BRPI0502016B1 - COMPOSITION UREÍDICOS, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AND ITS USE IN THE TREATMENT OF INFLAMMATORY DISEASES - Google Patents

Abstract

"urea compounds, pharmaceutical compositions containing them and their use in the treatment of inflammatory diseases". the present invention relates to functionalized ethyl 6-n-alkyl and / or 6-n-aryl ureas [1,3] dioxolo [5,4-g] quinoline-7-carboxylate derivatives (3a-z, 4a-z); and congeners (5a-z) of general formula (i, ii, iii and iv), useful in the treatment and / or prevention of diseases of inflammatory origin, such as inflammatory, proper, acute or chronic, different types of arthritis. , asthma, crohn's disease and type i diabetes mellitus, among others. These derivatives have the ability to modulate the inflammatory process by acting at the level of mitogen-activated protein kinase p-38 (mapk-p38). In addition, the derivatives of the present invention have significant anti-inflammatory properties measured in in vivo models. The present invention also discloses processes for producing such derivatives and pharmaceutical compositions containing them.

Description

Field of the Invention

The present invention relates to functionalized ethyl 6- / V-alkyl and / or 6-N-aryl urea [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3a-z, 4a- z); and the like (5a-z). Even more particularly, the present invention relates to the derivatives 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline'7carboxylate (LASSBio-948), 6- (4-bromophenylurea) - [1,3] ethyl dioxolo [5.4g] quinoline-7-carboxylate (LASSBio-947), 6- (4-chlorophenylurea) [1,3] dioxolo [5.4-g] quinoline-7-carboxylate ethyl (LASSBio-949), 6cic! oexilurea- [1,3] dioxolo [5,4-g] quino! ina-7-carboxy! ethyl act (LASSBio-998) 15 and its isosteres and regioisomers, to processes for its preparation, pharmaceutical compositions containing them, and its use as a therapeutic agent for the treatment of diseases of inflammatory origin, such as the different forms of arthritis, osteoarthritis, asthma, Crohn's disease and COPD (chronic obstructive pulmonary disease).

Background of the Invention

Several members of the protein kinase family have been identified to date. These enzymes catalyze the phosphorylation reaction of different substrates, performing essential functions in practically 25 all stages of cell life. Considering that about 1/3 of the known proteins in mammals contain covalently bound phosphate, any change in the functioning of these proteins can generate inadequate cellular responses, contributing to the development of pathologies such as diabetes, cancer, rheumatoid arthritis, among others [Cohen, P ., J. Biol. Chem.,

1999, 3, 459],

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• · • · • · • ·

Among the protein kinases are those activated by mitogen (mitogenactivated protein kinase, MAPK), belonging to the family of Serine-Threonine kinases that include the kinase regulated by extracellular signals (extra-cellular signa! Regulated kinase-2, ERKs), the amino kinase -terminal of c-junction (c-jun 5 amino terminal kinase, JNKs) and mitogen-activated protein p38 (mitogenactivated protein kinase p38, MAPK p38). These kinases have 60-70% homology to each other and are characterized by the presence of the sequence Thr-Xaa-Tyr at the activation site, thus being able to be doubly phosphorylated in the residues of the amino acids threonine and tyrosine by MAPK kinases (MKK) in all response to extracellular stimuli [Muzio, M. et. there, Science, 1997, 278, 1612],

Activation of MAPK-p38 occurs in response to osmotic shock, heat, ultraviolet light, pathogens such as gram-negative bacteria (LPS) lipolysaccharides and different interleukins (IL) such as IL-1, IL15 2, IL-7 , IL-17, IL-18, cytokines as the growth transforming factor

□ (TGF-β) and tumor necrosis factor □ (TNF-α). Once activated, MAPKp38 acts by promoting the activation of other kinases, nuclear transcription factors responsible for the expression of pro-inflammatory cytokines, adhesion molecules and cytoplasmic proteins [Clark, AR, et a /., FEBS 20 Letters, 2003, 546].

Currently, four members of the MAPK-p38 family are known: designated by the letters α, β, γ and δ. These isoforms differ in tissue distribution, activation of other kinases and phosphorylation of substrates [Lee, J. C. et al, Nature, 1994, 372, 739].

The degree of homology of p38a in relation to ρ38β, ρ38γ and p38õ is 75,

62, and 64%, respectively. Although the expression of p38a and related kinases can vary, this enzyme is predominantly expressed in cells involved with the organism's inflammatory and immunomodulatory response [Lee, JC et al, Nature, 1994, 372, 739], justifying its central role in development of pathologies of inflammatory origin.

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ΜΑΡΚ-ρ38α is involved in cellular events in response to LPS that induce cell adhesion and may lead to the activation of nuclear transcription factors with consequent synthesis of TNF-α and IL-1 β [Reingeaud, J. et. al., Mol. Cell. Biol. 1995, 16, 1247], The biological action of these cytokines 5 can be attributed to the ability to activate the nuclear transcription factor kB (NFüB), thus contributing to the orchestration of the inflammatory response [Baeuerle, PA and Baltimore, D, Ce // , 1996, 87, 13].

Due to the central role played in the different stages of the inflammatory process, the activity of MAPK-p38 has been related to several pathogens, among which it is important to highlight rheumatoid arthritis [Kumar, S. et. al., Nature Drug Discovery 2003, 2, 717]. In the development of the inflammatory process of rheumatoid arthritis, the presence of a large number of mononuclear cells in the synovium is closely related to the degree of pathogenesis of the disease. Macrophages in the rheumatoid synovium have a high concentration of MAPK-p38 activated with consequent production of TNF-α and

Q>

IL-1 β, essential cytokines in the development of pathogenesis.

The realization that MAPK-p38 played a key role in inflammatory processes made the enzyme inhibition an attractive therapeutic strategy for the treatment of different pathological conditions of inflammatory origin.

The first synthetic prototype capable of selectively inhibiting MAPK-p38 was the imidazole pyridinyl derivative SFK-86002 [Lee, J. C. et. al., Int. J. Immunopharmacol. 1988, 10, 835; Lee, J. C. et al. Ann. NY Acad. Know. 1993,

696, 149], which was later replaced by the 2,4,5-triaryl imidazolic derivative SB-203580 [Gallagher, T. F. et al. Bioorg. Med. Chem. Lett.1995, 5, 1171], both used as a pharmacological tool in the search for new molecular targets involving the regulation of cytokines.

Several patents describe MAP kinase inhibitors, and some describe p38 MAP kinase inhibitors. We can mention several, such as WO 30 95/09851, WO 97/16442, WO 98/06715, WO 98/07425, WO 98/56377, WO

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99/01136, WO 00/01688, WO 00/07991, WO 00/06563, WO 00/12074, WO 01/29041, WO 01/62731, WO 01/05744, WO 04/089929, WO 04/016267.

Currently, several MAPK-p38 inhibitors are in the phase of clinical studies [Jessie M. et. a., TRENDS in Pharm. Sciences, 2002, 23, 40] and 5 some examples are illustrated below.

Summary of the Invention

It is an object of the present invention to provide alternatives for ίο treatment and prevention of inflammatory and / or inflammatory diseases, in particular, different forms of arthritis, osteoarthritis, asthma, among others. In one aspect of the invention, the main limitations and complications associated with drug therapy, usually employed in the treatment of inflammatory pathologies, would be circumvented or minimized with the use of 15 ureidic derivatives, which act as inhibitors of MAPK-p38 and / or lower levels of activation of NFkB

6- A derivative of the general formula (I) and / or (II) and / or (III) and / or (IV) below is a further object of the present invention:

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Where:

• * 9 9 9 « • • * * V • 4 • • · • · 9 9 9 »· • · • 9 • 9 9 9 9 • 9 9 9 9 9 9 • · 9 9 9 * * The t * 9 9 • · 9 9 « THE 9 9 • • * · 9 9 • · ·

Ri corresponds to OCH ₃ or OCH ₂ CH ₃ or OPh or OBn or NH ₂ or NHCH ₃ or nhnh ₂ ;

W = (2 and / or 3 and / or 4 and / or 5 and / or 6) -F or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CI or (2 and / or 3 and / or 4 and / or 5 and / or 6) -Br or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CH ₂ CH3 or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CF ₃ or

(2 and / or 3 and / or 4 and / or 5 and / or 6) -OCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -OCF ₃ io or (2 and / or 3 and / or 4 and / or 5 and / or 6) - (2 and / or 3 and / or 4 and / or 5 and / or 6) -NO ₂ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -NH ₂ ; (2 and / or 3 and / or 4 and / or 5 and / or 6) -NHCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -NHCOCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) NHSO ₂ CH ₃ ;

R ₂ CH ₃ or CH ₂ CH ₃ or (CH ₂ ) ₂ CH ₃ or (CH ₂ ) ₃ CH ₃ or (CH ₂ ) ₄ CH ₃ or (CH ₂ ) ₅ CH ₃ or 15 CH (CH ₃ ) ₂ or C (CH ₃ ) 3OU cyclopropyl, or cyclopentyl or cyclohexyl or cycloheptyl;

Ar corresponds to 2-Py or 3-Py or 4-Py or 2-thiophene or 2-furan or 2-pyrrole or 1-naphthyl or 2-naphthyl or quinoline, or quinoxaline or oxazole or thiazole or thiadiazole, oxadiazole or pyrimidine or triazole or imidazole;

A further object of the present invention is a process for preparing ureidic derivatives. More specifically, such a process comprises synthetic steps such as: regioselective aromatic electrophilic substitution; condensation

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• · <·· • • THE • · • · • · • · • • · • • · • · • · • · • · • · • • • W • · • · • · • · • • • ··· •

• · ♦ aldolic type with ethyl cyanoacetate; reduction followed by cyclization through intramolecular nucleophilic addition; condensation (amino intermediate with functionalized isocyanates); interconversion of functional groups

It is a further object of the present invention to prepare pharmaceutical compositions containing urelic derivatives and their use in the treatment of inflammatory diseases and pathological conditions. More specifically, such pharmaceutical compositions are capable of inhibiting p38 MAP-Kinase and / or inhibiting NFkB activation.

