WO2012054996A1 - Functionalized aryl and/or heteroaryl urea compounds; a method for synthesizing same; a pharmaceutical composition containing such compounds and uses thereof - Google Patents

Abstract

The present invention relates to functionalized aryl and/or heteroaryl urea compounds of general formula (I) and (II), and also salts and/or solvates and polymorphs thereof which can inhibit protein kinases from the MAPK family and also modulate cytokines such as TNF and IL1β. Furthermore, the present invention relates to a method for synthesizing such compounds, a method for preparing a pharmaceutical composition which will be used in the production of medicines for treating or preventing disorders associated with acute or chronic pain, and also for treating inflammatory diseases, said inflammation being acute or chronic.

Description

 Descriptive Report

ARIL COMPOUNDS AND / OR HETERO ARIL FUNCTIONALIZED UREAS;

 SUMMARY PROCESS OF THESE COMPOUNDS; COMPOSITION

 PHARMACEUTICAL CONTAINING SUCH COMPOUNDS AND USES

Field of the Invention

 t

 The present invention relates to functionalized and congenic aryl and / or heteroaryl urea derivatives of formula (I) and (II), more particularly, it relates to ethyl 2- (3-cyclohexylurido) -4,5-dimethoxybenzoate derivatives (LASSBIO-

1494) Methyl 6- (3-cyclohexylurido) -1,3-benzodioxola-5-carboxylate (LASSBIO).

1495), ethyl 2- (3-cyclohexylureido) -benzoate (LASSBio-1496), methyl 2- (3-cyclohexylureido) -pyridine-3-carboxylate (LASSBio-1497) and its solvates and polymorphs, as well as to a process for their preparation, pharmaceutical compositions containing them, and their use as a therapeutic agent for the treatment of diseases of inflammatory origin and acute and / or chronic and / or neuropathic pain.

Background of the Invention

Mitogen-Activated Protein Kinase p38 (MAP p38) is a serine threonine kinase activated by stress factors and inflammatory stimuli [Zhang, J .; Shen, B .; Lin, A. TRENDS in Pharmacological Sciences, 2006, 28, 286]; It is involved in the biosynthesis of proinflammatory cytokines such as TNF-α and IL-Ι β at transduction and translation levels. Several members of the protein kinases family have been identified so far. These enzymes catalyze the phosphorylation reaction of different substrates, performing primary functions at virtually every stage of cell life. There are currently four known members of the MAP-p38 family designated by the letters α, β, γ and δ. These isoforms differ in tissue distribution, activation of other kinases, and substrate phosphorylation [Lee, JC et ah, at 'ature, 1994, 372, 739].

The degree of homology of p38a in relation to ρ38β, ρ38γ and ρ38δ is 75, 62, and 64%, respectively. Although expression of p38a and related kinases may 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 the development. of pathologies of inflammatory origin.

Most compounds described as capable of inhibiting p38 MAPK exert their mechanism of action through competitive inhibition with ATP. however, although less numerous, allosteric MAPK p38 inhibitors are known and some examples are illustrated on pages 3/13 below. [Montalban, A. G. et al., Bioorganic and Medicinal Chemistry Letlers, 2008, 18, 1772].

The fact that p38 MAPK played a key role in inflammatory processes, coupled with demonstration of the beneficial effects of p-38 inhibitors in animal models of inflammation and pain, make p38 MAPK an attractive target for therapeutic intervention to treat different diseases of acute and / or chronic inflammatory origin and for the control of inflammatory and neuropathic pain [Coulthard, LR et al., Trends in Molecular Medicine, 2009, 75, 369].

Summary of the Invention

 An object of the present invention is the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), as well as their salts and / or solvates and / or polymorphs, capable of inhibiting human and non-human mammalian animals. protein kinases belonging to the MAPK family.

(D < ⁿ >

Still further object of the present invention are the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II). as well as their salts and / or solvates and / or polymorphs capable of modulating the expression and / or inhibition of cytokines, particularly TNF and IL 1 β in human and non-human mammalian animals.

 The third object of the present invention relates to the process of synthesizing functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), as well as their derivatives, their possible salts and / or solvates and / or polymorphs capable of inhibit the protein kinases of the MAP family.

 (X) W

The fourth object of the present invention relates to a pharmaceutical composition containing the functionalized aryl and / or heteroaryl urea compounds of general formula.

(I) and (II), and / or their salts and solvates and / or polymorphs, capable of inhibiting MAPK family protein kinases.

