ES2948511A1 - N-SULFONYLUREA DERIVATIVES AND THEIR THERAPEUTIC USE (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Derivatives of n-sulfonylureas and their therapeutic use. The present invention relates to a series of compounds derived from N-suffoniureas, compounds of general formula (1), with pharmacological activity that inhibits the NLRP3 inflammasome. {IMAGE-01} The use of the compounds referred to with the general formula (I) is claimed as agents for the treatment of preferably human diseases that involve an inflammatory process, preferably mediated by what is known as an inflammasome, preferably of the type called NLRP3. Among these diseases are the so-called neurodegenerative diseases, such as Alzheimer's and Parkinson's, inflammatory diseases, metabolic diseases, autoimmune diseases and, in general, any pathology caused by the alteration of biological functions where the NLRP3 inflammasome is involved. The present invention can be framed in the field of the pharmaceutical industry. (Machine-translation by Google Translate, not legally binding)

Description

DESCRIPTION

N-SULFONYLUREA DERIVATIVES AND THEIR THERAPEUTIC USE

STATE OF THE PRIOR ART

The NLRP3 inflammasome is activated by a wide variety of stimuli of pathogenic and endogenous origin, known as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The activation of the inflammasome involves its assembly and the processing and release of the proinflammatory cytokines IL-ip and IL-18, responsible for initiating and propagating the inflammatory response (Nat Rev Immunology, 2019, 8:477-489). Given the heterogeneity of signals capable of activating the inflammasome, its involvement in various diseases of a wide range is expected. Overactivation of the NLRP3 inflammasome has been related to chronic inflammation pathologies such as gout, rheumatoid arthritis or Crohn's disease (Journal of Inflammation research, 2011, 4, 39-49), diseases of the central nervous system such as Alzheimer's , Parkinson's, stroke or brain trauma (Frontiers in Molecular Neuroscience, 2018, 11,320), cardiovascular disorders, including atherosclerosis (Translational Research 2020, 215, 75-85) and myocardial infarction (Nat Rev Cardiology, 208, 15, 203 214), metabolic pathologies such as diabetes (Biomolecules, 2019, 9, 850), or autoimmune pathologies, such as contact dermatitis and psoriasis (Dermathology, 2016, 232:534-540). In addition to these diseases, in whose progression the inflammasome is involved, there is a group of pathologies caused directly by gain-of-function mutations in the gene that codes for the NLRP3 protein. These are cryopyrin-associated syndromes (CAPS), a group of rare autoinflammatory diseases, of autosomal dominant inheritance, which include familial cold urticaria syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) (Nat Rev Immunology, 2019, 8:477-489).

Although each of these diseases has its own epidemiology and pathophysiology, all of them are characterized by sharing common inflammatory alterations, characterized by the uncontrolled release of proinflammatory cytokines, mainly IL-ip. Many of them are some of the most disabling and most prevalent diseases in the population, such as gout (1-4% in the general population) (Journal of Advanced Research, 2017, 8, 495-511) or stroke (1.1 millions of people year in Europe) (European Journal of Neurology, 2006, 13:581-598). Furthermore, the incidence of these pathologies is expected to increase due to the growth in the life expectancy of the population. These reasons place the NLRP3 inflammasome as a new and promising drug target for a wide variety of pathologies.

Currently there are several therapies directed against the Interleukin-1 pathway, these act either directly on IL-ip/IL-1a or on its receptor, thus avoiding the triggered inflammatory response (Nat Rev Drug Discovery, 2012, 11(8) :633-652). The first drug developed against IL-1 was Anakinra (Kineret ®). Anakinra is a recombinant version of the endogenous IL-1 receptor antagonist (IL-1RA), which competitively inhibits the binding of IL-ip and IL-1a to their receptor. It is approved for use by the FDA for the treatment of rheumatoid arthritis and NOMID, and by the EMA for rheumatoid arthritis and all CAPS phenotypes. (Expert Review of Clinical Pharmacology, 2017, 10(8):855-864). Another drug directed against IL-1 is Rilonacept (Arcalyst ®). This was approved in 2008 by the FDA for the treatment of FCAS and MWS, and a year later by the EMA for all CAPS, however, the EMA withdrew it from the market in 2012 due to its limited marketing in Europe. Rilonacept is a construct of the extracellular fraction of the IL-1 receptor (IL-1R1) and its accessory protein (IL-1RAP), fused to the Fc region of human immunoglobulin G1 (IgG1-Fc). This drug works as a decoy for IL-1a and p, as well as IL-1 RA, preventing them from binding to the IL-1R1 receptor and triggering the inflammatory response. (Expert Review of Clinical Pharmacology, 2017, 10(8):855-864). The last of the drugs approved against interleukin-1 is canakinumab (Ilaris ®). Unlike the previous two, canakinumab is a monoclonal antibody, based on the structure of human IgG1. Canakinumab traps and neutralizes IL-ip in serum and thus prevents binding to its receptor and consequent signaling. Canakinumab treatment for FCAS and MWS was approved in 2009 by the FDA and EMA for all CAPS phenotypes. Expert Review of Clinical Pharmacology, 2017, 10(8):855-864). In addition to its already approved therapeutic uses, clinical trials are currently underway for the use of Anakinra (1 phase II, 3 phase IV), Rilonacept (1 phase III) and canakinumab (1 phase II, 2 phase III), against various pathologies such as gout (Anakinra), COVID-19 (Anakinra), recurrent pericarditis (Rilonacept) and non-small cell lung cancer (Canakinumab), among others (REF: clinicaltrials.gov).

However, despite the positive results that these treatments have on the pathologies for which they are approved, they present several limitations. The main route of administration is subcutaneous and daily application (Anakinra), weekly (Rilonacept) or in the best case every 8 weeks (Canakinumab). Furthermore, all of them present common side effects, mainly reactions at the injection site and increased infections, mainly of the upper respiratory tract, as they are immunosuppressive drugs (Expert Review of Clinical Pharmacology, 2017, 10(8):855-864) . Part of these side effects are explained because in addition to NLRP3, other inflammasomes such as NLRC4, AIM2 or NLPR1 are responsible for the processing and release of interleukin-1. The activation of these inflammasomes occurs in the face of other stimuli of viral or bacterial origin to which NLRP3 does not respond, so blocking the entire interleukin-1 signaling pathway generates an unwanted immunosuppressive effect. Furthermore, these drugs directed against interleukin-1 do not prevent the release of other proinflammatory factors that occur as a consequence of NLRP3 activation, such as IL-18 or the alarmin HMGB1 and other molecules released together with the cellular content as a consequence of the pyroptosis that occurs after activation of the inflammasome (Nat Rev Drug Discovery, 2018, 17(8):588-60). The lack of specificity of anti-IL-1 drugs, the side effects they generate and their lack of efficacy against other factors dependent on the inflammasome mean that the approach of new drugs against these inflammatory pathologies is directed around the selective inhibition of the NLRP3 inflammasome.

Although great efforts are being made by the scientific community in the study of the inflammasome and the development of inhibitors, and some of them are in advanced phases of clinical trials, to date none of them have been approved as treatment for the aforementioned pathologies. For these reasons, we propose the need to generate new inhibitory molecules of the NLRP3 inflammasome, such as compounds derived from N-Sulfonylureas.

With these precedents, we have proposed the synthesis of simplified analogues of MCC950 {3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-1-([4-(2- hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (Figure 1), where the two cyclopentane rings fused around the benzene ring have been eliminated, and replaced by simpler substituents, as schematized in the formula general 1b-14b of figure 1. This design has allowed us to synthesize a significant number of compounds through a simple synthetic protocol, which according to the retrosynthetic scheme of Figure 1, takes advantage of the availability of commercial isocyanates 1a-14a which already incorporate substituents of different chemical nature in different positions of the aromatic ring attached to urea, and the easy and described methodology for the synthesis of 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide ( 15 )( Synth Commun 2003, 33: 2029-2043), key compound in this process. R in figure I being a benzene ring with different substitution. In a single case, and in a similar embodiment, the obtaining and use of a compound analogous to MCC950 is also claimed where the tricyclic ring of s-indacene is replaced by 9H-fluorene linked by the only non-aromatic carbon, compound 14b . In summary, the selection of these new analogues of MCC950 will allow us to evaluate the pharmacological effect of the elimination of the two cyclopentane rings in MCC950 , simplifying the structure, and have data to establish a structure-activity analysis, which allows us to design new and more efficient derivatives of MCC950 .