Description of the Figures

Figure 1: Genesis of the new derivatives (3a-z; 4a-z; 5a-z), drawn from the prototypes (GK00687,1) and (2)

Figure 2: PlC50 values proposed for some of the 15 ureldic derivatives planned as MAPK-p38 inhibitors, compared to the plCSO values of the GK 00687 and SB 203580 prototypes, based on the CoMFA model

Figure 3: Effect of LASSBio-947 (3d) and SB202190 on MAPK-p38 activation of murine peritoneal macrophages stimulated with LPS, indicating autoradiography (A) with the respective columns representing 20 relative optical densities of each band ( B). Preparations: RPMI =

macrophages in / ve; LPS = macrophages stimulated with LPS 10 pg / ml; LASSBio-947 = macrophages stimulated with LPS in the presence of different concentrations of the LASSBio-947 molecule (3d) (1, 10, 100 and 1000 μΜ); SB = macrophages stimulated with LPS in the presence of different concentrations of 25 SB202190 (1 and 10 μΜ). IC ₅₀ (LASSBio-947 (3d)) = 8.7 μΜ.

Figure 4: Effect of LASSBio-948 (3a) on the activation of MAPK-p38 of murine peritoneal macrophages stimulated with LPS, indicating the autoradiography (A) with the respective columns that represent the reported optical densities of each band (B). Preparations: RPMI = 30 macrophages in / ve; RPMI + DMSO = naive macrophages in the presence of DMSO

0.5%; LPS = macrophages stimulated with LPS 10 pg / ml; LPS + DMSO =

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• · • and • · · · · · • · · · · · · • • • · • · • • · • • · · • * · • «· · •

macrophages stimulated with LPS 10 pg / ml in the presence of 0.5% DMSO; LASSBio-948 = macrophages stimulated with LPS in the presence of different concentrations of the molecule LASSBio-948 (3a) (1, 10, 100 and 1000 μΜ). IC ₅ o

(LASSBio-948 (3a)) = 13.6 μΜ.

Figure 5: Effect of LASSBio-949 (3c) on MAPK-p38 activation of murine peritoneal macrophages stimulated with LPS, indicating autoradiography (A) with the respective columns representing the reported optical densities of each band (B). Preparations: RPMI = naive macrophages; RPMI + DMSO = naive macrophages in the presence of 0.5% DMSO io; LPS = macrophages stimulated with LPS 10 pg / ml; LASSBio-949 = macrophages stimulated with LPS in the presence of different concentrations of the molecule LASSBio-949 (3c) (1, 10, 100 and 1000 μΜ); SB = macrophages stimulated with LPS in the presence of different concentrations of SB202190

(1, 10 and 100 μΜ). IC ₅₀ (LASSBio-949 (3c)) = 30 μΜ.

Figure 6: Effect of LASSBio-998 (4m) on MAPK-p38 activation of murine peritoneal macrophages stimulated with LPS, indicating autoradiography (A) with the respective columns representing the reported optical densities of each band (B). Preparations: RPMI = naive macrophages; LPS = macrophages stimulated with LPS 10 pg / ml;

LASSBio-998 = macrophages stimulated with LPS in the presence of different concentrations of the molecule LASSBio-998 (4m) (1, 10, 100 and 1000 μΜ); SB = macrophages stimulated with LPS in the presence of different concentrations of

SB202190 (10 μΜ). IC ₅₀ (LASSBio-998 (4m)) = 5.5 μΜ.

Figure 7: Reduction in the increase in weight of the left popliteal lymph node in mice that received zimosan and were treated with the substances LASSBio-947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c).

Groups of 8 animals received s.c. injection of sterile saline or 150 pg of zimosan (prepared in saline) in the left paw. Seventy-two hours after the injection, the animals were treated i.p. with 10 mg / kg of substances L-947, L3o 948 and L-949 for 4 days. After this period, the left popliteal lymph node was

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dissected and weighed. Values are presented as the mean + SEM, where ** p <0.01 and *** p <0.001.

Figure 8: Reduction of the number of lymphocytes in the left popliteal lymph node in mice that received zimosan and were treated with the 5 substances LASSBio-947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c).

Groups of 8 animals received s.c. injection of sterile saline or 150 pg of zimosan (prepared in saline) in the left paw. Seventy-two hours after the injection, the animals were treated i.p. with 10 mg / kg of substances L-947, L948 and L-949 for 4 days. After that period, the lymph node cells were isolated and counted in a Neubauer chamber.

Figure 9: Inhibition of NFkB translocation of lymphocytes from the lymph nodes of C57BI6 mice treated with the compounds LASSBio-947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c). Auto-radiography image obtained from the lymphocyte nuclear extract after electrophoretic run on a 15 polyacrylamide gel. Ctr ⁺ = positive control, HeLa cells treated with 10 Cg LPS; SF = negative control, non-radioactive probe; Salt = animals injected with saline; Animals injected with 150 pg of zimosan and treated ip with 0.5% DMSO for 4 days (Veie); with 10 mg / kg of rofecoxib (Vioxx) or with 10 mg / kg of the compounds LASSBio-947, LASSBio-948 or LASSBio-949.

Detailed Description of the Invention

Having made a brief reference to the objects of the present invention, we will now proceed to describe it in detail, using, whenever appropriate, the preferred embodiments of the invention.

This invention has as one of its innovative features the synthesis of new functionalized 6-Wa! Quil and / or 6- / V-aryl urea [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3a -z, 4a-z); and the like (5a-z). Even more particularly, that of the derivatives 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7carboxylate (hereinafter called LASSBio-948), 6- (430 bromophenylurea) - [1,3] dioxolo [5.4-g] ethyl quinoline-7-carboxylate (hereinafter referred to as LASSBio-947), 6- (4-chlorophenylurea) - [1,3] dioxolo [5,4-g] quinoline-7 • · «· · · · · ·

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• · · · ·· ··· ······· · · · • · ·· * · ···

ethyl carboxylate (hereinafter referred to as LASSBio-949), ethyl 6-cyclohexylurea [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (hereinafter referred to as LASSBio-998), its isosteres and regioisomers (3a-z _t 4a-z, 5a-z), planned based on structural modifications in ureidic prototypes (1) and (2) and 5 designed rationally as MAPK-p38 inhibitors using QSAR / CoMFA (Quantitative Structure-Activity Relationship / Comparative) techniques Molecular Field Analysis) (Figures 1 and 2).

The new compounds were obtained in good to excellent chemical yields, using the synthetic methodology described here, according to the scheme below, which is characterized by having few steps, starting from commercially available compounds, which qualifies this synthetic methodology for industrial use .

The compounds of the present invention were designed through convergent syntheses, using classic reactions such as:

Regioselective Aromatic Electrophilic Replacement

Aldolic-type condensation with ethyl cyanoacetate

Reduction followed by cyclization through intramolecular nucleophilic addition

Condensation (amino intermediate with functionalized isocyanates)

Interconversion of Functional Groups

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Conditions: a) HNO ₃ . ok, 15 min. 95%; b) NCCHsOOCHíCHa, EtOH, KF / AI ₂ O ₃ , 35 ^D C,

2h30min., 94%; c) Zn, TiCU, THF, reflux, 3h30min., 84%; d) 4-W-phenyl-isocyanate (or 5 cyclohexylisocyanate), Toluene, reflux, 72h.

More specifically, the compounds (3a-z; 4a-z; 5a-z) of the present invention can be prepared by a process comprising the steps of:

io · Regioselective aromatic electrophilic substitution of the benzo [dK1,3] dioxo! a-5-carbaldehyde or piperonal system (7).