The fifth object of the present invention relates to the use of the pharmaceutical composition containing the aryl and / or heteroaryl urea compounds and / or their salts, solvates and / or polymorphs capable of inhibiting the MAPK family protein kinases in the treatment of processes. or diseases related to the regulation of MAPK family protein kinases in human and non-human mammalian animals. The sixth object of the present invention relates to the use of the pharmaceutical composition for the manufacture of a medicament containing the aryl and / or heteroaryl urea compounds and / or their salts, solvates and / or polymorphs capable of modulating expression and / or TNF and IL1 β production and / or inhibit the protein kinases of the family

> MAPK, in the treatment of acute and / or chronic inflammatory diseases in human and non-human mammalian animals.

 The seventh object of the present invention relates to the use of the pharmaceutical composition for the manufacture of a medicament containing the aryl and / or heteroaryl urea compounds and / or their salts, solvates and / or polymorphs capable of modulating the composition.

) expression and / or production of TNF and IL1 β and / or inhibit MAPK family protein kinases in the treatment of acute and / or chronic and / or neuropathic pain-related disorders in human and non-human mammalian animals.

Description of the Figures

 Figure 1- Figure 1 shows the effect of LASSBio-1494, LASSBio-1495, LASSBio-1496 and LASSBio-1497, compared to the effect of LASSBio-998 and SB203580 standards on TNF (A) gene expression and secretion. TNF (B) by LPS-stimulated THP-1 cells. P <0.05 relative to the vehicle.

Figure 2- Figure 5 shows the effect of LASSB io-1494, LASSBio-1495, LASSBio-1496 and LASSBio-1497, compared to the effect of LASSBio-998 and SB203580 standards on the human macrophage cell viability model. performing the MTT test.

Figure 3- Figure 3 shows the effect of LASSBio-1 94, LASSBio-1495, LASSBio-1496 and LASSBio-1497, compared to the effect of LASSBio-998 and SB203580 standards on IL-β β (A) gene expression. and in the secretion of IL-β in LPS-stimulated THP-1 cells. P <0.05 relative to the vehicle. Figure 4- Figure 4 shows the effect of LASSBio-1494, LASSBio-1495, LASSBio-1496, and LASSBio-1497 compared to the effect of LASSBio-998 and SB203580 standards on inhibition of MAPK p38 phosphorylation by Western blot. Blotting.

Figure 5- Figure 5 shows the temporal antihypernociceptive effect of LASSBio-1494, LASSBio-1495, LASSBio-1496, and LASSBio-1497 compared to the effect of LASSBio-998 and SB203580 standards on the capsaicin-induced thermal hypernociception model ( A) and (B). N of 8-10 animals, dose = 100 imol / kg orally, * P <0.05 compared to vehicle.

Detailed Description

 The production and secretion of mediators released in inflammatory processes and diseases are dependent on the intracellular signaling cascade regulated by protein kinases and phosphatases. Kinases are responsible for protein phosphorylation in cells, with ATP as a substrate, while phosphatases regulate this phosphorylation. In recent years kinases have become the most studied pharmacological target by pharmaceutical industries in the search for inhibitors of these proteins for the treatment of chronic inflammatory diseases.

The functionalized aryl and / or heteroaryl urea compounds of general formula (I) and (II), as well as their salts and solvates and / or polymorphs which are the object of this invention, are capable of inhibiting protein kinases, being more precise those of MAPK family such as extracellularly regulated protein kinases (ERKs), N-terminal C-junction protein kinases (JNKs) stress-activated protein kinases (MAPK p38) and ERK5 (also known as BMK 1), most preferably , for the present invention, inhibition of MAPKp-38 protein kinase and its isoforms. Inhibition of p-38 MAPK by the compounds is prevalent because they bind to a different site than ATP, known as the allosteric site. Following this binding, p-38 MAPKs decrease their affinity for their natural substrate, ATP, thereby disrupting activation and transcription cascade of proinflammatory cytokines involved in inflammatory processes and diseases,

 (D (D)) wherein for both the compound of formula (I) and (II) R may be any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; whereas such radicals may further be optionally substituted, unsaturated and / or branched Preferably for R a group is OH, OCH 3, OC 2 H 5, OCH (CH 3) 2, OC (CH 3) 3, NH 2, NHCH 3, NHC 2 H 5, NHCH (CH 3), NC (CH 3) 3, N (C 2 H 5) 2, N (CH 3) 2, NH H 2 where Y may be C, CH, N, NH where Y 1 may be C 1 CH, N, NH where R 1 is any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl, and such radicals may further be optionally substituted, unsaturated and / or branched. cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, linear alkyl, branched alkyl, aryl and heteroaryl.

i Only for the compound of formula (I), where X may be H, O, OH,

OCH 3, N, NH, NH 2; where XI may be H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂ ; where n may be 0, CH ₂ , CH, C ₂ H ₄ .

