-(3-HYDROXYPHENYL)-4,6,7,8-TETRAHYDROQUINAZOLINE-2,5(1H,3H)-DIONE (DHPM 4BS):

White solid with 70% yield. Melting Point 220-222°C (no literature data) and Rf 0.36 (hexane/AcOEt 7:3).

Spectroscopic data: FT-IR (KBr, cm -1 ): 3577, 3314, 2957, 1678, 1628, 1514, 1266, 728. H NMR (DMSO-d6, 300 MHz, δ in ppm): 9.52 (s, 1H) , 7.09 (t, 1H, J= 7.5 Hz), 6.81 (s, 1H), 6.67 (d, 1H, J=4.5 Hz), 6.57 (s, 1H), 6.50 (d, 1H, J= 3 Hz) , 3.56 (s, 2H), 2.50 (s, 2H), 1.75 (s, 3H), 1.70 (s, 3H). C NMR (DMSO-d6, 75 MHz, δ in ppm): 209.8, 205.2, 193.6, 157.8, 138.5, 129.8, 119.5), 116.1, 66.6, 62.8, 56.06, 54.29, 30.5, 28.4.

EXAMPLE 5.2: OBTAINING 6-METHYL-[4-BENZO-[1,3]DIOXOL-5-YL)-2-THIOXO-1,2,3,4-TETRAHYDROPYRIMIDINYL-5-ETHANONE (DHPM 4BP):

Yellow colored solid with 71% yield. Melting Point 238-240°C (no literature data) and Rf 0.48 (hexane/AcOEt 7:3).

Spectroscopic data: FT-IR (KBr, cm -1 ): 3395, 3286, 3177, 2677, 1613, 1478, 1406, 1185, 1043, 729, 485. H NMR (DMSO-d6, 300 MHz, δ in ppm): 10.25 (s, 1H), 9.7 (s, 2H), 6.85-5.99 (m, 3H), 5.18 (d, 1H, J=3.3 Hz), 2.29 (s, 3H), 2.11 (s, 3H). 13 C NMR (DMSO-C/6, 75 MHz, δ in ppm): 195.3, 174.3, 147.9, 147.2, 144.9, 137.3, 120.3, 110.7, 108.6, 107.4, 101.5, 53.9, 30.8 and 18.6.

EXAMPLE 6: CATALYST RECYCLING IN BIGINELLI REACTIONS.

Carrying out recycling reactions is a prime objective of modern catalysis in order to achieve ecologically sustainable processes. In this sense, the recycling of the catalytic system was tested for the Biginelli reaction, the results obtained are shown in Figure 6. Thus, it was evidenced that the catalyst with dual activation remains active for at least 8 cycles. It should be noted that the chosen strategy of using the ionically marked catalyst and supporting it in the appropriate LI provided expressive results, making the process very attractive from the point of view of catalytic and ecological efficiency.

The catalyst was reused without loss of activity in eight recycles. Initially, the protocol was followed and 1 equivalent of β-dicarbonyl, 3 equivalents of aldehyde, 1 equivalent of urea or thiourea and 1 mL of LI were added to the system. Lys can be easily recovered together with the catalyst by washing the precipitate with ice-cold ethanol or by adding a polar solvent after removing the product by column chromatography, as required by the process.

EXAMPLE 7: ANTIPROLIFERATIVE ACTIVITY STUDIES OF BIGINELLI ADDUCTS

Due to the studies already carried out for monastrol, piperastrol, enastron and dimethyleneastron, the synthesized compounds were also evaluated for antitumor activity.

Specific cytotoxic assays were performed on human mammary adenocarcinoma (MCF-7) strains. The viability of MCF-7 cells treated with compounds derived from 3,4-dihydropyrimidinone was determined by the standard assay for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) according to the manufacturer's recommendations. Cells seeded in 96-well plates and treated with the thirty-seven DHPM derivatives at concentrations ranging from 0.5 μM to 1 mM were analyzed for their viability at 24, 48 and 72h times.

As a negative control of the experiment, cells that did not receive the treatment with the derivatives were used, incubated for each of the indicated times. The positive control was performed by treating the cells with 1 mM monastrol. The MTT assay was performed in triplicate for each compound and concentration used. The percentage of inhibition was determined by comparing the cell density of treated cells with control (untreated) cells in the same incubation period [inhibition percentage = (1 - treated group cell density)/control group cell density]. The experiments were carried out in a series of three repetitions.