Figure 1 . Structure of MCC950 , the new N-sulfonylureas 1b-14b , and the key intermediates 1a - 14a and 15 of its synthesis.

DESCRIPTION OF THE INVENTION

The present invention is related to the ability of inhibitors of NLRP3 activation to exert anti-inflammatory effects, through a mechanism of action that would involve the inhibition of the release of pro-inflammatory cytokines such as IL-1beta. These effects have been observed in the family of compounds described in the present invention.

More specifically, the present invention relates to a family of compounds with the structural characteristic of being simplified derivatives of MCC950 {((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) ((4-(2-hydroxypropan-2-yl)furan-2-yl)sulfonyl)amide} of general structure I and with the substitution on the benzene ring as reflected in Figure 1, which present potentially useful pharmacological properties for him treatment of diseases that involve an inflammatory process, such as gout, rheumatoid arthritis or Crohn's disease; diseases of the central nervous system such as Alzheimer's, Parkinson's, stroke or brain trauma; cardiovascular disorders, including atherosclerosis and myocardial infarction; metabolic pathologies such as diabetes; or autoimmune in nature, such as contact dermatitis and psoriasis.

In the pharmacological studies to which they have been subjected, the compounds of the present invention have shown a series of potentially very useful activities in the treatment of inflammatory diseases, without prejudice to the fact that in more in-depth studies, new biological properties of possible interest may appear. . The activities studied, and which have shown positive results, have been:

- Inhibition of IL-1beta release in 3 "in vitro" experimental models.

- Anti-inflammatory effect in an "in vivo" model of arthritic gout.

- Antiallodynic effect in an "in vivo" model of arthritic gout.

As has been described in the state of the art prior to the present invention, and there is an increasing number of experimental evidences, the uncontrolled release of IL-1beta is strongly related to the progression of diseases of very different etiologies that share a inflammatory component such as gout, rheumatoid arthritis, Crohn's disease, head trauma or atherosclerosis, among other diseases.

Therefore, a first aspect of the present invention relates to a compound of general formula (I) (hereinafter compounds of the invention):

where:

R is a benzene ring or a 9H-fluorene ring differently attached to the sulfonylurea nucleus.

When R is a benzene ring, it may have additional chemical substitution as detailed in Figure 2:

R1 and R2 are the same or different groups and are each independently selected from an alkyl group (methyl, ethyl, or larger hydrocarbon or fluorocarbon chains, or bidentate substituents, that is, doubly linked to the benzene ring), alkoxide (methoxide , ethoxide, or larger chains, or bidentate substituents of the type -O-alkylene-O-), amino and aminoalkyl, halogens, nitro =-alkyl groups) or, in general, any substituent located in any position.

The term "alkyl" refers in the present invention to aliphatic chains, linear or branched, having 1 to 6 carbon atoms, for example, methyl, ethyl, or larger hydrocarbon chains or fluorocarbons, etc. Preferably the alkyl group has between 1 and 3 carbon atoms.

By "compound of the invention" the present invention also refers to any of its derivatives, isomers, pharmaceutically acceptable salts, in any of the ionizable positions, and/or solvate thereof.

The relative position of R1 and R2 on the benzene ring can be either any of the positions of the phenyl ring, that is, ortho, meta and para positions, and the combination of these is chemically possible.

In another more preferred embodiment, the compound of the invention is selected from the list comprising:

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(2-methylphenyl)urea

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(3-methylphenyl)urea

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(-4-methylphenyl)urea

1-(3,5-dimethylphenyl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(2-methoxyphenyl)urea

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(4-methoxyphenyl)urea

1-(3,5-dimethoxyphenyl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea

3-(2H-1,3-benzodioxol-5-yl)-1-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 1-(4-dimethylaminophenyl)-3- ([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(-4-nitrophenyl)urea

1-(4-chloro-2-(trifluoromethyl)phenyl-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 3-(2,3-dihydro-1H-inden -5-yl)-1-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 3-(9H-fluoren-3-yl)-1-([4-(2 -hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea

1-(9H-fluoren-9-yl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea

The compounds of the present invention of formula (I) can be obtained or produced by a chemical synthetic route or obtained from a natural material of different origin. An embodiment for obtaining the compounds of the invention of formula (I), or an isomer, pharmaceutically acceptable salt and/or solvate thereof, comprises the following steps:

(a) Obtaining 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) has been carried out as shown in Scheme 1, according to the method described in the literature ( Synth Commun 2003, 33: 2029-2043), from and by reaction of ethyl furan-3-carboxylate ( 16 ) with chlorosulfonic acid, to give 4-(ethoxycarbonyl)furan-2-sulfonic acid which, by treatment with phosphorus pentachloride in pyridine, led to ethyl (chlorosulfonyl)furan-3-carboxylate, whose reaction with ammonium bicarbonate, generated 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide, which by reaction with Excess methylmagnesium chloride gave rise to the desired sulfonamide 15 .

Scheme 1. Synthesis of 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide ( 15 ) (Synth Commun 2003, 33: 2029-2043).

(b) reaction of 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide with isocyanates 1a-14a according to scheme 2.

Scheme 2. Synthesis of N-sulfonylurea amidides 1b - 14b .

where R represents all the proposed substituents indicated above when describing the general formula (I). The amide form formed after the reaction in the basic medium generated by sodium methoxide (Scheme 2) is converted into the neutral urea form once the product has been reconstituted in an aqueous, physiological solution or buffer at neutral or acidic pH (Scheme 2), so slow but irreversible. For this type of functional groups such as acylated sulfonilamides, a half-life in human plasma for neutralization of around 5 min is described. Therefore, access to this amide intermediate is not exclusive to the treatment with the sodium methoxide base, but rather the use of other reagents with sufficient basicity to induce the nucleophilic addition of the sulfonylurea on the isocyanates 1a-14a , form amide species with different counterions other than Na+, and all of them can give rise to the products 1b-14b claimed in this invention, through the aforementioned reconstitution in aqueous solution (Scheme 2). The intermediate amide form, with any of the possible counterions, is also the object of the invention since it offers a pharmaceutical alternative as an appropriate formulation for injection at high doses in an aqueous bolus.

Yet another aspect of the present invention relates to any of the compounds of general formula (I) for use as a medicine or pharmaceutical composition, and preferably a medicine or pharmaceutical composition that is used for the treatment of pathologies or inflammatory diseases caused by release excessive IL-1beta or, in general, diseases susceptible to benefit from the biological activities shown by the products described in the present invention, or from a pharmaceutically acceptable salt, derivative, prodrug or solvate thereof.

Compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds (e.g., Z and E), or optical isomers or enantiomers, depending on the presence of chiral centers in the R1 chains. and R2. Individual isomers, enantiomers or diastereomers and mixtures thereof fall within the scope of the present invention. The individual enantiomers or diastereoisomers, as well as their mixtures, can be separated by conventional techniques.

As used herein, the term "derivative" includes both pharmaceutically acceptable compounds, that is, derivatives of the compound of formula (I) that can be used in the manufacture of a medicament, and non-pharmaceutically acceptable derivatives since these can be useful in the preparation of pharmaceutically acceptable derivatives. The nature of the pharmaceutically acceptable derivative is not critical, as long as it is pharmaceutically acceptable.

Likewise, within the scope of this invention are prodrugs of the compounds of formula (I). The term "prodrug" as used herein includes any compound derived from a compound of formula (I), for example, esters, including carboxylic acid esters, amino acid esters, phosphate esters, sulfonate esters of metal salts, etc., carbamates, amides, etc., which, when administered to an individual is capable of providing, directly or indirectly, said compound of formula (I) in said individual. This definition also includes prodrugs known as bioprecursors, substances that, through metabolic or chemical transformation within a living organism, give rise to compounds defined by the general formula (I). This point includes the amide form immediately precursor of the sulfonylureas 1b-14b , which once in the body form the compounds claimed here at a rate dependent on the pKa of each compound. Advantageously, all types of prodrug are compounds that increase the bioavailability, affect the metabolism, stability or site of pharmacological action of the compound of formula (I) when administered to an individual or that enhance the release of the compound of formula (I) in a biological receptor. The nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (I) at a biological receptor of an individual. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.

The compounds of the invention may be in crystalline form as free compounds or as solvates and both forms are intended to be within the scope of the present invention. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, and pharmaceutically unacceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts. The nature of the pharmaceutically acceptable solvate is not critical, as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. The solvates can be obtained by conventional solvation methods well known to those skilled in the art. For their application in therapy, the compounds of formula (I), their isomers, salts, prodrugs or solvates, will preferably be in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding the normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels. Purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or its salts, solvates or prodrugs.