Treatment of the nitrated intermediate 8 with ethyl cyanoacetate, in the presence of potassium fluoride supported on alumina (KF / AI2O3) as a base, ethanol as a solvent, at a temperature of 35 ° C, exploring a diastereoselective aldolic condensation reaction.

Reduction of the configuration nitro-acrylate (E) 9, using titanium tetrachloride (TiCI ₄ ) in the presence of zinc (Zn) and tetrahydrofuran as a solvent, at reflux temperature, for later cyclization of the amino-formed intermediate through addition intramolecular nucleophilic to group 20 nitrile.

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• · • · • · · · · · • · · · · · · • · · • · · · • · · • · · · ♦

Condensation of the amino derivative 10 with arylisocyanates and / or cycloalkylisocyanates and / or alkylisocyanates and / or heteroarylisocyanates, in the presence of anhydrous toluene at reflux temperature.

Interconversions of functional groups from intermediate (10) or derivatives (3a-z; 4a-z; 5a-z), exploring transesterification, hydrolysis, aminolysis and hydrazinolysis reactions.

As an example, in this report we describe the synthesis of the following compounds:

ίο 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3a); 6- (4-fluoro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3b); 6- (4-chloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3c); 6- (4-bromo-phenylurea) - [1,3] dioxolo [5 ₁ 4-g] quinoline-7-carboxylate (3d); 6- (4-methyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3e);

6- (4-trifluoromethyl-phenylurea) - [1,3] dioxide [5,4-g] quinoIin-7-carboxylate

(3f);

6- (4-methoxy-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3g); 6- (4-trifluoromethylether-phenylurea) - [1,3] dioxolo [5 _> 4-g] quino! Ethyl-7-carboxylate (3h);

6- (4-nitro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3i); 6- (4-amino-phenylurea) - [1,3] dioxide [5,4-g] quinoline-7-carboxylate (3j); 6- (4-methylamino-phenylurea) - [1,3] dioxolo [5,4-g] choline! 7-carboxyate ethyl (31);

6- (4-acetamido-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3m);

6- (4-methanesulfonamide-phenylurea) - [1,3] dioxolo [5 ₁ 4-g] quinoline-7-carboxylate (3n);

6- (2,6-difluoro-phenylurea) - [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (3rd);

6- (2-chloro-phenylurea) - [1,3] dioxolo [5 ₁ 4-g] quinoinine-7-carboxylate (3p);

6- (3-chloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3q);

6- (2,3-dichloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxy ethyl (3r);

V

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6- (2,6-dichloro-phenylurea) - [1 _l 3] dioxolo [5 _l 4-g] quinoline-7-carboxylate (3s); 6- (4-ethyl-phenylurea) - [1,3] dioxolo [5,4-ff] quinoline-7-carboxylate (3t); 6- (2,6-ethyl-phenylurea) - [1 _l 3] dioxolo [5.4-g] quinoline-7-carboxylate (3u); 6- (2,6-methyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxy ethyl (3v);

6- (2-methoxy-phenylurea) - [1,3] dioxolo [5,4-g] quinoin-7-carboxy ethyl act (3x);

6- (2-nitro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3z); Ethyl 6-methylurea- [1,3] dioxolo [5.4-g] quinine-7-carboxylate (4a);

Ethyl 6-ethylurea- [1,3] dioxide [5,4-g] quinoline-7-carboxylate (4b); Ethyl 6-propylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4c);

ethyl 6-isopropylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4d);

Ethyl 6-terbutillureia- [1,3] dioxide [5,4-g] quinoline-7-carboxylate (4e);

6-butylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxy ethyl (4f);

Ethyl 6-pentylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4g); Ethyl 6-hexylurea- [1,3] dioxo [o 4,4-g] quinoline-7-carboxylate (4h);

ethyl 6-benzylurea- [1 ₍ 3] dioxolo [5,4-g] quinoline-7-carboxylate (4i);

Ethyl 6-cyclopropylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4j); Ethyl 6-cyclopentylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (41); Ethyl 6-cyclohexylurea- [1,3] dioxide [5,4-g] quinoline-7-carboxylate (4m); Ethyl 6-cycloeptylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (4n);

Methyl 6-cyclohexylurea- [1,3] dioxolo [5,4-quinquinoline-7-carboxylate (4o);

Phenyl 6-cyclohexylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4p);

Benzyl 6-phenylurea- [1,3] dioxide [5,4-g] quinoline-7-carboxylate (4q);

6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxamide acid (4r);

6-phenylurea- [1,3] dioxide [5,4-g] quinoline-7-methylcarboxamide (4s);

6-phenylurea- [1,3] dioxolo [5,4-g] quinoinine-7-carbonylhydrazine (4t);

Methyl 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4u);

6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxamide (4v);

6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylic acid (4x);

6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carbonylhydrazine (4z);

6- (2-pyridine! Urea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5a);

Ethyl 6- (3-pindinylurea- [1,3] dioxolo [5,4-Sf] quinoline-7-carboxylate (5b);

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• · • ····· · · • · · • • · • ···· · · · · · ·· • ♦ • ··· * · * · i · • Λ • • · · ····· • · · •

6- (4-pyridinylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5c); 6- (2-thienylurea- [1,3] dioxolo [5,4-g ] ethyl quinoline-7-carboxylate (5d);

6- (2-furylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5e); 6- (2-imidazolylurea- [1,3] dioxo! O [5,4 -g] ethyl quinoline-7-carboxylate (5f);

6- (2-pyrrolylurea- [1 ₁ 3] dioxolo [5.4-g] quinoline-7-carboxylate (5g);

6- (2-pyrazolylurea- [1,3] dioxolo [5,4-g] quinoinine-7-carboxylate (5h); 6- (1 ₎ 3,4-thiadiazolylurea- [1 _l 3] dioxolo [5.4-g] ethyl quinoline-7-carboxylate (5i);

6- (1,3,4-oxadiazolurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5j); 6- (1-naphthylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5I);

ίο 6- (2-naphthylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5m);

Ethyl 6- (2-quinoline) [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5n);

6- (4-pyrimidinylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5o);

6- (4-quinazolinylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5p); 6- (1,3-oxazolylurea- [1,3] dioxolo [5.4 -g] ethyl quinoline-7-carboxylate (5q);

Ethyl 6- (1,3-thiazolylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5r);

6- (1H-5-imidazolylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5s); 6- (4 / - / '1 _l 2,4-triazolylurea- [ 1 _l 3] _ethyl dioxolo [5.4-g] quinoline-7-carboxylate (5t);

6- (4-methanesulfonyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoinine-7-carboxylate (5u);

6- (4-methanesulfonyl-phenylurea) - [1,3] dioxide [5,4-g] quinoline-7-carboxamide (5v);

6- (4-methanesulfonyl-phenylurea) - [1 _l 3] dioxolo [5.4'9] quinoline-7-carboxylic acid (Sx);

6- (4-methanesulfonyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7carbonylhydrazine (5z).

A detailed description of the synthetic methods of this invention for some of the claimed compounds is reported below. The following examples illustrate, but do not limit the present invention.

Example 1

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• · • · • · * ·· · • «· · · · · • · · • · · · • · • r · • • · · • «· · ·« · *

6-nitrobenzo [d] [1,3] dioxolo-5-carbaldehyde [adapted from Barreiro, E.

-. J. ct al., J. Chem. Rcs., (S), 1982, 102] <

2nd

The piperonal (7) (6.66 mmol;

1g) and 3.3 mL of concentrated HNO ₃ , the resulting suspension remaining at

is under vigorous magnetic stirring. Immediate color change (colorless —► yellow) is observed. Follow-up by CCF reveals completion of the reaction in 15 minutes. The isolation is done by cooling the reaction medium in an ice bath, observing immediate precipitation. The precipitated yellow solid is filtered through a funnel and washed with saturated NaHCO ₃ solution, followed by washing with distilled water until the washing water has a pH = 7.

Ethyl 2-cyano-3- (6-nitrobenzene [d] [1,3] dioxol-5-I) - (E) -2-propenoate [adapted from Zhou, L. et al., J. Chem. Research (S), 1998, 398],

O O NCCH ₂ CO ₂ Eí / \ KF / A1 ₂ Oj * \ ^no 2 EtOH / ta. no ₂ 8 2 h 30 min 9 15 94%

In a round-bottomed flask containing nitro-piperonal (8) (1.9512g; 10mmol), KF / AI ₂ O ₃ (200mg), ethyl cyanoacetate (1.133g, 10mmol) and 10ml of dry ethanol. The resulting suspension was maintained under vigorous magnetic stirring and heated to 35 ° C. Monitoring by

2nd CCF indicates completion of the reaction in 2 hours and 30 minutes. The solution is yellow in color from start to finish. Isolation is done by reducing the volume of solvent in a rotary evaporator, followed by diluting the medium with dichloromethane, followed by filtration of the white solid (KF / AI ₂ O ₃ ) in a funnel.