 The compounds of formula (I) and (II), as well as six salts and / or solvates and / or polymorphs, in addition to inhibiting MAPK protein kinases, are:

) capable of modulating the expression of TNF and IL proinflammatory cytokines. This modulation is established because these compounds compete for the binding site of cytokines. When compounds (I) and (II) bind to the site they elicit an antagonistic response to the proinflammatory cytokines mentioned above. Thus, these compounds, by binding to this site, promote the paralysis of the activation cascade that would be generated by proinflammatory cytokines.

 The compounds of formula (I) and (II)

where, for both the compound of formula (I) and (II) R may be any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched. Preferably R is OH, OCH 3, OC 2 H 5, OCH (CH 3) 2, OC (CH 3) 3, NH 2, NHCH 3, NHC 2 H 5, NHCH (CH 3), NC (CH 3) 3, N (C 2 H 5) 2, N (CH 3 ) 2, NHNH 2; where Y may be C, CH, N, NH; where Y1 may be C, CH, N, NH; where R1 is any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched. Preferably for this radical R 1 is a cycloeptyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl group. Linear alkyl, branched alkyl, aryl and heteroaryl. Only for the compound of formula (I), where X may be H, O, OH, OCH 3, N, NH, NH 2; where XI may be H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂ ; where n may be 0, C¾, CH, C 2 H 4. 1,000389

 9th

 Some radicals proposed in this invention can only be inserted if the compounds of formula (I) and (II) are in salt form. Otherwise, these radicals will not have their valences completed.

 The synthesis process of the compounds of formula (I) and (II) comprises the formation of a functionalized carbamate intermediate obtained by the reaction between a functionalized amine and p-nitrophenyl chloroformate.

 (Π)

The synthesis process of the compound of formula (I) and (II) is divided into the following steps:

 Step (a) - Condensation of the amine of molecular formula (III) and / or molecular formula (IV) to -nitrophenyl chloroformate to obtain carbamate of formula (V) and / or formula (VI)

Step (b) - Nucleophilic addition followed by elimination of functionalized amines (H ₂ R 1) to the carbamate intermediate of formula V and / or VI.

What differs in the synthesis process from compound (I) to compound (II) is related to the precursor amine. In the case of the synthesis of the compound (I), the precursor amine is of the formula (III), in the case of the compound of formula (II) the precursor amine is of the formula (IV). The other process steps are identical for both compounds, respecting the number of steps, all concentrations, all solvents involved, all separation and purification methods, as well as temperatures and pressures. Step (a) occurs by nucleophilic addition of the amine of formula (III) for synthesis of the compound of formula (I) or the amine of formula (IV) to form the compound of formula (II).

General Formula (III) General Formula (IV)

where the radicals R may be OH, OCH _3, OC ₂ H ₅₎ OCH (CH ₃ ) ₂ . OC (CH ₃ ) ₃₎ NH ₂ , NHCH ₃ , NHC ₂ H ₅ , NHCH (CH ₃ ) ₂ , NHC (CH ₃ ) ₃ , N (C ₂ H ₅ ) ₂ , N (CH ₃ ) ₂ ; where Y may be C, 0; where Y1 may be N, CH, NH; where X may be H, O, OH, OCH _3; CH ₂ , N, NH, NH ₂ ; and where XI may be O, OH, OCH ₃ . CH ₂ , N, NH, NH ₂ with the -nitrophenyl chloroformate in chloroform medium.

 The reaction begins with the addition of 0.2 to 2 mmol of the chosen amine, preferably 0.5 to 1.0 mmol of the precursor amine in a flask containing chloroform and β-nitrophenylchloroformate. The mixture is kept at room temperature under magnetic stirring for up to 24 hours. The step is completed with the formation of a compound, the carbamate of formula V and / or VI. Purification of the intermediate carbamate is accomplished by recrystallization from organic solvent such as ethanol, propanol, hexane, propanone, preferably hexane, most preferably n-hexane.