Significant differences in treated and untreated cells were observed in cell viability assays, with several of the compounds having an inhibitory activity on cell proliferation in dose and time dependence. Within 24 hours some derivatives have already exhibited activity and cell viability profiles according to treatment and incubation time are shown in Figures 7-9.

Derivatives 4bo, 4bq, 4x and 4h (Figures 7A, 7C, 7D and 7F, respectively) exhibited 50% inhibitory activity at the highest concentration tested when compared to the untreated control. The piperonal-derived compounds showed this group to be about 30 times more potent than monastrol when they were tested on different cancer cell lines.

DHPM derivatives with benzaldehyde, 2-hydroxy-benzaldehyde or 4-hydroxy-3-methoxy-benzaldehyde and 4-chloro-benzaldehyde also showed a significant cytotoxic effect at 1.00 mM in 24 hours, but with activity below 50% (Figures 7B). and 7D, respectively). Acetaldehyde and formaldehyde derivatives did not show significant activity.

At 48 hours (Figure 8), the derivatives that showed better inhibitory activity at 50% were 4bt, 4bq, 4m, 4r, 4p, 4bc, 4ba and 4i (Figures 8 C-E and 8G) and three of them showed greater antiproliferative activity than 75%: 4bo (79%), 4x (87%) and 4h (85%) - (Figures 8A, 8D and 8G, respectively).

After 72 hours of treatment, 33 of the 37 compounds tested showed statistically significant inhibitory activity (Figure 9) at the highest concentration tested. Among the 23 compounds tested, some showed activity greater than 50%, 4bo, 4br, 4bs, 4bt, 4k, 4bq, 4j, 4m, 4v, 4x, 4t, 4u, 4p, 4bc, 4n, 4ba, 4bv, 4h, 4i and 4f (Figures 9A, 9C, 9D, 9E, 9F and 9G). The groups treated with compounds 4bo (500.00 mM), 4bt (1.00 mM), 4x (1.00 mM), 4t (1.00 mM), 4bc (1.00 mM) and 4h (1.00 mM) showed an average cell viability of 26%, 11%, 10%, 9%, 4% and 10%, respectively. This shows that these derivatives have a significant cytotoxic effect on tumor cells (Figures 9A, 9C, 9D, 9E and 9G).

The highest concentrations of DHPMs with benzaldehyde and formaldehyde did not show satisfactory activity at any of the three times tested (Figures 9B and 9F).

Inhibitory activity was also observed in cells treated with derivatives 4bt, 4n and 4p at lower doses compared to untreated cells at 72 h (Figure 9C and 9E). These compounds are promising chemotherapeutic agents in the treatment of cancer, since they showed cytotoxic and/or cytostatic activity for tumor cells in small doses, without any considerable damage to normal cells.

The morphological changes caused by 72 h of treatment with the derivatives with the best cytotoxic activity, which were 4bt (800 μM), 4m (1 mM), 4x (800 μM), 4p (400 μM) and 4bc (1 mM), can be seen in figures 10C, 10D, 10E, 10F and 10G, respectively. All these compounds cause tumor cell death at different rates, which can be observed by the presence of rounded and detached cells from the bottom of the plate. Untreated (Figure 10A) and cells treated with 1 mM monastrol (Figure 10B) were used as controls.

Preliminary studies using human fibroblasts from primary culture showed that the tested compounds did not show relevant cytotoxic activity against these normal cells. These data indicate specificity of action of this class of compounds on tumor cell lines, which makes these compounds potential candidates for the treatment of cancer.

Claims (30)