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• · • · «* · • • • 9 • · «· «· · • • • • · 0 • • · • » • · · • · • • • • • • · • «·  · • • • • · * · • • • · · • · · •

buckner. The filtrate is added to a separating funnel, washed with distilled water, then the organic phase is dried with anhydrous Na ₂ SO ₄ and concentrated to provide yellow amorphous solid (9) in 94% yield.

Ethyl 6-amino [1,3] dioxolo [5.4-g] quinoline-7-carboxylate

In a two-mouthed balloon equipped with a condenser and

N ₂ , containing zinc (1.04 g, 16 mmol), previously treated with HCl 10% and dried in an oven for 24 hours, is added with the aid of a syringe 8 mL of THF, initiating the magnetic stirring. Then, with the aid of a syringe, 0.88 mL of TiCI ₄ (8 mmol) are carefully dripped. There is an immediate change in the color of the reaction medium that takes on a dark green color, the medium is kept stirring at reflux temperature for 2 hours. Heating is switched off, and after cooling the reaction medium, 15 drops of cyano-derivative 9 (0.580g, 2mmol) solubilized in 5 mL of THF are added.

A change in color is observed, assuming the reaction medium in black-red color. The reaction mixture is subjected to magnetic stirring at r.t. per hour and 30min.

Isolation is done by pouring the contents of the balloon into a Becker

2o containing 40 mL of 10% aqueous K ₂ CO _{3 solution} . Then, about 100 mL of dichloromethane is added, leaving the resulting suspension under vigorous magnetic stirring until extraction into the organic phase. The suspension is filtered under vacuum, washing thoroughly with dichloromethane. The filtrate is transferred to a separatory funnel and is washed with water. The organic phase is dried with anhydrous Na ₂ SO ₄ and concentrated to provide an amorphous brown colored solid in 84% yield. Subsequently, purification is carried out through recrystallization in a hydro-alcoholic mixture.

• · ·· · · · • «· ··» ···· • · · «·· · · ·

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General procedure for the synthesis of the functionalized ethyl 6-N-alkyl and / or 6N-aryl urea [l] ldioxolo ^. ^ Glquinoline ^ carboxylate (3a-z, 4a-z, 5a-z) [adapted from Dumas, J. et al., Bioorg. Med. Chem. Lett. 2000, 10, 2054]

In a round bottom flask connected to a reflux condenser,

containing the ortho-aminoquinoline derivative 10 (0.5g; 1.823mmol), the properly formalized isocyanate (3.65mmol) and anhydrous toluene as solvent (100ml) are added. The reaction mixture is stirred magnetically at reflux temperature for 72 hours.

Isolation begins by diluting the reaction medium with dichloromethane, followed by reducing the volume of solvent in a rotary evaporator. Then, 100 ml of AcOEt are added, the contents of the flask are poured into a separating funnel, washing with saturated NaCI solution, followed by washing with distilled water. The organic phase is dried with

In anhydrous ₂ SO ₄ , concentrated in a rotary evaporator to provide the desired urea in an average yield of 78% after purification through recrystallization in a hydroalcoholic mixture.

Ethyl 6-phenylurea- [1,3] dioxofo [5.4-g] quinoline-7-carboxylate (3a)

This derivative was obtained in 96% yield, through the nucleophilic addition of the 2-amino-quinoline derivative (10) to the phenylisocyanate, as a light brown amorphous solid, mp .: 202-203 ° C.

¹ H NMR (200 MHz; DMSO-d ₆ ) S: 1.39 (3H, t, RCOOCH ₂ CH ₃ , J = 6, 95

Hz); 4.41 (2H, q, RCOOChhCHs, J = 6, 95 Hz); 6, 27 (2H, s, 000): 7, 09 (1H, t, C4'-H, J = 7, 28 Hz); 7, 37 (2H, t, C3’-H and C5’-H, J = 7.33 Hz); 7,52 (1H, s, C8 • · • ♦ ·

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H); 7.54 (1H, s, C5-H); 7.75 (2H, d, C2'-H and C6'-H, J = 7.33 Hz); 8.88 (1H, s, C4-H); 10.26 (1H. S, CO-NH-Ph); 12.19 (1H, s, Pyr-NfckOC) ppm.

¹³ C NMR (50 MHz, DMSO-dj) δ: 13, 9 (RCOOCH ₂ CH ₃ ); 61, 8 (RCOOCH2CH3.); 102, 5 (OCHzO); 103.1 (C8); 104.0 (C3); 107, 5 (C4 '); 119, 25 (C5); 119, 4 (C2 'and C6'); 123, 1 (C4a); 128, 9 (C3 'and C5'); 138, 4 (C1 '); 141, 3 (C4); 145.0 (NÇON); 146, 8 (C8a); 149, 1 (C7); 151, 1 (C6); 157, 5 (C2); 162.0 (RÇOOR ') ppm.

IR (KBr pellet): 3273 (v NH); 3214 (v _s NH); 1683 (v C = O of ester); 1616 (v C = O of urea); 1527 (v ester COC); 1480 (v C = C); 1240 (v C-C O10); 1032 (v _s COC) cm '.

6- (4-chloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3c);

This derivative was obtained in 85% yield, by adding 15 nucleophilic derivative 2-amino-quinoline (10) to 4-chloro-phenylisocyanate, as a brown amorphous solid, mp .: 199-201 ° C.

¹ H NMR (200 MHz, DMSO-d ₆ ) δ: 1.39 (3H, t, RCOOCH ₂ CH ₃₁ J = 6, 95 Hz); 4.40 (2H, q, RCOOCH2CH3. J = 6, 95 Hz); 6.26 (2H, s, OCH2O); 7.39 (2H, d, C3'-H and C5'-H, J = 8.79 Hz); 7.46 (1H, s, C8-H); 7.80 (2H, d, C2-H and C6'-H, 20 J = 8.79 Hz); 8.86 (1H, s, C5-H); 8, 87 (1H, s, C4-H), 10.28 (1H, s, CO-NHPhCI); 12.25 (1H, s, Pyr-NHzOC) ppm.

¹³ C NMR (50 MHz, DMSO-cfe) δ: 15, 1 (RCOOCH ₂ ÇH ₃ ); 60, 4 (RCOOÇH ₂ CH ₃₁ ); 105.5 (OCH2O); 109, 7 (C8); 119, 9 (C3); 120.0 (C2 'and C6'); 122, 2 (C5); 125, 1 (04 '); 125, 3 (C4a); 128, 8 (03 'and C5'); 138, 4 (C1 '); 138.625 (C4); 145.0 (NÇON); 147, 8 (C8a); 149, 8 (C7); 151, 1 (C6); 154, 6 (C2); 167.0 (RÇOOR ') ppm.

IR (KBr pellet): 3292 (v NH); 3268 (v _s NH); 1683 (v C = O of ester); 1618 (v C = O of urea); 1526 (v ester COC); 1492 (v C = C); 1243 (v CO

Ç); 1030 (v _s COC) cm ^-1 .

6- (4-bromo-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3d);

• ·

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This derivative was obtained in 95% yield, through the nucleophilic addition of the 2-amino-quinoline derivative (10) to the 4-bromo-phenylisocyanate, as a dark brown amorphous solid and mp: 213-215 ° C.

¹ H NMR (200 MHz, Pyd ₅ ) δ: 1, 04 (3H, t. RCOOCH ₂ CH ₃ , J = 7, 12 Hz);

4.10 (2H, q, RCOOCH2CH _3. J = 7, 14 Hz); 5.99 (2H, s, OCH2O); 7:39 (2H, d,

C3’-H and C5’-H, J = 8.79 Hz); 7, 78 (2H, d, C2’-H and C6’-H, J = 8.78 Hz); 8.49 (1H, s, C8-H); 9.27 (2H, s. C4-H and C5-H); 10.58 (1H, s, CO-NH-PhBr); 12, 44 (1H, s, Pyr-NH4 OC) ppm.

¹³ C NMR (50 MHz, Pyd ₅ ) δ: 14, 5 (RCOOCH ₂ ÇH ₃ ); 60, 8 (RCOOÇH ₂ CH _3. Io.); 104, 6 (OChkO); 108, 5 (C8); 133, 9 (C3); 115, 1 (C5); 119, 9 (C4 '); 120, 8 (C2 'and C6'); 122.0 (C4a); 132, 1 (03 'and C5'); 138, 3 (C1 '); 139, 4 (C4); 145, 7 (NÇON); 147, 4 (C8a); 151, 7 (C7); 152, 8 (C6); 154, 3 (C2); 167, 3 (RÇOOR ')

ppm.