Step (b) is based on treating the functionalized carbonate intermediate of formula (V) and / or formula (VI) with a functionalized amine (NH ₂ R |) to obtain functionalized aryl and / or heteroaryl ureas. (I) and (II) which are purified by recrystallization using an organic solvent or organic-water solvent mixture, this organic solvent may be ethanol, propanol, isopropanol, isobutanol, acetone, acetate, dichloromethane, preferably ethanol being most preferably the ethanol / water mixture in a 1: 1 ratio. Functionalized carbonate prepared in the previous step (a) has the general formula V and / or VI

 General Formula (VI)

General Formula (V) where the radicals R may be OH, OCH ₃ , OC ₂ H ₅ , OCH (CH ₃ ) ₂ . OC (CH ₃ ) ₃ , NH ₂ . NHCH ₃ , NHC _: H ₅ , NHCH (CH ₃ ) ₂ , NHC (CH ₃ ) ₃ , N (C ₂ H ₅ ) ₂ , N (CH) ₂ ; where Y may be C, 0; where Y1 may be N, CH, NH; where W may be N, CH, NH; where X may be H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂ ; and where XI may be H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂ The functionalized amine has the general formula (NH ₂ -R ₁ ), where the radical R | may be any cycloalkane group of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched.

The fourth object of the invention is a pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and / or (II), and / or their salts and solvates and / or polymorphs. inhibition of MAP family protein kinases, preferably MAP p38 and its isoforms ρ38α, ρ38β, ρ38γ and ρ38δ, in human and non-human mammals. For such formulation we accept, in addition to the compounds mentioned above, other non-active pharmaceutical substances such as adjuvants, excipients, dispersants, antioxidants, emollients, sweeteners, flavorings, preservatives, in addition to other non-active pharmaceutical substances already known to one skilled in the art.

 Our fifth object is a pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), and / or their salts and solvates and / or porphorphs, for the modulation of expression of TNF and IL 1 β proinflammatory leucines in human and non-human mammalian animals. Other non-active pharmaceutically active substances already known in the art are included in this composition, preferably being adjuvants, excipients, dispersants, antioxidants, emollients, sweeteners, flavorants, preservatives.

 The concentration of compounds found in these compositions are all those pharmaceutically acceptable for them, and may range from 0.026 mmol to 2.6 mmol, preferably 0.078 mmol to 0.78 mmol.

 Our sixth object describes the use of the pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), and / or their salts and solvents and / or polymorphs, for production. of a medicament used for the treatment and / or prevention of acute and / or chronic inflammatory diseases associated with inhibition of MAPK family protein kinases and modulation of TNF and IL 1 β proinflammatory leucine expression in human and non-human mammalian animals.

The last object of this invention relates to the use of a pharmaceutical composition containing alone or in combination the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II), and / or their salts and solvates and / or polymorphs, for the manufacture of a medicament for the treatment and / or prevention of acute and / or chronic and / or neuropathic pain-related disorders in human and non-human mammalian animals. These compounds are capable of modulating TNF and IL 1β expression and / or production and / or inhibiting MAPK family protein kinases. Experiments were performed with LPS-stimulated THP-1 cells. P <0.05 with respect to the vehicle, where it has been shown that the compounds of the present invention are capable of modulating TNF expression and / or production as shown in Figure 1.

 Such disorders and diseases mentioned above include the different forms of arthritis, preferably rheumatoid arthritis, osteoarthritis, lupus, psoriasis, Crohn's disease, asthma. COPD, melanoma, Alzheimer's disease, Parkinson's disease. In addition to acute and / or chronic pain, including neuropathic pain, associated with the aforementioned disorders and / or any pain (i.e. painful) manifestation dependent on the involvement of MAPKs. preferably MAPK p38, and / or proinflammatory cytokines, particularly IL1β and TNFα.

 The foregoing medicaments may be found in various pharmaceutical forms described in the state of the art, however, preferably being the oral dosage forms. More preferably, for this invention, the oral dosage forms are tablets, lozenges, capsules, pills, pills, syrups, suspension, emulsion and solutions, including the slow, sustained or prolonged release oral dosage forms. .

Claims

 Claims: Aryl and / or heteroaryl urea compounds characterized by their general formula (I) and (II)

R being any group from cycloalkanes of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched, preferably OH, OCH 3, OC 2 H 5, OCH (CH 3) 2, OC (CH 3) 3, NH 2, NHCH 3, NHC 2 H 5, NHCH (CH 3), NC (CH 3 ) 3, N (C 2 H 5) 2, N (CH 3) 2, NHNH 2; X being H, O, OH, OCH 3, N, NH, NH 2; XI being H, O, OH, OCH 3, CH 2, N, NH, NH 2; n may be 0, CH 2, CH, C 2 H 4; Y is CH, N, NH; Y1 is CH, N, NH; R1 is any group of cycloalkanes of 3 to 7 carbon atoms, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl; wherein such radicals may further be optionally substituted, unsaturated and / or branched, preferably a cycloeptyl group, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl. Linear alkyl, branched alkyl, aryl and heteroaryl; pharmaceutically acceptable salts thereof and / or solvates and / or polymorphs. Compounds of formula (I) and (II) according to Claim 1, characterized in that they inhibit, as well as their salts and / or solvates and / or polymorphs, the protein kinases belonging to the MAPK family, preferably ERKs, JNKs. , ERK5, even more preferably MAPK p38 and its isoforms, in human and non-human mammalian animals. Compounds of formula (I) and (II) according to claim 1, characterized in that they modulate and / or inhibit, as well as their salts and / or solvates and / or polymorphs, the expression of interleukins such as TNF and ILi p. in human and non-human mammal animals. 4. Synthesis process of the functionalized aryl and / or heteroaryl urea compounds of formula (I) and (II),