1. IONICALLY LABELED CATALYST FOR MULTI-COMPONENT REACTIONS, characterized by the association between a transition metal chloride, which is FeCl3, and an ionically labeled Br0nsted acid, the cation of this acid being an imidazolium. 2. IONICALLY MARKED CATALYST, according to claim 1, characterized in that the chloride transition metal is selected from the group comprising iron, zinc, tin, nickel, palladium, platinum, copper, cobalt, titanium, chromium, vanadium. 3. IONICALLY MARKED CATALYST, according to claim 1, characterized in that the ionically marked Br0nsted acid is constituted by cations selected from imidazoliums, pyridiniums, phosphoniums and ammoniums. 4. IONICALLY MARKED CATALYST, according to claim 1, characterized in that the Br0nsted acid is preferably 3-carboxymethyl-1-methyl-imidazolium chloride. 5. IONICALLY LABELED CATALYST, according to claim 1, characterized in that it is 3-carboxymethyl-1-methylimidazolium tetrachloride ferrate (MAI.FeCl4) or 3-carboxymethyl-1-methylimidazolium heptachloride-bisferrate (MAI.Fe2Cl7) . 6. PROCESS FOR OBTAINING THE IONICALLY LABELED CATALYST, according to one of claims 1 to 5, characterized in that it comprises the following steps: i) Adding the transition metal chloride to the ionically labeled Br0nsted acid; ii) Stir the mixture obtained in step i for a period 7. PROCESS FOR OBTAINING THE IONICALLY LABELED CATALYST, according to claim 6, characterized in that the ionically labeled Br0nsted acid is preferably 3-carboxymethyl-1-methyl-imidazolium chloride (MAI.Cl). 8. PROCESS FOR OBTAINING THE IONICALLY MARKED CATALYST, according to claim 6 or 7, characterized in that using the molar ratio of FeCl3: MAI.Cl in 1:1 provides 3-carboxymethyl-1-methylimidazolium tetrachloride ferrate (MAI .FeCl4). 9. PROCESS FOR OBTAINING THE IONICALLY MARKED CATALYST, according to claim 6 or 7, characterized by the fact that using the molar ratio of FeCl3: MAI.Cl in 2:1 provides 3-carboxymethyl-1-methylimidazolium heptachloride-bisferrate ( MAI.Fe2Cl7). 10. PROCESS FOR OBTAINING THE IONICALLY MARKED CATALYST, according to one of claims 6 to 9, characterized in that the temperature of the reaction medium is preferably in the range of 50 to 80 °C. 11. PROCESS FOR OBTAINING THE IONICALLY MARKED CATALYST, according to one of claims 6 to 10, characterized in that the stirring period or reaction time is in the range of 2 to 4 h. 12. METHOD OF OBTAINING 3,4-DIHYDROPYRIMIDIN-2-(1H)-ONAS AND 3,4-DIHYDROPIRIMIDIN-2-(1H)-TIONAS, especially via multicomponent reactions of the Biginelli type, characterized by the fact that it has the formula VI :

wherein: X denotes sulfur or oxygen, (1) denotes alkyl or aryl or heteroaryl, (2) denotes alkyl or aryl or heteroaryl or OAlkyl or OAryl or OHeteroaryl, (3) denotes alkyl or aryl or heteroaryl, Optionally: R2 and R3 denote -CH2C(R4)2CH2-(4) denotes H or methyl which comprises: (5) a β-dicarbonyl compound, an aldehyde and a urea or a thiourea; (6) an ionically labeled catalyst as claimed in one of claims 1 to 7. (7) one or more ionic liquids as solvents. 13. PROCESS FOR OBTAINING 3,4-DIHYDROPYRIMIDIN-2-(1H)-ONAS AND 3,4-DIHYDROPIRIMIDIN-2-(1H)-TIONAS, especially via multicomponent reactions of the Biginelli type, characterized by the fact that it has the formula VI:

wherein: X denotes S or O, R1 denotes alkyl or aryl or heteroaryl, R2 denotes alkyl or aryl or heteroaryl or OAlkyl or OAryl or OHeteroaryl, R3 denotes alkyl or aryl or heteroaryl, Optionally: R2 and R3 denote -CH2C(R4)2CH2 - R4 denotes H or methyl which comprises the following steps: a) Preparing the catalytic system by mixing the ionically labeled catalyst, according to one of claims 1 to 5, with at least one ionic liquid; b) Then, adding to the mixture obtained in step (a) a β-dicarbonyl compound, an aldehyde and a urea or a thiourea; c) Stirring the resulting mixture at a controlled temperature; d) After the end of the reaction time, cool the system and remove the final product from the catalytic system of step (a) by washing the solid formed with solvent; e) Then the solid obtained in step (d) is filtered and dried, the supernatant containing the reserved catalytic system; f) Optionally, the reaction mixture is separated from the catalytic system by column chromatography; g) Additionally, the supernatant reserved in step (e), or the fraction containing the catalytic system in step (f), is evaporated to recover the catalytic system, which is reused for a new reaction cycle through the addition of the reagents from step ( B). Process according to claim 13, characterized in that β-dicarbonyl compounds are preferably selected from the group comprising ethyl acetoacetate, acetyl ketone, 1,3-cyclohexanedione and 5,5-dimethyl-1,3-cyclohexanedione. Process according to claim 13, characterized in that the aldehydes are preferably selected from the group comprising 2-nitro-benzaldehyde, 3-nitro-benzaldehyde, 2-hydroxy-benzaldehyde, 3-hydroxy-benzaldehyde, 4 -hydroxy-3-methoxy-benzaldehyde, 4-chloro-benzaldehyde, furfuraldehyde, piperonaldehyde, benzaldehyde, acetaldehyde and p-formaldehyde. 16. PROCESS, according to claim 13, characterized in that ionic liquids are composed of anions selected from the group comprising chloride, bromide, tetrachloroindate, perchlorate, nitrate, tetrafluoroborate, tetrachloroborate, hexafluorophosphate, hexafluoroantimonate, fluoroarsenate, hexafluorothantalate, trifluoromethyl sulfate, fluorosulfonate, tetrachloroaluminate and dichlorocuprate in the formation of a homogeneous or heterogeneous liquid phase. 17. PROCESS, according to one of claims 13 to 16, characterized in that the ionic liquids are composed of cations selected from the group comprising 1,3-dialkylimidazolium, tetraalkylammonium, alkylpyridinium, tetraalkylphosphonium in the formation of a homogeneous or heterogeneous liquid phase. 18. PROCESS, according to one of claims 13 to 17, characterized in that the ionic liquids are selected from 1-n-butyl-3-methylimidazolium hexafluorophosphate (BMI.PF6), 1-butyl-3 bis-tetrafluoroborate -methyl-imidazolium (BMI.BF4) and 1-n-butyl-3-methylimidazolium bis-trifluoromethanesulfonimidate (BMI.NTf2). 19. PROCESS, according to one of claims 13 to 18, characterized in that the molar proportions between urea (or thiourea), the β-dicarbonyl compound, the aldehyde and the catalyst are in the range between 1.00 :0.20:0.20:0.01 and 1.00:5.00: 5.00:0.10. 20. PROCESS, according to one of claims 13 to 19, characterized in that the ratio between volume (mL) of ionic liquid and the molar amount (mmol) of urea (or thiourea) is in the range between 0, 10 and 1.00. Process according to one of claims 13 to 20, characterized in that the temperature of the reaction medium comprises the range from 25 to 180°C, preferably the range from 30 to 90°C. Process according to one of claims 13 to 21, characterized in that the stirring period or reaction time is 1 min to 720 minutes, preferably between 1 to 180 minutes. Process according to claim 13, characterized in that the solvent in step (d) is selected from ethanol, acetone, acetonitrile and water. 24. PROCESS, according to claim 13, characterized by the recovery of the components of the catalytic system, ionically marked catalyst and ionic liquids, as mentioned in steps (d) to (g), providing for its reuse numerous times in a new cycle of the process. 25. PROCESS, according to one of claims 13 to 24, characterized in that it operates in batch (batch), semi-continuous or continuous mode. 26. 3,4-DIHYDROPYRIMIDIN-2-(1H)-ONA characterized by the fact that it has the formula VII:

being obtained by the process as defined in claims 13 to 25. 27. 3,4-DIHYDROPYRIMIDIN-2-(1H)-TIONA characterized by the fact that it has the formula VIII:

being obtained by the process as defined in claims 13 to 25. 28. USE of the ionically marked catalyst, according to one of claims 1 to 5, characterized in that it is in multicomponent reaction methods, especially Biginelli reactions. 29. USE of the ionically labeled catalyst, according to one of claims 1 to 5, characterized in that 3,4-dihydropyrimidin-2-(1H)-ones and 3,4-dihydropyrimidin-2-(1H)-thiones are used in the preparation. 30. USE of 3,4-dihydropyrimidin-2-(1H)-ones and 3,4-dihydropyrimidin-2-(1H)-thiones characterized in that they are of formula VI:

wherein: X denotes sulfur or oxygen, R1 denotes alkyl or aryl or heteroaryl, R2 denotes alkyl or aryl or heteroaryl or OAlkyl or OAryl or OHeteroaryl, R3 denotes alkyl or aryl or heteroaryl, Optionally: R2 and R3 denote -CH2C(R4)2CH2 - R4 denotes H or methyl, in the preparation of medicaments or pharmaceutical compositions for the treatment of breast cancer.

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