IR (KBr pellet): 3299 (v NH); 3218 (v ₅ NH); 1682 (v C = O of ester); 15 1616 (v 0 = 0 urea); 1525 (v ester COC); 1488 (v C = C); 1243 (v C-OC); 1030 (v _s COC) cm * ¹ .

6- (4-nitro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3i);

This derivative was obtained in 75% yield, by adding the 2nd nucleophilic derivative 2-amino-quinoline (10) to the 4-nitro-phenylisocyanate, as yellow amorphous solid and mp: 227-230 ° C.

¹ H NMR (200 MHz, Pyd5) δ: ¹ H NMR (200 MHz; DMSO-d6) δ: 1, 39 (3H, t, RCOOCH ₂ CH ₃₁ J = 7, 08); 4.45 (2H. Q, RCOOCHzCHjj, J = 7.09); 6.54 (2H, s, OCH2O); 8. 11 (2H, d, C3-H and C ₅ -H. J = 9.28 Hz); 8, 84 (2H. D, C2'-H and C6'-H,

J = 9.28); 8.92 (1H, s, C8-H); 9.47 (1H, s, C5-H); 9.48 (1H, s, 04-H), 10.67 (1H, s, CO-NH-PhNO ₂ ); 13, 19 (1H, s, Pyr-NhbOC) ppm.

¹³ C NMR (50 MHz, DMSO-d _e ) δ: 15, 3 (RCOOCH ₂ CH ₃ ); 60.7 (RCOOCliCHa,); 105. 8 (OCFbO); 109, 7 (08); 117, 9 (C3); 118, 4 (02 'and 06'); 127, 2 (C5); 128. 5 (C4a); 130, 1 (04 '); 136, 5 (03 'and C5'); 143, 4 (CT); 145, 30 (04); 145.7 (NÇON); 148, 8 (C8a); 150, 2 (C7); 154, 4 (C6); 158, 4 (C2); 170, 1 (RÇOOR ') ppm.

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IR (KBr pellet): 3270 (v NH); 3253 (v _s NH); 1747 (v C = O of ester); 1684 (v C = O of urea); 1598 (v ester COC); 1499 (v C = C); 1247 (v C-OC); 1033 (v _s COC) cm '.

Ethyl 6-cyclohexylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate 5 (4m);

This derivative was obtained in 80% yield, through the nucleophilic addition of the 2-amino-quinoline derivative (10) to the cyclohexylisocyanate, as a brown amorphous solid, mp .: 179-182 ° C.

¹ H NMR (200 MHz, DMSO-d _e ) δ: 1, 42 (3H, t, RCOOCH ₂ CH ₃₎ J = 6, 96

Hz); 1. 61-2, 17 (10 H, m, C2'-H ₂ / C6'-H2, C3'-H ₂ / C5'-H ₂ , C4'-H ₂ ); 3.80-4.01 (1H, m, C1 '); 4.38 (2H, q, RCOOCfhCHs. J = 6, 96 Hz); 6.13 (1H, s, OCH3);

7.02 (2H, s, C5 and C8); 8, 62 (1H, s, C4); 10.01 (1H, d, CO-NH-C6Hn, J = 7, 69 Hz); 10, 12 (1H, s, Pyr-NHzOC ppm.

¹³ C NMR (50 MHz, DMSO-d _e ) δ: 14, 1 (RCOOCH ₂ ÇH ₃ ); 24, 2 and 24, 6 (C3 'and C5'); 25, 3 (C4 '); 32, 5 and 33, 4 (C2 'and C6); 47, 9 (CT); 54.9 (RCOOÇH ₂ CH ₃ ); 102, 6 (OCfcbO); 102, 7 (C8); 105.0 (C5); 107, 8 (C3); 119.0 (C4a); 141, 4 (C4); 145.0 (C8a); 146, 7 (NÇON); 150, 0 (C7); 153, 0 (C6); 154, 2 (C1); 166, 1 (RÇOOR ¹ ) ppm.

IR (KBr pellet): 3285 (v NH); 3213 (v _s NH); 1681 (v C = O of ester);

1617 (v C = O of urea); 1528 (v ester COC); 1480 (v C = C); 1240 (v C-OC); 1032 (v _s COC) cm ^-1 .

Ethyl 6-acetylamino [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (11)

ZE

In a round-bottomed flask containing the ortho-aminoquinoline derivative 10 (6.04mg; 2.21 mmol), anhydrous toluene (30mL) and acetic anhydride were added

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• · (0.5mL), the resulting mixture remaining in vigorous magnetic stirring at reflux temperature for 48 hours. The isolation is done by cooling the reaction medium in an ice bath, followed by filtration in a buckner funnel of the formed solid, which is then washed with hot AcOEt, to provide 5 brown-colored powder in 78% yield.

¹ H NMR (200 MHz; DMSO-d _e ) δ: 1,21 (3H, t, RCOOCH ₂ CH ₃ , J = 6, 95);

2.11 (3H, s, NCOCH ₃ ); 4, 2 (2H, q, RCOOCH2CH3, J = 6, 95); 6.27 (2H, s, OCH2O); 7.2 (1H. S, C _to -H); 7.43 (1H, s, C ₅ -H); 8:47 (1H, s. C ₄ -H); 10, 66 (1H, s, Pyr-NÜOC) ppm.

IV (KBr tablet): 3284 (see _aa NH); 3217 (v, NH); 1666 (v C = O of ester);

1605 (v C = O of acetyl); 1526 (v ester COC); 1439 (v C = C); 1200 (v C-OC); 1040 (v _s COC) cm ^-1 .

The new ureidic compounds LASSBio-947 (3d), LASSBio-948 (3a), 15 LASSBio-949 (3c) and LASSBio-998 (4m) were characterized spectroscopically, and initially evaluated in in vitro models using the Western blot technique.

Western blot is one of the most commonly used immunochemical techniques for detecting proteins in complex mixtures. The method is based on the electrophoretic separation of proteins in polyacrylamide gel in the presence of anionic detergent sodium duodecyl sulfate (SDS), which are transferred to an immobilizing membrane and incubated with specific antibodies to the protein-antigen in question (primary antibody) , and sequentially with the antibody conjugated to an indicator (secondary antibody 25). The optical density of the produced signal can be quantified with an image analysis system [Quintas L. E. M. et al., Biochem Pharmacol. 2000, 60, 741; Quintas, L. E. M. et al, Biochem Pharmacol. 2002, 64.1431].

Western blot detection of the MAPK-p38 enzyme in its active, phosphorylated form is widely used using polyclonal antibodies 30 specific to the phosphopeptide sequence that contains the amino acids threonine and tyrosine at positions 180 and 182, respectively. This technique comes / 28

being used to identify and characterize inhibitors of MAPK-p38 activation, such as pyridinylimidazoles [Chun, K. S. et al., Carcinogcnesis, 2004, 25, 713].

In the tests described here, macrophages obtained from peritoneal lavages of male mice of the C57BI6 strain weighing approximately 25 g were used. Macrophages placed in RPMI culture medium and distributed in 24-well plates were stimulated with 10 pg / ml of LPS in the absence or presence of the original synthetic molecules called LASSBio-947 (3d), LASSBio-948 (3a), LASSBio-949 (3c) and LASSBio-998 (4m). ίο In parallel, controls were performed in the presence of 0.5% dimethyl sulfoxide (DMSO), the same concentration used to dissolve the original molecules. After 1 hour, the cells were disrupted and the proteins separated by electrophoresis on 10% polyacrylamide-SDS gel. The macrophages were stimulated with LPS in the presence of synthetic molecules 3a, 3c, 3d, 4m in the 15 concentrations 1, 10, 100 and 1000 μΜ or of the pyridinylimidazole prototype SB202190

at concentrations 1, 10 and / or 100 μΜ, used as a standard inhibitor. After the electrophoretic run, the transfer was made for 1h to the nitrocellulose matrix, which was then incubated for 1h with Tris-PBS buffer with

0.1% Tween 20 containing 5% skimmed-milk powder, so that all 20 regions of nitrocellulose with free pores were impregnated with casein

of milk. Subsequently, the same nitrocellulose was incubated for 1h with primary polyclonal anti-MAPK-p38 phosphorylated antibody (BioSource International, USA), followed by incubation with secondary antibody conjugated to the peroxidase enzyme (Promega Corporation, USA). Immunoreactivity was detected by the ECL system (enhanced chemiluminescesce, Amersham Bioscience, UK). The quantification of the reactive bands present in autoradiographies was performed by capturing the image using a GS-700 densitometer (Bio-Rad Laboratories, USA) and analyzed by the Quantity One software (Bio-Rad Laboratories, USA). The values obtained 3rd were represented as arbitrary units of relative optical density.