Unless otherwise indicated, compounds of the invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having such a structure, with the exception of the substitution of a hydrogen for a deuterium or for tritium, or the substitution of a carbon for a carbon enriched in 13C or 14C or a nitrogen enriched in 15N, are within the scope of this invention.

The compounds described in the present invention, their pharmaceutically acceptable salts, prodrugs and/or solvates as well as the pharmaceutical compositions containing them can be used together with other additional drugs to provide a combination therapy. Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for administration simultaneous or not with that of the pharmaceutical composition comprising a compound of formula (I), or a prodrug, solvate, derivative or a pharmaceutically acceptable salt thereof.

The "pharmaceutically acceptable vehicles" that can be used in said compositions are the vehicles known to those skilled in the art and commonly used in the preparation of therapeutic compositions.

Another preferred embodiment of the present invention refers to a pharmaceutical composition useful for the treatment of inflammatory human pathologies or diseases or, in general, of diseases capable of benefiting from the biological activities shown by the products described in the present invention, hereinafter composition pharmaceutical of the invention, comprising a compound, in a therapeutically effective amount, of formula (I), or mixtures thereof, a pharmaceutically acceptable salt, prodrug, solvate or stereoisomer thereof together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for administration to a patient.

In another aspect, the present invention relates to a method for the treatment of patients affected by inflammatory diseases or other processes in which the products of the present invention produce a beneficial effect. This treatment consists of the administration to individuals affected by these diseases of therapeutically effective amounts of a compound of formula (I), or a pharmaceutical composition that includes it. By way of example, diseases contemplated in this invention are chronic inflammation pathologies such as gout, rheumatoid arthritis or Crohn's disease; diseases of the central nervous system such as Alzheimer's, Parkinson's, stroke or traumatic brain injury; cardiovascular disorders, including atherosclerosis and myocardial infarction; metabolic pathologies such as diabetes; or autoimmune in nature, such as contact dermatitis and psoriasis; or pathology produced by alteration of biological functions where the NLRP3 inflammasome is involved.

In the sense used in this description, the expression "therapeutically effective amount" refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other reasons, due to the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.

In another particular embodiment, said therapeutic composition is prepared in the form of a solid form or aqueous suspension, in a pharmaceutically acceptable diluent. The therapeutic composition provided by this invention can be administered by any appropriate administration route, for which said composition will be formulated in the pharmaceutical form appropriate to the chosen administration route. In a particular embodiment, the administration of the therapeutic composition provided by this invention, both in ionized and neutral form, according to scheme 2, is carried out orally, topically, rectally or parenterally (including subcutaneous, intraperitoneal, intradermal, intramuscular, intravenous , etc.). A review of the different pharmaceutical forms of drug administration and the excipients necessary to obtain them can be found, for example, in the "Treatise of Galénic Pharmacy", C. Faulí i Trillo, 1993, Luzán 5, S.A. Ediciones, Madrid, or in other usual or similar ones of the Spanish and United States Pharmacopoeias.

The use of the compounds of the present invention is compatible with their use in protocols in which the compounds of formula (I), their prodrugs, or their mixtures are used by themselves or in combinations with other treatments or any medical procedure.

Throughout the description and claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will emerge partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.

EXAMPLES

The invention will be illustrated below through tests carried out by the inventors, which develop the selection process of the compounds of the invention.

1. OBTAINING THE COMPOUNDS OF THE INVENTION

The synthesis of 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide (15) has been carried out as shown in Scheme 1, according to the method described in the literature. (Synth Commun 2003, 33: 2029-2043), from and by reaction of ethyl furan-3-carboxylate (16) with chlorosulfonic acid, to give 4-(ethoxycarbonyl)furan-2-sulfonic acid, which by treatment with phosphorus pentachloride, in the presence of pyridine, led to ethyl (chlorosulfonyl)furan-3-carboxylate, whose reaction with ammonium bicarbonate, in an acetone-water mixture, generated 4-(2-hydroxypropan-2-yl) furan-2-sulfonamide which, in turn, and by reaction with excess methylmagnesium chloride, in THF, gave rise to the desired sulfonamide 15.

Next, the reaction of 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide (15) with isocyanates 1a-14a, promoted by sodium methoxide in acetonitrile, at room temperature, led to the sulfonamides 1b-14b (Scheme 2), isolated as sodium amides, with good yields (Table 1).

Scheme 1. Synthesis of 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide ( 15 ) (Synth Commun 2003, 33: 2029-2043).

Scheme 2. Synthesis of N-sulfonylureas 1b - 14b

Table 1. Amide intermediates of the N-Sulfonylureas 1b-14b prepared in this Report, precursor isocyanates, reaction times and yields.

Finally, the anionic amides object of the invention, isolated and characterized, are subjected to neutralization conditions in usual aqueous, physiological media, buffers at neutral pH, or water to give rise to the claimed compounds, object of pharmacological study and use for the treatment of diseases.

Materials and methods. Monitoring of the reactions was carried out by thin layer chromatography (TLC), using Merck type 60 F254 silica gel plates of 0.2 mm thickness. Detection was performed with an ultraviolet light lamp (A = 254 nm). 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a Varian System 500, Varian Mercury-400, or Varian Inova-300. Chemical shifts are expressed on the 5 (ppm) scale and in the case of 1H NMR spectra, the multiplicity of the signals is indicated as s (singlet), d (doublet), t (triplet), dd (doublet). of doublets), td (triplet of doublets), and m (multiplet). Figure 7 shows the carbon numbering for the purposes of their assignment for compounds 1b - 7b, and 9-11b . High resolution mass spectra (EMAR) were obtained on an Agilent 6250 Accurate Mass Q-TOF LC/MS using the API-ES technique in positive mode (Hewlett-Packard HP-5873 MSD spectrometer). Infrared spectra were recorded on a Perkin-Elmer Espectrum One spectrophotometer. Melting points were determined on a Reichert microscope with a thermoregulatory base and are uncorrected. Purification was performed in a Biotage® Isolera One flash purification system.

General procedure for the synthesis of N-sulfonylureas 1b-14b. 4-(1-Hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (1 equiv), dissolved in CH ₃ CN (20 mM) was added, drop by drop, to a suspension of MeONa (1.1 equiv) in CH ₃ CN, in an ice bath, under argon, and stirring. After stirring for 30 min, at room temperature (rt), it was cooled again in an ice-water bath, and after 10 min, the corresponding isocyanate was added, previously dissolved in CH ₃ CN (30 mM) if solid. , stirring the mixture then, at rt, for the time indicated in each case. The product was isolated by vacuum filtration, through a No. 3 filter plate, washing with cold DCM, or after removing the solvent in vacuum, in a rotary evaporator, by column chromatography, using DCM/CH ₃ OH mixtures. Reconstitution in aqueous solution provides the corresponding N-sulfonylurea.

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(2-methylphenyl)urea (1b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (53.3 mg, 0.26 mmol), dissolved in CH ₃ CN (13 mL), was treated with NaOCH ₃ (15.7 mg, 0.29 mmol), and with o-tolyl isocyanate ( 1a ) (0.04 mL, 0.32 mmol), for 1 h, at rt, and reflux for 30 min. After filtration, the sodium amide of compound 1b (70 mg, 73.6%) was obtained as a solid: mp 150-2 °C; IR (KΒr): v 3366, 1621, 1520, 1274, 1144, 1118 cm-1; 1H NMR (300 MHz, DMSO-da) 57.79 (d, J = 8.0 Hz, 1H, H-6'), 7.57 (s, 1H, NH), 7.38 (d, J = 1.0 Hz, 1H, H- 5), 7.06 - 6.96 (m, 2H, H-3' and H-5'), 6.77 (t, J = 7.4 Hz, 1H, H-4'), 6.63 (d, J = 1.0 Hz, 1H, H-3), 4.92 (s, 1H, OH), 2.14 (s, 3H, CH ₃ ), 1.35 (s, 6H, 2 CH ₃ ); 13C NMR (75 MHz, DMSO) 5 157.9 (1C, C-2", CO), 155.9 (1C, C-2), 139.7 (1C, C-1'), 137.8 (1C, C-5), 136.1 (1C, C-4), 130.1 (1C, C-3'), 126.9 (1C, C-2'), 126.0 (1C, C-5'), 121.49(1C, C-4'), 121.0 (1C, C-6'), 109.8 (1C, C-3), 66.9 (1C, C-1"), 31.4 (2C, 2 CH ₃ ), 18.2 (1C, CH ₃ ). HRMS (ESI neg): Calculated for C15H1rN ₂ O5SNa [M ] i 337.08637. Found: 337.08602. By treatment with water, 1b is achieved quantitatively.