 (D characterized by the following steps:  A) Condensation of amine B) Nucleophilic Addition Synthesis process according to claim 4, characterized in that step (A) occurs the condensation of the amine of molecular formula (III) or (IV) p-nitrophenyl chloroformate.

 General Formula (III) General Formula (IV) Synthesis process according to claim 5, characterized in that the amines of formula (III) and (IV) have the radicals R as OH, OCH ₃ OC 2 H 5, OCH (CH ₃ ) 2, OC (CH ₃ ) 3, NH ₂ , NHCH ₃ , NHC ₂ H ₅ , NHCH (CH ₃ ) ₂ , NHC (CH ₃ ) ₃ , N (C ₂ H ₅ ) ₂ , N (CH ₃ ) ₂ ; Y is C, O; Y1 may be N, CH, NH; X is H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂ ; and X1 may be H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂  Synthesis process according to claim 5, characterized in that step (A) starts with a concentration ranging from 0.2 to 2 mmol of the precursor amine, preferably 0.5 to 1.0 mmol, in a flask containing the chloroform and p-nitrophenyl chloroformate. Synthesis process according to Claim 7, characterized in that the reaction is maintained for up to 24 hours at room temperature to form a carbamate of formula (V) or (VI).

 General Formula (VI) General Formula (V) Synthesis process according to claim 8, characterized in that the carbamate radicals of formula (V) and (IV) are for R OH, OCH ₃ OC ₂ H ₅ , OCH (CH ₃ ) 2, OC (CH ₃ ) 3, NH ₂ , NHCH ₃ , NHC ₂ H ₅ , NHCH (CH ₃ ) ₂₁ NHC (CH ₃ ) ₃ , N (C ₂ H ₅ ) ₂ , N (CH ₃ ) ₂ , for YC, 0; for Y1 may be N, CH, NH; for W may be N, CH, NH; for X may be H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂ ; for X1 can be H, O, OH, OCH ₃ , CH ₂ , N, NH, NH ₂ Synthesis process according to claim 4, characterized in that step (B) is based on treating the carbamate with a functionalized amine of the formula (NH ₂ -R 1), wherein R 1 may be any cycloalkane group of 3 to 7 atoms. carbon, alkyl group of 1 to 7 carbon atoms, aryl and heteroaryl group and may be substituted, unsaturated and / or branched. 1 1. Synthesis process according to Claim 6, characterized in that the treatment of carbamate with the functionalized amine forms the aryl and heteroaryl compounds of formula (I) and (11), which are purified by recrystallization. Synthesis process according to Claim 11, characterized in that the crystallization process uses an organic solvent or a mixture of organic solvent and water in a ratio of 1: 1.  Synthesis process according to claim 12, characterized in that the organic solvent employed belongs to the group consisting of ethanol, propanol, isopropanol, isobutanol, acetone, acetate,  dichloromethane, preferably ethanol, most preferably the ethanol / water mixture in a 1: 1 ratio Pharmaceutical composition characterized in that it contains the functionalized aryl and / or heteroaryl compounds of formula (I) and (II), their salts and / or their solvates and / or polymorphs, alone or in combination.

 (Π) and a pharmaceutically acceptable vehicle  Pharmaceutical composition according to claim 14,  characterized by inhibiting MAPK family proteins, preferably MAPK p-38. Use of the pharmaceutical composition according to claim 14, characterized in that they are used for the manufacture of a medicament used for the treatment and / or prevention of pain-related disorders. acute and / or chronic and / or neuropathic in human and non-human mammalian animals.  Use of the pharmaceutical composition according to claim 16, characterized in that the medicament is found in various pharmaceutical forms described in the state of the art, preferably orally, most preferably, tablets, lozenges, capsules, dragees, pills, syrups, suspensions, emulsions, including prolonged, slow or sustained release oral dosage forms.