The results shown in Figures 3, 4, 5 and 6 reveal the activation of the

22/28 • ·· ♦ · · · ···· · · · · · • * ·· · · · «· ·

MAPK-p38 enzyme in macrophages stimulated with LPS, indicating that DMSO in the concentration used as a vehicle to prepare the substances did not interfere with this activation. Figures 3, 5 and 6 confirm that the process was inhibited by SB202190, validating the model. It can be seen that the 5 derivatives LASSBio-947 (3d), LASSBio-948 (3a), LASSBio-949 (3c) and

LASSBio-998 (4m) were able to inhibit LPS-induced MAPK-p38 activation in a concentration-dependent manner. The IC ₅ o values calculated, determined by the densitometry technique, for the derivatives

LASSBio-947 (3d), LASSBio-948 (3a), LASSBio-949 (3c) and LASSBio-998 (4m) ίο were 8.7 μΜ, 13.6 μΜ, 30 μΜ and 5.5 μΜ, respectively ( Figures 3, 4, 5 and

6).

From these results, confirming the action of the derivatives 6- / Vcycloalkyl and 6- / V-aryl ureas [1,3] dioxolo [5,4-g] quinoline-7-carboxy! Ethyl actuated as MAPK enzyme inhibitors -p38, designed by is Sperandio da Silva and collaborators [Sperandio da Silva, GM et. al., Bioorg.

Med. Chem. 2004, 12, 3159], through the QSAR studies, using the CoMFA model, it was decided to investigate the anti-inflammatory activity in vivo in the model of inflammation of arthritis induced by zimozan in C57BI6 mice.

Inflammation was induced by intraplantar injection of zimozan and assessed by increasing the weight of the corresponding popliteal lymph node, compared to animals that were not treated [Ibrahim, T. et a! International Immunopharmacology 2002, 2, 875].

The weight of the popliteal lymph node used as a parameter for assessing inflammation is based on similarities found between the synovial membrane and the lymph node, such as:

❖ Organization of lymphoid infiltrate and high levels of TNF-a associated with the presence of IFN-γ produced by lymphocytes.

❖ Interaction between macrophages and lymphocytes in the paracortical area rich in CD4 + lymphocytes, with occasional formation of germinal centers and areas characterized by the predominance of CD8 + cells.

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• · • • • · · • • t • ♦ • • • ♦ • · • · • · • • · • • · * • · • · • * • • · · • «· • * · «· · · • ·

• · • · • ·

Groups of 6 to 8 C57BI6 mice received a subcutaneous injection of 150 pg of zimozan (solution prepared in sterile saline) in the left paw. The control group received sterile saline. Seventy-two hours after the injection, the animals were treated daily with intraperitoneal injections 5 containing the derivatives LASSBio-947 (3d), LASSBio-948 (3a), LASSBio-949 (3c) at a dose of 10 mg / kg, during the four (4) day period. After this period, the animals were sacrificed, the lymph nodes extracted and weighed.

Figure 7 shows that the intraplantar injection of zimosan increases about 10 times the weight of the left lymph drainage lymph node. Treatment with compound L-949 (3c) reduced this increase by 60% (p <0.001), with L948 (3a) reduced by 45% and with L-947 (3d) by 10%, indicating anti-inflammatory action of these compounds.

The compound 6- (4-chloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-715 ethyl carboxylate (3c; LASSBio-949), a new MAPK-p38 inhibitor prototype, had an anti-inflammatory action similar to rofecoxib (10 mg / kg), used as a reference compound (data not shown).

Weight reduction after treatment with the original compounds was accompanied by a decrease in the number of lymphocytes in the lymph node, as shown in Figure 8, suggesting an immunomodulatory effect for these substances.

Considering that the MAPK-p38 pathway may be involved in the activation of NFkB and synthesis of pro-inflammatory cytokines, it was decided to investigate the effect of treatment with ureidic derivatives, designed as inhibitors of

MAPK-p38, on the translocation of NFkB from the lymphocyte cytoplasm to the nucleus. In unstimulated cells, NFkB is inactive in the cytoplasm, forming a complex with the ΙκΒ protein. Activation of MAPK kinases leads to phosphorylation of other kinases such as the one that phosphorylates ο ΙκΒ, releasing NFkB 30 to translocate to the nucleus and bind to the DNA sequence that will lead to • ·

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transcription of pro-inflammatory cytokines. [Sem, R et al., Cell 1986, 46, 705; Min-Jean, Y. et. al., Nature, 1998, 396, 77].

Figure 9 shows that treatment with the compounds LASSBio-947 (3d), LASSBio-948 (3a) and LASSBio-949 (3c) inhibited the translocation of NFkB 5 to the lymphocyte nucleus, measured using the mobility change technique electrophoretic. These results reinforce the possibility that the reduction of the inflammatory response to zimosan by these derivatives in the arthritis model is dependent on MAPK-p38 inhibition. The anti-inflammatory profile of urelic derivatives was different from that of rofecoxib, a known ίο cyclooxygenase 2 (COX-2) inhibitor, used as a reference compound.

Together these results point to the ability of the new 6-N-alkyl and / or 6-N-aryl urea [1,3] dioxolo [5,4-g] quinoline-7carboxylate derivatives to inhibit the MAPK- enzyme p38 and inhibit the NFüB activation pathways, with a consequent reduction in the inflammatory response, 15 measured in an in vivo model of chronic inflammation, suggesting the therapeutic potential of these substances in the treatment of inflammatory pathologies such as different types of arthritis, asthma, Crohn's disease and type I diabetes mellitus, among others.

Methodologies used for bioassays

Western-blottinq assay for p38a-MAPK

Obtaining peritoneal macrophages: C57BI6 mice weighing approximately 25 g were used. The cells were collected by washing the peritoneal cavity with 5 mL of RPMI medium

1640 / sodium bicarbonate (Sigma Chemical Co., USA) without serum. Then, they were washed 3 times with the same medium and counted in a

Neubauer. To separate the macrophages, 10 ⁸ cells were resuspended in

300 gL of RPMI / BIC medium and placed in 24-well plates at 37 ° C with humidified atmosphere containing 5% CO ₂ . After 1 hour, the plates were washed with medium to remove the non-adhered cells. The adhered cells were then used for the assay.

♦

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MAPK-p38 inhibition assay: Adhered macrophages were stimulated with. 1 pg / mL of LPS for 1 h, in the presence of the compounds LASSBio-947, LASSBio-948, LASSBio-949 and LASSBio-998 in increasing concentrations in log order (Figures 3, 4, 5 and 6). The control was treated 5 with 0.5% DMSO.

Cell Collection for Immunodetection (Western blotting): After treatment with the LASSBio 948 molecule, 100pL of sample buffer (1mM Tris pH 6.8, 20% glycerol, 10% sodium dodecyl sulfate - SDS, 20%

β-mercaptoethanol) to each well of the 24-well plate with rotating movements of the pipette tip. The cells were collected from the plate, kept at 100 ° C for 5 minutes and centrifuged for 10 minutes at 6000 xg (Costar Mini Centrifuge centrifuge). The supernatant was collected and stored at -20 ° C until detection by western blotting.

SDS-Polyacrylamide Gel Electrophoresis and Western Blotting: SDS-polyacrylamide gel electrophoresis was performed according to Laemmli (1970). The samples were separated on gel with 10% polyacrylamide and transferred to nitrocellulose papers. Nitrocellulose was incubated for 1 h in TBS (Tris-buffered saline) + Tween 20 (TTBS) containing 5% skimmed-milk powder. Subsequently, the same nitrocellulose was incubated for 1 h with 20 phosphorylated anti-MAP kinase p38-MAPK monoclonal antibody ((Biosource), followed by incubation with anti-IgG antibody of

rabbit conjugated to peroxidase. Immunoreactivity was detected by the system

ECL (enhanced chemiluminescence, Amersham) [Quintas et al., 2000]. The quantification resulting from the densitometric analysis to compare the different 25 groups is performed by computerized reading of autoradiographies.

Detection of NFkB in the nuclear extract

Nuclear extract: Lymphocytes from the lymph node were incubated with 100 µL of 10 mM HEPES buffer; 10 mM KCI; 2 mM MgCl ₂ ; 0.1 mM EDTA - pH 8.0; 0.01 mM PMSF, 1.0 mM DTT, 10 mg / ml aprotinin and 100mM NaF.

(buffer A) at 4 ° C for 10 minutes. After the incubation period, 6 pL of nonidet P 40 (NP-40) was added and centrifuged at 16,000 x g for 20

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s. After centrifugation, the precipitate was resuspended in 100 μL of buffer A and re-cetrifuged for 16,000 xg 4 ^o C for 20 s. This operation was repeated 2 times. After the last wash with buffer A, the precipitate containing the nuclei was incubated for 10 min at 4 ^o C with nuclear lysis buffer containing 5 50 mM HEPES; 50 mM KCI; 300 mM NaCl; 0.1 mM EDTA - pH 8.0; 10% glycerol, 0.01 mM PMSF, 1.0 mM DTT, 10 mg / ml aprotinin and 100mM NaF (buffer C). After the incubation period, centrifugation was performed at 16,000 xg for 10 min at 4 ^o C. The supernatant containing the nuclear extract was collected and stored at -70 ° C.