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(3-methylphenyl)urea (2b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (52.3 mg, 0.255 mmol), dissolved in CH ₃ CN (12.8 mL), was treated with NaOCH ₃ (15.1 mg, 0.28 mmol), and with m-tolyl isocyanate ( 2a ) (0.04 mL, 0.31 mmol), for 1 h. After filtration, the amide of compound 2b (75.2 mg, 81.8%) was obtained as a solid: mp 233-5 °C; IR(KΒr): v 3348, 1616, 1541, 1314, 1271, 1137 cm'1; 1H NMR (300 MHz, DMSO-06) 58.34 (s, 1H, NH), 7.36 (d, J = 1.1 Hz, 1H, H-5), 7.29 (s, 1H, H-2'), 7.21 ( d, J = 9.1 Hz, 1H, H-6'), 6.96 (t, J = 7.8 Hz, 1H, H-5'), 6.64 (d, J = 1.1 Hz, 1H, H-3), 6.56 ( d, J = 7.4 Hz, 1H, H-4'), 4.95 (s, 1H, OH), 2.17 (s, 3H, CH ₃ ), 1.35 (s, 6H, 2 CH ₃ ); 13C NMR (101 MHz, DMSO) 5 159.0 (1C, C-2", CO), 156.0 (1C, C-2), 142.5 (1C, C-1'), 137.8 (1C, C-5), 137.5 (1C, C3'), 136.2 (1C, C-4), 128.4 (1C, C-5'), 121.0 (1C, C-4'), 118.4 (1C, C-2'), 115.1 (1C , C-6'), 110.0 (1C, C-3), 67.0 (1C, C-1"), 31.6 (1C, 2 CH ₃ ), 21.8 (1C, CH ₃ ). HRMS (ESI neg): Calculated for C15H17N ₂ O5SNa [M]_: 337.08637. Found: 337.08747. By treatment with water, 2b is achieved quantitatively.

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(-4-methylphenyl)urea (3b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (55.9 mg, 0.27 mmol), dissolved in CH ₃ CN (13.5 mL), was treated with NaOCH ₃ (16.5 mg, 0.30 mmol), and with p-tolyl isocyanate ( 3a ) (0.04 mL, 0.32 mmol), for 4 d. After column chromatography, using DCM/CH ₃ OH in gradient (6%-10%), the amide of compound 3b (51 mg; 53.4%) was obtained as a solid: mp 190-2 °C; IR (KΒr): v 3396.1620, 1569, 1321, 1282, 1143 cm'1; 1H NMR (400 MHz, DMSO-da) 58.37 (s, 1H, NH), 7.37 (d, J = 1.1 Hz, 1H, H-5), 7.33 (d, J = 8.5 Hz, 2H, H-2' and H-6'), 6.90 (d, J = 8.3 Hz, 2H, H-3' and H-5'), 6.65 (d, J = 1.1 Hz, 1H, H-3), 4.94 (s, 1H, OH), 2.16 (s, 3H, CH ₃ ), 1.35 (s, 6H, 2CH ₃ ); 13C NMR (101 MHz, DMSO) 5 159.0 (1C, C-2", CO), 156.0 (1C, C-2), 140.0 (1C, C-1'), 137.8 (1C, C-5), 136.2 (1C, C-4), 129.0 (2C, C-3' and C-5'), 128.8 (1C, C4'), 118.0 (2C, C-2' and C-6'), 110.0 (1C , C-3), 67.0 (1C, C-1''), 31.6 (2C, 2CH ₃ ), 20.8 (1C, CH ₃ ). HMS (ESI pos): Calculated for C15H^N ₂ NaO5SNa [M+H ]+: 361.08286. Found: 361.08356. By treatment with water, 3b is obtained quantitatively.

1 -(3,5-dimethylphenyl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (4b) . Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (56.7 mg, 0.277 mmol), dissolved in CH ₃ CN (13.8 mL), was treated with NaOCH ₃ (17.8 mg, 0.33 mmol), and with 3,5-dimethylphenyl isocyanate ( 4a ) (0.045 mL, 0.32 mmol), for 20 h at RT, and 1 h at reflux. After column chromatography, using DCM/CH ₃ OH gradient (5-10%), the amide of compound 4b (62.9 mg, 63.7%) was isolated as a solid: mp 198-200 °C; IR (KΒr): v 3370, 2925, 1612, 1292, 1251, 1141 cmr1; 1H NMR (500 MHz, DMSO-da) 58.33 (s, 1H, NH), 7.37 (s, 1H, H-5), 7.07 (s, 2H, H-2' and H-6'), 6.63 ( s, 1H, H-3), 6.39 (s, 1H, H-4'), 4.92 (s, 1H, OH), 2.12 (s, 6H, 2CH ₃ b), 1.34 (s, 6H, 2CH ₃ a ); 13C NMR (126 MHz, DMSO) 5 158.7 (CO, C-2''), 155.9 (C, C-2), 142.2 (C, C-1'), 137.8 (C, C-5), 137.2 (2C, C-3' and C-5'), 136.1 (C, C-4), 122.1 (C-4'), 115.8 (2C, C-2' and C-6'), 110.1 (C, C-3), 66.94 (C, C-1''), 31.5 (2C, 2CH3a), 21.7 (2C, 2CH3b). HRS (ESI neg): Calculated for C16H^N ₂ O5SNa [M]_ : 351.10202. Found: 351.10103. By treatment with water, 4b is achieved quantitatively.

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(2-methoxyphenyl)urea (5b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (57.8 mg, 0.28 mmol), dissolved in CH ₃ CN (14 mL), was treated with NaOCH ₃ (16.7 mg, 0.31 mmol), and with 2-methoxyphenyl isocyanate ( 5a ) (0.045 mL, 0.34 mmol), for 19 h. After filtration, the amide of compound 5b (97.2 mg, 92%) was obtained as a solid: mp 225-7 °C; IR (KΒr): v 3405, 1594, 1510, 1245, 1239, 1220 cm'1; 1H NMR (500 MHz, DMSO-da) 58.06 - 8.04 (m, 1H, H-6'), 7.37 (d, J = 1.1 Hz, 1H, H-5), 7.33 (s, 1H, NH), 6.89 - 6.86 (m, 1H, H-3'), 6.79 - 6.73 (m, 2H, H-4' and H-5'), 6.63 (d, J = 1.1 Hz, 1H, H-3), 4.92 (s, 1H, OH), 3.78 (s, 3H, OCH ₃ ), 1.34 (s, 6H, 2CH ₃ ); 13C NMR (126 MHz, DMSO) 5157.8 (1C, C-2", CO), 155.7 (1C, C-2), 147.3 (1C, C-2'), 138.0 (1C, C-5), 136.1 (1C, C-4), 130.8 (1C, C-1'), 120.8 (1C, C-5'), 120.6 (1C, C-4'), 117.8 (1C, C-6'), 110.6 ( 1C, C-3'), 110.1 (1C, C-3), 66.9 (1C, C-1''), 56.1 (1C, OCH ₃ ), 31.5 (2C, 2CH ₃ ). EMAR (ESI neg): Calculated for Ci5H H N ₂ O6SNa [M]—: 353.08128. Found: 353.08214. By treatment with water, 5b is achieved quantitatively.

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(4-methoxyphenyl)urea (6b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (63.2 mg, 0.31 mmol), dissolved in CH ₃ CN (15.4 mL), was treated with NaOCH ₃ (18.4 mg, 0.34 mmol), and with 4-methoxyphenyl isocyanate ( 6a ) (0.05 mL, 0.34 mmol), for 24 h. After column chromatography, using DCM/CH ₃ OH gradient (5-10%), the amide of compound 6b (105.5 mg, 91%) was isolated as a solid: mp 235-7 °C; IR (KΒr): v 3337, 1610, 1536, 1513, 1296, 1274, 1248, 1239 cm-1; 1H NMR (400 MHz, DMSO-CÍ6) 58.35 (s, 1H. NH), 7.38 (s, 1H, H-5), 7.36 (d, J = 8.9 Hz, 2H, H-2' and H-6 '), 6.71 (d, J = 8.9 Hz, 2H, H-3' and H-5'), 6.67 (s, 1H, H-3), 4.95 (s, 1H, OH), 3.66 (s, 3H , OCH ₃ ), 1.37 (s, 6H, 2CH ₃ ); 13C NMR (101 MHz, DMSO) 5159.1 (1C, C-2", CO), 156.1 (1C, C-2), 153.5 (1C, C-4'), 137.8 (1C, C-5), 136.2 (1C, C-4), 135.9 (1C, C-1'), 119.2 (2C, C-2' and C-6'), 113.9 (2C, C-3' and C-5'), 109.9 ( 1C, C-3), 67.0 (1C, C-1''), 55.5 (1C, OCH ₃ ), 31.6 (2C, 2 CH ₃ ). HMS (ESI neg): Calculated for C15H17N ₂ O6SNa [M]— : 353.08128. Found: 353.08212. By treatment with water, 6b is obtained quantitatively.