ίο Nucleotide labeling: oligonucleotides were radioactively labeled with the ³² Pi isotope using the T4 polynucleotide kinase enzyme. The technique consists in transferring the Pi radical from the y position of the ATP to the 5 'terminal hydroxyl region of the oligonucleotide. For the labeling, 5 pM of oligonucleotide, 4 pL of [y - ³² P] -ATP (10 15 pCi - Amersham, USA), 4 pL of Tris-HCI 70 mM incubation, 10 mM MgCl_ ₂ , dithiotreitol, were used 5 mM pH 7.6 at 25 ° C, containing 1.0 pL of the T4 polynucleotide kinase enzyme (20 Richardson units) and 7.5 pL of deionized water.

Electrophoretic mobility change test: electrophoresis was performed on a 6% non-denaturing polyacrylamide gel. HeLa cells were used as a positive control. The extracts were incubated with the ³² Pi labeled oligonucleotide (Gibco BRL Tech, USA) for 30 min at 37 ° C. In each well, 4 pg of protein and approximately 100,000 cpm of the labeled probe were applied. After 2 h at 150 V, the gel was dehydrated and analyzed by autoradiography on the Storm Scan Molecular Dynamics device (USA).

Induction of zimozan-induced inflammation

Male isogenic mice of the C57BI6 strain, weighing approximately 25 g, were obtained from the Vivarium of Universidade Federal Fluminense. All manipulations with animals are in accordance with the 3rd international standards used by the Brazilian College of Animal Experimentation. Each mouse received a subcutaneous injection of 150 pg of

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• • · · • • • · • · • · • • · • · • · • · • • ♦ • · • · • • · • ·· • · • • · • • · • • · • · • ♦ • · • • · • • · • • • ·· · • • ·· •

zimozan prepared in sterile saline on the left paw. The control group received saline.

Treatment of the inflammatory process with the test compounds L947, L-948 and L-949.

Seventy-two hours after zimosan injection, the animals were treated intraperitoneally (i.p.) with the test substances at a dose of 10 mg / kg dissolved in 0.5% DMSO, for four days. After this period, the animals were sacrificed by cervical dislocation and the popliteal lymph nodes were extracted and weighed. The cells were counted in a Neubauer ion chamber and used to prepare the nuclear extract.

The compounds of the invention can be administered in a variety of dosage forms, for example, orally, in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions or suspensions; rectal route in the form of suppositories; parenterally, this is intramuscularly, or by intravenous and / or intrathecal and / or intraspinal infusion or injection.

The present invention also includes pharmaceutical compositions comprising compounds of the formula (3a-z; 4a-z; 5a-z), or pharmaceutically acceptable salts thereof, in combinations with a pharmaceutically acceptable excipient (which may be a carrier or

diluent).

Pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in an appropriate pharmaceutical form.

For example, solid oral forms may contain, together with the active compound, diluents, i.e. lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, i.e. silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrolidone; disaggregating agents, for

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example a starch, alginic acid, alginates or sodium starch glycolate; effervescent mixture; dyes; sugary; wet agents such as lectins, polysorbates, lauryl sulfates; and, in general, pharmacologically inactive and non-toxic substances used in pharmaceutical formulations.

Said pharmaceutical preparations can be manufactured in a known manner, for example, by means of mixing, granulating, tablet pressing, sugar coating, or film coating processes.

Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions. Syrups can contain as a carrier, for example, sucrose or sucrose with glycerin and / or manita and / or sorbitol. Suspensions and emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, i.e. sterile water, olive oil, ethyl oleate, glycols, ie propylene glycol, and, if desired, an appropriate amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as a carrier, for example, sterile water or preferably they may be in the dorma of sterile, aqueous, isotonic saline solutions or they may contain as

propylene glycol carrier.

Suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, polyoxyethylene sorbitan, fatty acid ester surfactant or lecithin.

Claims (17)

Claims 1- N-aryl-urea derivatives [1,3] dioxolo [5,4-g] quinoline-7-functionalized characterized by having general formula (I): H where: R ₁ corresponds to OCH ₃ or OCH ₂ CH ₃ or OC ₆ H ₅ or OCH ₂ C ₆ H ₅ or NH ₂ or NHCH3 or NHNH2; W = (2 and / or 3 and / or 4 and / or 5 and / or 6) -F or (2 and / or 3 and / or 4 and / or 5 and / or 6) Cl or (2 and / or 3 and / or 4 and / or 5 and / or 6) -Br or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CH ₂ CH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) CF ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -OCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) OCF ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6 ) - (2 and / or 3 and / or 4 and / or 5 and / or 6) -NO ₂ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -NH ₂ ; (2 and / or 3 and / or 4 and / or 5 and / or 6) -NHCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -NHCOCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) NHSO2CH ₃ ; or their pharmaceutically acceptable salts. 2- N-alkyl urea derivatives [1,3] dioxolo [5,4-g] quinoline-7-functionalized characterized by having general formula (II): Petition 870190027017, of 03/21/2019, p. 8/21 2/12 R2 H (II) where: R ₁ corresponds to OCH ₃ or OCH ₂ CH ₃ or OC ₆ H ₅ or OCH ₂ C ₆ H ₅ or NH ₂ or NHCH3 or NHNH2; R2 CH3 or CH2CH3 or (CH2) 2CH3 or (CH2) 3CH3 or (CH2) 4CH3 or (CH2) 5CH3 or CH (CH3) 2 or C (CH3) 3 or cyclopropyl, or cyclopentyl or cyclohexyl or cycloheptyl; or their pharmaceutically acceptable salts. 3- N-cycloalkyl-urea derivatives [1,3] dioxolo [5,4-g] quinoline-7- functionalized characterized by having general formula (III): (III) where: R1 corresponds to OCH3 or OCH2CH3 or OC6H5 or OCH2C6H5 or NH2 or NHCH3 or NHNH2; X corresponds to CH2 or (CH2) 3 or (CH2) 4 or (CH2) 5; or their pharmaceutically acceptable salts. 4- N-heteroaryl-urea derivatives [1,3] dioxolo [5,4-g] quinoline-7- functionalized characterized by having general formula (IV): Petition 870190027017, of 03/21/2019, p. 9/21 3/12 H (IV) where: R ₁ corresponds to OCH ₃ or OCH ₂ CH ₃ or OC ₆ H ₅ or OCH ₂ C ₆ H ₅ or NH ₂ or NHCH3 or NHNH2; Ar corresponds to 2-Pyridine or 3-Pyridine or 4-Pyridine or 2-thiophene or 2-pyrrole or 1-naphthyl or 2-naphthyl or quinoline, or quinoxaline or oxazole or thiazole or thiadiazole, oxadiazole or pyrimidine or triazole or imidazole; or their pharmaceutically acceptable salts. 5- Derivative, according to claims 1 and / or 2 and / or 3 and / or, characterized by being chosen from a group comprising: Ethyl 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3a); 6- (4-fluoro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3b); 6- (4-chloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3c); 6- (4-bromo-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3d); 6- (4-methyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3e); 6- (4-trifluoromethyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3f); 6- (4-methoxy-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3g); 6- (4-trifluoromethylether-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3h); Petition 870190027017, of 03/21/2019, p. 10/21 4/12 6- (4-nitro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3i); 6- (4-amino-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3j); 6- (4-methylamino-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3l); 6- (4-acetamido-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3m); 6- (4-methanesulfonamide-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3n); 6- (2,6-difluoro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3rd); 6- (2-chloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3p); 6- (3-chloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3q); 6- (2,3-dichloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3r); 6- (2,6-dichloro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3s); 6- (4-ethyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3t); 6- (2,6-ethyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3u); 6- (2,6-methyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3v); 6- (2-methoxy-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3x); 6- (2-nitro-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (3z); Ethyl 6-methylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4a); Ethyl 6-ethylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4b); Ethyl 6-propylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4c); Ethyl 6-isopropylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4d); Ethyl 6-terbutillureia- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4e); Petition 870190027017, of 03/21/2019, p. 11/21 5/12 Ethyl 6-butylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4f); Ethyl 6-pentylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4g); Ethyl 6-hexylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4h); Ethyl 6-benzylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4i); Ethyl 6-cyclopropylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4j); Ethyl 6-cyclopentylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4l); Ethyl 6-cyclohexylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4m); Ethyl 6-cycloeptylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (4n); Methyl 6-cyclohexylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4o); Phenyl 6-cyclohexylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4p); Benzyl 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4q); 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxamide acid (4r); 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-methylcarboxamide (4s); 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carbonylhydrazine (4t); Methyl 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (4u); 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxamide (4v); 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylic acid (4x); 6-phenylurea- [1,3] dioxolo [5,4-g] quinoline-7-carbonylhydrazine (4z); 6- (2-pyridinylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5a); 6- (ethyl 3-pyridinylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5b); 6- (4-pyridinylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5c); 6- (2-thienylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5d); 6- (2-furylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5e); Petition 870190027017, of 03/21/2019, p. 12/21 6/12 Ethyl 6- (2-imidazolylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5f); 6- (2-pyrrolylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5g); 6- (2-pyrazolylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5h); 6- (1,3,4-thiadiazolylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5i); 6- (1,3,4-oxadiazolurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5j); 6- (1-naphthylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5l); 6- (2-naphthylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5m); 6- (2-quinolylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5n); 6- (4-pyrimidinylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5o); 6- (4-quinazolinylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5p); 6- (1,3-oxazolylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5q); Ethyl 6- (1,3-thiazolylurea- [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5r); 6- (1H-5-imidazolylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5s); 6- (4H-1,2,4-triazolylurea- [1,3] dioxolo [5.4-g] quinoline-7-carboxylate (5t); 6- (4-methanesulfonyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxylate (5u); 6- (4-methanesulfonyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7-carboxamide (5v); 6- (4-methanesulfonyl-phenylurea) - [1,3] dioxolo [5.4-g] quinoline-7-carboxylic acid (5x); 6- (4-methanesulfonyl-phenylurea) - [1,3] dioxolo [5,4-g] quinoline-7carbonylhydrazine (5z). 6- Derivative, according to claims 1 and / or 2 and / or 3 and / or 4, characterized by having the ability to inhibit the activation of NFkB Petition 870190027017, of 03/21/2019, p. 13/21 7/12 Derivative according to claims 1 and / or 2 and / or 3 and / or 4, characterized in that it inhibits MAPK-p38. 8- Derivative, according to claims 1 and / or 2 and / or 3 and / or 4, characterized by having anti-inflammatory property. 9- Derivative, according to claims 1 and / or 2 and / or 3 and / or 4, characterized in that it is used in the treatment of diseases of inflammatory origin. 10. Derivative, according to claims 1 and / or 2 and / or 3 and / or 4, characterized by being used in the regression of acute and / or chronic inflammatory conditions. 11- Production process of derivatives of general formula (I) and / or (II) and / or (III) and / or (IV) below: Petition 870190027017, of 03/21/2019, p. 14/21 8/12 R2 (I) (II) H H Air (III) (IV) characterized by understanding the stages of: A) Regioselective aromatic electrophilic substitution of the benzo [d] [1,3] dioxola-5-carbaldehyde or piperonal system; B) Treatment of the nitrated intermediate with ethyl cyanocyanetate in the presence of potassium fluoride supported on alumina (KF / AL ₂ O ₃ ) Petition 870190027017, of 03/21/2019, p. 15/21 9/12 as base, ethanol as solvent, at a temperature of 35 ° C, exploring condensation reaction of diastereoselective aldolic type; C) Reduction of the configuration nitro-acrylate (E), using titanium tetrachloride (TiCl ₄ ) in the presence of zinc (Zn) and tetrahydrofuran as a solvent, at reflux temperature, for later cyclization of the amino-formed intermediate through intramolecular nucleophilic addition to the nitrile group; D) Condensation of the amino derivative with arylisocyanates and / or cycloalkylisocyanates and / or alkylisocyanates and / or heteroarylisocyanates, in the presence of anhydrous toluene at the reflux temperature; E) Interconversions of functional groups from the intermediate or derivatives, exploring transesterification reactions, hydolysis, aminolysis and hydrazinolysis. 12-Pharmaceutical composition characterized by comprising: A) a N-aryl-urea [1,3] dioxolo [5,4-g] quinoline-7-functionalized derivative characterized by having general formula (I): H where: R ₁ corresponds to OCH ₃ or OCH ₂ CH ₃ or OC ₆ H ₅ or OCH ₂ C ₆ H ₅ or NH ₂ or NHCH3 or NHNH2; W = (2 and / or 3 and / or 4 and / or 5 and / or 6) -F or (2 and / or 3 and / or 4 and / or 5 and / or 6) Cl or (2 and / or 3 and / or 4 and / or 5 and / or 6) -Br or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -CH ₂ CH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) Petition 870190027017, of 3/21/2019, p. 16/21 10/12 CF ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -OCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) OCF ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) - (2 and / or 3 and / or 4 and / or 5 and / or 6) -NO ₂ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -NH ₂ ; (2 and / or 3 and / or 4 and / or 5 and / or 6) -NHCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) -NHCOCH ₃ or (2 and / or 3 and / or 4 and / or 5 and / or 6) NHSO2CH3; or their pharmaceutically acceptable salts. B) a pharmaceutically acceptable vehicle. 13- Pharmaceutical composition characterized by comprising: A) a functionalized N-alkyl urea [1,3] dioxolo [5,4-g] quinoline-7 derivative characterized by having general formula (II): HELLO) H where: R ₁ corresponds to OCH ₃ or OCH ₂ CH ₃ or OC ₆ H ₅ or OCH ₂ C ₆ H ₅ or NH ₂ or NHCH ₃ or NHNH2; R ₂ CH ₃ or CH ₂ CH ₃ or (CH ₂ ) ₂ CH ₃ or (CH ₂ ) ₃ CH ₃ or (CH ₂ ) ₄ CH ₃ or (CH ₂ ) ₅ CH ₃ or CH (CH ₃ ) ₂ or C (CH ₃ ) ₃ or cyclopropyl, or cyclopentyl or cyclohexyl or cycloheptyl; or their pharmaceutically acceptable salts. B) a pharmaceutically acceptable vehicle. 14-Pharmaceutical composition characterized by comprising: A) a functionalized N-cycloalkyl-urea [1,3] dioxolo [5,4-g] quinoline-7 characterized by having general formula (III): Petition 870190027017, of 03/21/2019, p. 17/21 11/12 (III) where: R ₁ corresponds to OCH ₃ or OCH ₂ CH ₃ or OC ₆ H ₅ or OCH ₂ C ₆ H ₅ or NH ₂ or NHCH3 or NHNH2; X corresponds to CH2 or (CH2) 3 or (CH2) 4 or (CH2) 5; or their pharmaceutically acceptable salts. B) a pharmaceutically acceptable vehicle. 15-Pharmaceutical composition characterized by comprising: A) a functionalized N-heteroaryl-urea [1,3] dioxolo [5,4-g] quinoline-7 derivative characterized by having general formula (IV): Air H (IV) where: R1 corresponds to OCH3 or OCH2CH3 or OC6H5 or OCH2C6H5 or NH2 or NHCH3 or NHNH2; Ar corresponds to 2-Pyridine or 3-Pyridine or 4-Pyridine or 2-thiophene or 2-pyrrole or 1-naphthyl or 2-naphthyl or quinoline, or quinoxaline or oxazole or thiazole or thiadiazole, oxadiazole or pyrimidine or triazole or imidazole; or their pharmaceutically acceptable salts. Petition 870190027017, of 03/21/2019, p. 18/21 12/12 B) a pharmaceutically acceptable vehicle. 16- Pharmaceutical composition, according to claims 13, 14 and 15, characterized by being used in the treatment and / or control of pathologies of acute and / or chronic inflammatory origin. 17. Pharmaceutical composition according to claims 13, 14 and 15, characterized in that it is used as an anti-inflammatory. Petition 870190027017, of 03/21/2019, p. 19/21 • · · • ♦ 1/8 2-Py; 3-Py; 4-Py; a-naphthyl; β-naphtho, 2-thiophene, 2-furan, thiazole, Lsoiazola; thiadiaznla; pyrimidine, quinoalin, pyrrole, pyrazine, triazine, osazole, imidazole (5a-z) W »2 and / or 3 and / or 4 and / or 5 and / or 6 11; l ·; (1; Br; Cllj; (Η ₂ (11 ₃ ; CFj; OCHj; (X Fj; NO ₂ ; Ml ₂ ; NlKllj; ΝΙΚΧΧΊΙμ ΝΚΟ, αΐ, R | = OMe; OEi; OPr, OiPn OPh, OCll ₂ Ph; Nllj. ΝΙΚΊΙ »Oll» NIINIIj (l! J; (CH ₂ ) nCHj branched alkyl; cidopropyl; cidopentyl, cidoeptyla FIGURE 1 W = H; plC _M = 7.19 W = Cl; pICbq = 7.17 W = Br; plC _w = 7.19 W = NO ₂ ; plC _M * 6.99 w = kin _q - pir „= fi <Í7 _______ W = NHSO ₂ CH ₃ ; pIC ₅₀ = 7.58 plC _eo = 7.71 W = H; plC _M = 7.07 W = Cl; plC ₅₀ = 7.08 W = Br; plC _so = 7, O8 c = s W = H; plCso = 7.01