1-(3,5-dimethoxyphenyl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (7b) . Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (63.6 mg, 0.31 mmol), dissolved in CH ₃ CN (15.5 mL), was treated with NaOCH ₃ (18.4 mg, 0.34 mmol), and with 3,5-dimethoxyphenyl isocyanate ( 7a ) (84 mg, 0.47 mmol) dissolved in CH ₃ CN (15.6 mL), for 21 h . After column chromatography, using DCM/CH ₃ OH in gradient (5-10%), the amide of compound 7b (112.5 mg, 89.4%) was isolated as a solid: mp 123-5 °C; IR (KΒr): v 3359, 1667, 1607, 1290, 1153, 1132 cmr 1; 1H NMR (400 MHz, DMSO-da) 58.45 (s, 1H, NH), 7.40 (d, J = 1.1 Hz, 1H, H-5), 6.76 (d, J = 2.3 Hz, 2H, H-2 ' and H-6'), 6.66 (d, J = 1.1 Hz, 1H, H-3), 5.95 (t, J = 2.3 Hz, 1H, H-4'), 4.96 (s, 1H, OH), 3.64 (s, 6H, 2OCH ₃ ), 1.37 (s, 6H, 2CH ₃ ); 13C NMR (101 MHz, DMSO) 5 160.7 (2C, C-3' and C-5'), 158.7 (1C, C-2", CO), 155.8 (1C, C-2), 144.2 (1C, C-1'), 137.9 (1C, C-5), 136.2 (1C, C-4), 110.1 (1C, C-3), 96.4 (2C, C-2' and C-6'), 92.7 ( 1C, C-4'), 67.0 (1C, C-1"), 55.3 (2C, 2OCH ₃ ), 31.5 (2C, 2CH ₃ ). HRS (ESI neg): Calculated for C ^H ^^O rS N a [M]—: 383.09185. Found: 383.09316. By treatment with water, 7b is achieved quantitatively.

3-(2H-1,3-benzodioxol-5-yl)-1-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (8b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255)(103 mg, 0.5 mmol), dissolved in CH ₃ CN (25 mL), was treated with NaOCH ₃ (30 mg, 0.56 mmol), and with 5-isocyanatobenzo[d]1,3-dioxol ( 8a ) (90 mg, 0.55 mmol) dissolved in CH ₃ CN (18.4 mL ), for 22 hours. After filtration, the amide of compound 8b (113 mg, 57.8%) was obtained as a solid: mp 230 °C (dec.); IR(KΒr): v 3334, 1603, 1547, 1503, 1346, 1248, 1130 cm-1; 1H NMR (500 MHz, DMSO-da) 58.41 (s, 1H, NH), 7.36 (d, J = 1.1 Hz, 1H, H-5), 7.28 (d, J = 2.1 Hz, 1H, H-4 '), 6.76 (dd, J = 8.4, 2.1 Hz, 1H, H-6'), 6.64 (d, J = 8.4 Hz, 1H, H-7'), 6.64 (d, J = 1.1 Hz, 1H, H-3), 5.85 (s, 2H, CH ₂ , H-2'), 4.90 (s, 1H, OH), 1.34 (s, 6H, CH ₃ ); 13C NMR (126 MHz, DMSO) 5159.0 (1C, C-2", CO), 156.0 (1C, C-2), 147.2 (1C, C-3a'), 140.8 (1C, C-7a'), 137.8 (1C, C-5), 137.3 (1C, C-5'), 136.2 (1C, C-4), 110.0 (1C, C-6'), 109.9 (1C, C-3), 108.1 (1C , C-7'), 100.7 (2C, C-2', CH ₂ ), 100.4 (1C, C-4'), 66.9 (1C, C-1"), 31.5 (2C, 2CH ₃ ). HRMS (ESI neg): Calculated for C15H15N ₂ O7SNa [M]_: 367.06055. Found: 367.06132. By treatment with water, 8b is achieved quantitatively.

1-(4-dimethylaminophenyl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (9b) . Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (103 mg, 0.5 mmol), dissolved in CH ₃ CN (25 mL), was treated with NaOCH ₃ (30 mg, 0.56 mmol), and with 4-dimethylaminophenyl isocyanate ( 9a ) (0.08 mL, 0.56 mmol), for 19 h. After filtration, the amide of compound 9b (120 mg, 61.6%) was obtained as a solid: mp 165 °C (dec.); IR (KΒr): v 3380, 1599, 1521, 1250, 1143, 640 cm'1; 1H NMR (400 MHz, DMSO-da) 58.16 (s, 1H, NH), 7.38 (d, J = 0.9 Hz, 1H, H-5), 7.29 (d, J = 8.9 Hz, 2H, H-3 ' and H-5'), 6.66 (d, J = 0.9 Hz, 1H, H-3), 6.58 (d, J = 8.9 Hz, 2H, H-2' and H-6'), 4.94 (s, 1H, OH), 2.76 (s, 6H, N-2CH ₃ ), 1.37 (s, 6H, 2CH ₃ ); 13C NMR (101 MHz, DMSO) 5 159.1 (1C, C-2", CO), 156.2 (1C, C-2), 145.6 (1C, C-4'), 137.7 (1C, C-5), 136.2 (1C, C-4), 133.1 (1C, C-1'), 119.4 (2C, C-2' and C-6'), 113.7 (2C, C-3' and C-5') 109.9 ( 1C, C-3), 67.0 (1C, C-1"), 41.5 (2C-N-2CH ₃ ), 31.6 (2C, 2CH ₃ ). HRMS (ESI neg): Calculated for C16H20N3O5SNa [M]_: 366.11292. Found: 366.11308. By treatment with water, 1b is achieved quantitatively.

3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(-4-nitrophenyl)urea (10b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (59 mg, 0.29 mmol), dissolved in CH ₃ CN (14.4 mL), was treated with NaOCH ₃ (17.9 mg, 0.33 mmol), and with 4-nitrophenyl isocyanate ( 10a ) (57.2 mg, 0.35 mmol) dissolved in CH ₃ CN (11.6 mL), for 22 h, at reflux for 3.5 h, and for 3 d, at rt. After column chromatography, using DCM/CH ₃ OH gradient (6-10%), the amide of compound 10b (83.3 mg, 74.2%) was isolated as a yellow solid: mp 203-5 °C; IR (KΒr): v 3352, 2926, 1625, 1505, 1302, 1243, 1142, 1110 cm-1; 1H NMR (500 MHz, DMSO-da) 59.33 (s, 1H, NH), 8.01 (d, J = 9.4 Hz, 2H, H3' and H-5'), 7.65 (d, J = 9.4 Hz, 2H , H-2' and H-6'), 7.38 (d, J = 1.1 Hz, H-5), 6.65 (d, J = 1.1 Hz, 1H, H-3), 4.92 (s, 1H, OH) , 1.35 (s, 6H, 2CH ₃ ); 13C NMR (126 MHz, DMSO) 5 158.0 (1C, C-2", CO), 155.5 (1C, C-2), 149.8 (1C, C-1'), 139.6 (1C, C-4') , 138.0 (1C, C-5), 136.2 (1C, C-4), 125.3 (2C, C-2' and C-6'), 116.7 (2C, C-3' and C-5'), 110.5 (1C, C-3), 67.0 (1C, C-1"), 31.5 (2C, 2CH ₃ ). HRS (ESI neg): Calculated for C uH u^O rSN a [M]_ : 368.05579. Found: 368.05531. By treatment with water, 10b is achieved quantitatively.

1-(4-chloro-2-(trifluoromethyl)phenyl-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (11b). Following the General Procedure, 4- ( 1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (103 mg, 0.5 mmol), dissolved in CH ₃ CN (25 mL), was treated with NaOCH ₃ (30 mg, 0.56 mmol), and with 4-chloro-2-(trifluoromethyl)phenyl isocyanate ( 11a ) (122 mg, 0.55 mmol) dissolved in CH ₃ CN (18.4 mL), for 24. After filtration, the amide of compound 11b (116 mg, 51.7%) was obtained as a solid: mp 226-8 °C; IR(KΒr): v 3340, 1590, 1369, 1276, 1133 cm'1; 1H NMR (500 MHz , DMSO-da) 58.25 (d, J = 8.6 Hz, 1H, H-'6), 7.56 (d, J = 2.6 Hz, 1H, H-3'), 7.55 (d, J = 8.6 Hz, 2.6 Hz , 1H, H-5'), 7.51 (s, 1H, NH), 7.40 (d, J = 1.1 Hz, 1H, H-5), 6.64 (d, J = 1.1 Hz, 1H, H-3), 4.92 (s, 1H, OH), 1.34 (s, 6H, 2CH ₃ ); 13C NMR (126 MHz, DMSO) 5 156.7 (1C, CO), 155.2 (1C, C-2), 138.4 (c, J = 1.4 Hz, 1C, C-1'), 138.3 (1C, C-5), 136.2 (1C, C-4), 133.0 (1C, C-5'), 125.7 (c, J = 5.6 Hz, 1C , C-3'), 125.0 (1C, C-4'), 124.2 (1C, C-6'), 123.9 (c, J = 273.2 Hz, 1C, CF3), 118.0 (c, J = 29.6 Hz 1C , C-2'), 110.4 (1C, C-3), 67.0 (1C, C-1”), 31.5 (2CH ₃ ). HRMS (ESI neg): Calculated for C15H13ClF3N ₂ O5Na [M]_: 425.01913. Found: 425.01819. By treatment with water, 11b is achieved quantitatively.

3-(2,3-dihydro-1H-inden-5-yl)-1-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (12b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (62 mg, 0.3 mmol), dissolved in CH ₃ CN (15 mL), was treated with NaOCH ₃ (19.1 mg, 0.35 mmol), and with 5-indanyl isocyanate ( 12a ) (0.065 mL, 0.45 mmol), for 20 h. After flash column chromatography, using DCM/CH ₃ OH gradient (6-8%), the amide of compound 12b (76.2 mg, 65.3%) was isolated as a solid: mp 195-7 °C; IR (KΒr): v 3380, 1597, 1537, 1281, 1164, 1135 cm'1; 1H NMR (300 MHz, DMSOda) 58.41 (s, 1H, NH), 7.41 (d, J = 1.1 Hz, 1H, H-5), 7.38 (d, J = 2.0 Hz, 1H, H-4'), 7.19 (dd, J = 8.1, 2.0 Hz, 1H, H-6'), 6.95 (dd, J = 8.1, 1.1 Hz, 1H, H-7'), 6.67 (d, J = 1.1 Hz, 1H, H-3), 4.95 ( s, 1H, OH), 2.73 (td, J = 7.5, 4.6 Hz, 4H, 2H-1' and 2H-3'), 1.95 (p, J = 7.5 Hz, 2H, H-2'), 1.37 ( s, 6H, 2CH ₃ ); 13C NMR (75 MHz, DMSO) 5158.5 (1C, C-2", CO), 155.6 (1C, C-2), 143.7 (1C, C-3a'), 140.5 (1C, C-5'), 137.8 (1C, C-5), 136.1 (1C, C-4), 135.2 (1C, C-7a'), 123.9 (1C, 7'), 116.1 (1C, C6'), 114.0 (1C, C- 4'), 110.1 (1C, C-3), 66.9 (1C, C-1"), 32.9 (1C, C-3', CH ₂ ), 32.0 (1C, C-1', CH ₂ ), 31.4 (2C, 2CH ₃ ), 25.5 (1C, C-2', CH ₂ ). HRMS (ESI neg): Calculated for C17H19N ₂ O5SNa [M]_: 363.10202. Found: 363.10159. By treatment with water, 12b is obtained quantitatively.

3-(9H-fluoren-3-yl)-1-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (13b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (55.4 mg, 0.27 mmol), dissolved in CH ₃ CN (13.5 mL), was treated with NaOCH ₃ (16.8 mg, 0.31 mmol), and with 9H-fluoren-2-yl isocyanate ( 13a ) (65.8 mg, 0.32 mmol) dissolved in CH ₃ CN (10.6 mL), for 24 hours After flash column chromatography, using DCM/CH ₃ OH gradient (5-8%), the amide of compound 13b (107.6 mg, 93.8%) was isolated as a solid: mp 223-5 °C; IR (KΒr): v 3370, 1599, 1538, 1314, 1249, 1135 cm-1; 1H NMR (500 MHz, DMSO-da) 58.62 (s, 1H, NH), 7.76 (m, 1H, H-1'), 7.68 (dt, J = 7.6, 0.9 Hz, 1H, H-5') , 7.59 (d, J = 8.3 Hz, 1H, H-4'), 7.46 (dt, J = 7.4, 1.0 Hz, 1H, H-8'), 7.43 (dd, J = 8.3, 2.0 Hz, 1H, H-3'), 7.38 (d, J = 1.1 Hz, 1H, H-5), 7.27 (td, J = 7.6, 1.1 Hz, 1H, H-6'), 7.15 (td, J = 7.4, 1.1 Hz, 1H, H-7'), 6.65 (d, J = 1.1 Hz, 1H, H-3), 4.91 (s, 1H, OH), 3.77 (s, 2H, H-9', CH ₂ ), 1.35 (s, 6H, 2CH ₃ ); 13C NMR (126 MHz, DMSO) 5 158.7 (1C-C-2", CO), 156.1 (1C, C-2), 143.8 (1C, C-9a'), 142.7 (1C, C-8a') , 142.2 (1C, C-4b'), 142.1 (1C, C-4a'), 137.7 (1C, C-5), 136.1 (1C, C-4), 133.6 (1C, C-2'), 127.0 (1C, C-6'), 125.6 (1C, C-7'), 125.3 (1C, C-8'), 120.1 (1C, C-4'), 119.2 (1C, C-5'), 116.6 (1C, C-3'), 114.4 (1C, C-1'), 110.0 (1C, C-3), 67.0 (1C, C-1"), 36.9 (1C, C-9', CH ₂ ) , 31.6 (2C, 2CH ₃ ). HRS (ESI neg): Calculated for C ₂ 1H19N ₂ O5SNa [M]_ : 411.10202. Found: 411.10136. By treatment with water, 13b is obtained quantitatively.

1-(9H-fluoren-9-yl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea (14b). Following the General Procedure , 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide ( 15 ) (Nat Med 2015, 21: 248-255) (57.4 mg, 0.28 mmol), dissolved in CH ₃ CN (14 mL), was treated with NaOCH ₃ (17.8 mg, 0.33 mmol), and with 9H-fluoren-9-yl isocyanate ( 14a ) (66 mg, 0.32 mmol) dissolved in CH ₃ CN (10.6 mL), for 4 d. After flash column chromatography, using DCM/CH ₃ OH in gradient (5-10%), the amide of compound 14b (97.8 mg, 85.3%) as a solid: mp 210 ^-2 °C; IR (KΒr): v 3393, 1582, 1512, 1333, 1259, 1172, 1120, 645 cm-1; 1H NMR (500 MHz, DMSO-da) 57.77 (d, J = 7.5 Hz, 2H, H-4' and H-5'), 7.49 (s, 1H, H-5), 7.44 (d, J = 7.5 Hz, 2H, H-1' and H-8'), 7.35 (td, J = 7.4, 1.1 Hz, 2H, H-3' and H-6'), 7.26 (td, J = 7.4, 1.1 Hz , 2H, H-2' and H-7'), 6.73 (s, 1H, H-3), 6.61 (d, J = 8.8 Hz, 1H, NH), 5.79 (d, J = 8.8 Hz, 1H, H-9'), 5.01 (s, 1H, OH), 1.39 (s, 6H, 2CH ₃ ); 13C NMR (126 MHz, DMSO) 5146.4 (2C, C-8a' and C-9a'), 140.1 (2C, C-4a' and C-4b'), 138.7 (1C, C-5), 136.4 ( 1C, C-4), 128.4 (2C, C-3' and C-6'), 127.8 (2C, C-2' and C-7'), 125.2 (2C, C-1' and C-8' ), 120.4 (2C, C-4' and C-5'), 110.7 (1C, C-3), 67.0 (1C, C-1”), 55.9 (1C, C-9'), 31.5 (2C, 2CH ₃ ). HRS (ESI neg): Calculated for C ₂ 1H19N ₂ O5SNa [M]_ : 411.10202. Found: 411.10253. By treatment with water, 14b is obtained quantitatively.

2. BIOLOGICAL ACTIVITIES STUDY IN THE COMPOUNDS OF THE INVENTION

2.1 IL-ip release reduction properties of the compounds of the invention.

The ability of the developed compounds to reduce the release of IL-1P was evaluated using an in vitro model of inflammasome activation in mouse bone marrow-derived macrophages (BMDMs). Macrophages were treated with bacterial lipopolysaccharide (LPS) and Adenosine tri-phosphate (ATP), in the presence of the different compounds, and the release of IL-1P to the medium by the macrophages was determined by ELISA.

The procedure used to evaluate the compounds, following a previously described method (Nature Medicine, 2015, 21(3): 248-255), was as follows: macrophages derived from mouse bone marrow were seeded and maintained in DMEM medium (Dulbeco's Modified Eagle Medium) supplemented with 10% fetal bovine serum, 25% L929 cell supernatant, 50 units per milliliter of penicillin and 50 micrograms per milliliter of streptomycin, at 37°C in humidified air with 5% CO ₂ . For assays, macrophages were subcultured in 12-well plates at a density of 6x105 cells per well. To study the effect of the compounds on inflammasome inhibition, macrophages were previously primed with lipopolysaccharide (LPS, E. coli serotype 026:B6, Sigma-Aldrich USA) 1 μg/ml in DMEM 10% FBS for 4 hours. After this time, the DMEM with LPS was removed and replaced with serum-free DMEM containing the different compounds at a concentration of 3 μM, they waited 15 minutes, and the cells were treated with 5 mM ATP (Sigma-Aldrich) for 30 minutes. . He retired supernatant from the stimulated cells and frozen at -20°C for subsequent determination. The measurement of IL-ip in the supernatant was carried out using the enzyme-linked immunosorbent assay (ELISA) technique following the supplier's (R&D) recommendations. In all assays there was a negative control that consisted of macrophages without treatment, as well as a positive control, macrophages treated with LPS+ATP without any inhibitory compound. In addition, the MCC950 molecule (Sigma-Aldrich) was included in the assays as a control for inhibiting IL-ip release.

The results obtained are shown in Table 1 , which indicates the percentage reduction in the release of IL-ip for each of the compounds in relation to Ilip in the supernatant of macrophages stimulated only with LPS (1 μg/ml ) ATP(5mM). These results indicate that, of the 14 compounds studied, 7 are capable of reducing the release of IL-ip induced by LPS+ATP in BMDMs (3b, 4b, 7b, 8b, 11b, 13b, 14b). Of these 7, statistically significant differences are observed with respect to the LPS+ATP control for compounds 4b and 7b, and for MCC950 used as an inhibition control in all assays. Compound 7b reduces the release of IL-ip by 67.20% ± 4i.09, while compound 4b does so by 92.09% ± 6.435, practically reaching the inhibition capacity of MCC950 (96.89% ± 11.10). This is why the study of compound 4b as a potential inhibitor of the NLRP3 inflammasome was carried out in depth.

Table 1 . Percentage reduction of IL-ip release from MCC950-derived compounds at the concentration of 3 μM. Statistical analysis using one-way ANOVA: *p<0.05;**p<0.01;***p<0.001.

2.2 NLRP3 inflammasome inhibition properties of compound 4b.

After pharmacological screening of MCC950 derivatives, compound 4b was selected as the lead compound of the family of derivatives by showing the greatest capacity to reduce IL-ip release.

Next, the ability to inhibit the NLRP3 inflammasome, responsible for the processing and release of the cytokine IL-ip (Nat Rev Immunology, 2019, 8:477-489), was studied for compound 4b in BMDMs previously primed with LPS and stimulated. with ATP or uric acid crystals (MSU).

0 The method to evaluate the inhibition of the NLRP3 inflammasome was as follows: BMDMs were subcultured in 6-well plates at the cell density of 1.2 x 106 cells per well, and, after being primed with LPS ( E. coli serotype 026:B6, Sigma-Aldrich USA) 1 μg/ml in DMEM 10% FBS for 4 hours, this medium was removed and DMEM without serum was added in the presence or absence of compound 4b at 1 μM for 15 minutes. Macrophages were then treated with 5mM ATP (Sigma-Aldrich) for 15 minutes (Fig. 1A) or 200 μg/ml MSU (invivogen) for 16 hours (Fig. 1D). After this time, the supernatant of the treated cells was collected and frozen at -20°C, and the cells on the plate were lysed in laemli buffer (Tris HCl pH 6.82M, SDS, p-mercaptoethanol, glycerol, bromophenol). Part of the supernatant was used for the determination of IL-ip by ELISA (R&D), and the rest was used for precipitation with trichloracetic acid for the detection by Western Blot of the cleaved IL-ip and caspase-1 fragments, signs activation of the NLRP3 inflammasome.

The procedure for precipitation of proteins present in the supernatant of stimulated macrophages was as follows: the supernatants were centrifuged at 1000 rpm for 5 minutes at 4°C, to eliminate any cellular debris that may be present. To the supernatant obtained from the centrifugation, 100% trichloracetic acid was added (500g of trichloracetic acid dissolved in 350 ml of H ₂ Odd) in a 1:2 ratio with respect to the volume of supernatant from which we started. The mixture was allowed to incubate at 4°C for two hours and centrifuged at 14 thousand rpm for 15 min at 4°C. The pellet obtained was washed with 200 μl of cold acetone and centrifuged again at 14 thousand rpm for 5 min at 4°C. The acetone washing step was repeated twice. Finally, the resulting pellet was dried at 95°C for 5 min on a thermoblock to evaporate the remaining acetone, and resuspended in 30 μl of 1x laemli buffer.

The proteins of the supernatant, as well as those of the cell lysate of the treated macrophages, were separated by electrophoresis in 10% (lysate proteins) or 15% (supernatant proteins) acrylamide gels. The proteins separated in the gel were transferred to a nitrocellulose membrane, which were blocked with TBS-T ( Tris-Buffer Saline and Tween-20) 4% fetal bovine serum albumin (BSA) (Sigma) for at least one hour to avoid nonspecific antibody binding. Membranes were then hybridized overnight with anti-ILip (1:1000; Abcam) and anti-caspase 1 (1:1000 Santa Cruz Biotechnology) primary antibodies. Subsequently, three washes were done with 1X TBS-T and hybridized for one hour with the corresponding secondary antibodies, anti-goat/rabbit (1:10,000; Santa Cruz Biotechnology) and with anti-actinap (1:50,000; Sigma, USA). These, after two washes with 1X TBS-T and a final wash with 1X TBS ( Tris-Buffer Saline; 0.4 M Tris HCl, 0.097 M Tris Base, 1.5 M NaCl) were revealed by chemiluminescence with the ECL detection reagent (GE HEalthcare LifeScience, Spain).

The results obtained ( Figure 1 ) indicate that compound 4b is capable of reducing the release of IL-1p in BMDMs induced by both LPS+ATP (Fig. 1B) and LPS+MSU (Fig. 1E) to practically zero. This reduction in the release of IL-1p is due to the NLRP3 inhibition property of the compound, since in the presence of 4b (1 μM) the cleavage of the IL-ip and caspase-1 proteins does not occur, which does occur. when macrophages are treated with LPS+ATP (Fig. 1C) or LPS+MSU (Fig. 1F) without compound, thus preventing the complete activation of the NLRP3 inflammasome and therefore the release of IL-ip.

Figure 1. Inhibitory effect of compound 4b on the NLRP3 inflammasome. Elisa of IL-1p in the supernatant of BMDMs previously primed with 1μg/ml LPS for 4 hours and treated with 1μM 4b 15 minutes prior to being stimulated with 5mM ATP 30 minutes (B) or MSU 200 μg/ml 16 hours (E ). Representative Western blots of pro-IL-1 p, caspase-1 p45 and p-actin in the lysate and IL-1p p17 and caspase-1 p10 in the supernatant of BMDMs previously primed with LPS treated with ATP (C) or MSU ( F) in the presence of 1μM 4b. Data corresponding to the mean ± standard error of 5 (B) and 6 (E) independent experiments. Statistical analysis using one-way ANOVA and Dunnet's multiple comparisons test: ***p<0.001, ****p<0.0001

2.3 Anti-inflammatory properties of compound 4b in an in vivo mouse gout model.

Given the potent effect of compound 4b observed on the reduction of IL-1p in macrophages stimulated with both LPS+ATP and LPS+MSU, it was decided to study the effect of this compound in an in vivo inflammatory model. A murine model of gout was used, due to the direct relationship of the NLRP3 inflammasome in the development and progression of this disease (Lancet, 2016, 388(10055):2039-2052) .

The mouse gout model was carried out in adult (3-6 months) wild strain mice (C57/BL6), which were injected with uric acid crystals intraplantarly, following a previously described procedure ( Arthritis Reseacrh and Therapy, 2018, 20:144). To prepare the crystals, 1 g of uric acid (Sigma-Aldrich) was dissolved in 190 ml of distilled water and 6 ml of 1M NaOH brought to the boil while stirring. The pH of the solution was adjusted with HCl to 7.4. The solution was poured onto a glass plate and allowed to dry for 24 hours at room temperature. After this time, they leaked the crystals obtained using filter paper and were allowed to dry on the paper in an oven at 56°C until they were completely dry. The resulting crystals were stored dry at -20°C.

For the gout model, mice were sedated with isoflurane and uric acid crystals were injected into the right paw pad (1 mg in 50 μl of sterile 1x PBS). In mice treated with 4b, it was dissolved in saline (0.9% NaCl in H ₂ Odd) and inoculated by intraperitoneal injection at doses of 3 mg/kg or 10 mg/kg just after the intraplantar injection of the 4b crystals. MSU. The rest were injected with vehicle (0.9% NaCl in H ₂ Odd) intraperitoneally. After 24 hours they were sacrificed and the perimeter of the right and left paws was measured with an electronic caliper. The level of inflammation of the punctured paw compared to the control paw was represented by the inflammation index in the paw.

In addition to this inflammatory parameter, the effect of uric acid crystals on the mechanical allodynia of mice was studied using the Von Frey test (Frontiers in Molecular Neuroscience, 2017, 10:284). The Von Frey test is used to measure mechanical allodynia. There are different methods of carrying out the test, in this case the "ascending stimulus" method was carried out. This method consists of the application of monofilaments of increasing force (0.02-15 mN) until reaching the withdrawal threshold. The test was carried out on two days, before the intraplantar injection of the vehicle or intraperitoneal 4b crystals (time 0) and at 24 hours (time 1). At time 0 the animals were placed individually in the Von Frey boxes positioned on a grid, to access to the paw pad. Each of the filaments was applied perpendicularly to the paw pad until bending, thus generating a constant force. Each filament was applied a total of 5 times, and the response of the animal, a positive response being considered a behavior associated with pain (sudden withdrawal of the paw or licking it), and a negative response an absence of such behavior. The force exerted by the filament that provoked three positive responses was considered the threshold of withdrawal for said animal. After the test, the animal was returned to its cage, and 24 hours after the injection of the crystals the test was repeated in order to compare the withdrawal thresholds pre- and post-injection of intraplantar MSU vehicle 4b intraperitoneal.

The results obtained are shown in Figure 2.

Figure 2. Anti-inflammatory effect of compound 4b in an in vivo mouse model of gout. Fig.2.B. Representative images of the paws of mice treated with MSU vehicle (I) or with MSU+4b 3 (II) or 10 (III) mg/kg. 24 hours post injection Fig. 2.C. Inflammation index in the paw, represented as [(left paw diameter/right paw diameter) -1] x 100, of the animals 24 hours post-injection of MSU, vehicle or 4b at 3 or at 10 mg/kg. Statistical analysis using one-way ANOVA ****p<0.0001. Fig. 2. D. Paw withdrawal threshold measured by the Von Frey test of the animals 24 hours after MSU injection, without treatment or with intra-peritoneal treatment from 4b to 3 or 10 mg/kg. Statistical analysis using two-way ANOVA of repeated measures and Tukey test of multiple comparisons: *p<0.05;**p<0.01;****p<0.0001.

Compound 4b exerts an anti-inflammatory effect on mice treated with intraplantar injection of uric acid crystals, as can be seen in the images in Figure 2B. This effect translates into a reduction of almost 50% in the paw inflammation index with the treatment of 4b at 3 mg/kg, and of more than 50% at 10 mg/kg, the differences being statistically significant. this index for the 3 and 10 mg/kg groups compared to the vehicle group (Fig. 2C).

Furthermore, compound 4b is able to reduce the mechanical allodynia caused by the injection of uric acid crystals (Fig. 2C). While in mice treated with vehicle this parameter drops in the 24 hours post-injection to 30%, this value recovers to 52% in animals treated with 4b 3 mg/hg and up to 81% in those treated with 4b at 10 mg/kg, with the differences in this parameter being statistically significant in both groups compared to the vehicle group.

Claims (12)

1. Compounds of general formula (I):

Where R is a differently substituted benzene ring or a 9H-fluorene ring according to:

2. Compounds of general formula (I) according to claim 1, where R is a benzene ring differently substituted by R1 and/or R2 according to general formula (II):

3. Compounds of general formula (II) according to claim 2, where: R1 and R2 are the same or different and are independently selected from an alkyl group (methyl, ethyl, or larger hydrocarbon chains or fluorocarbons, or bidentate substituents, that is i.e., doubly bonded to the benzene ring), alkoxide (methoxide, ethoxide, or larger chains, or bidentate substituents of the type -O-alkylene-O-), amino and aminoalkyl, halogens, nitro=-alkyl groups, ) or, in Generally, any substituent located in any position. 4. Compounds according to claim 3, where R1 and/or R2 can be hydrogen, methyl, methoxide, dimethylamino, nitro, chloro, trifluoromethyl. 5. Compound according to claim 3, where R1 and R2 are in adjacent positions and joined, forming a fused cycle (-R1-R 2-), according to the general formula (III).

6. Compound according to any of claims 1 to 5, selected from the list comprising: 3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(2-methylphenyl)urea 3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(3-methylphenyl)urea 3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(-4-methylphenyl)urea 1-(3,5-dimethylphenyl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(2-methoxyphenyl)urea 3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(4-methoxyphenyl)urea 1-(3,5-dimethoxyphenyl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 3-(2H-1,3-benzodioxol-5-yl)-1-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 1-(4-dimethylaminophenyl)-3- ([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)-1-(-4-nitrophenyl)urea 1-(4-chloro-2-(trifluoromethyl)phenyl-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 3-(2,3-dihydro-1H-inden -5-yl)-1-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 3-(9H-fluoren-3-yl)-1-([4-(2 -hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 1-(9H-fluoren-9-yl)-3-([4-(2-hydroxypropan-2-yl)furan-2-yl]sulfonyl)urea 7. Procedure for obtaining the compounds of formula (I) according to any of claims 1 to 5, which comprises the following steps: (a) Obtaining 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide by the reaction of ethyl furan-3-carboxylate with chlorosulfonic acid, to give the acid 4-(ethoxycarbonyl)furan- 2-sulfonic, which by treatment with phosphorus pentachloride, in the presence of pyridine, led to ethyl (chlorosulfonyl)furan-3-carboxylate, whose reaction with ammonium bicarbonate, in an acetone-water mixture, generated the 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide which, in turn, and by reaction with excess methylmagnesium chloride, in THF, gave rise to 4-(1-hydroxy-1-methyl-ethyl) -furan-2-sulfonamide. (b) reaction of 4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulfonamide with the isocyanates 1a-14a to obtain the compounds of formula (I). 8. Use of the compound according to any of claims 1 to 6, for the preparation of a medicine. 9. Use of the compound according to any of claims 1 to 6, for the preparation of a medicine for the treatment of inflammatory diseases. 10. Use of the compound according to the preceding claim, wherein the inflammatory diseases are selected from the list comprising chronic inflammation pathologies such as gout, rheumatoid arthritis or Crohn's disease; diseases of the central nervous system such as Alzheimer's, Parkinson's, stroke or traumatic brain injury; cardiovascular disorders, including atherosclerosis and myocardial infarction; metabolic pathologies such as diabetes; or autoimmune in nature, such as contact dermatitis and psoriasis; or pathology produced by alteration of biological functions where the NLRP3 inflammasome is involved. 11. Pharmaceutical composition comprising at least one compound of general formula (I) together with one or more pharmaceutically acceptable excipients. 12. Pharmaceutical composition according to the preceding claim, further comprising one or more active therapeutic agents.