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Definitions

• the present invention relates to 1-benzyl-3-hydroxymethylindazole derivatives, to a pharmaceutical composition comprising them, and to their use in the treatment of diseases based on the expression of MCP-1 , CX3CR1 and p40.
• the present invention relates to novel 1-benzyl-3-hydroxym- ethylindazole derivatives according to formula (I) below, and to a pharmaceutical composition comprising them together with a pharmaceutically acceptable vehicle.
• the present invention relates to the use of 1 - benzyl-3-hydroxymethylindazole derivatives for preparing a pharmaceutical composition that is active in the treatment of diseases based on the expression of MCP-1 , CX3CR1 and p40, and to their use in a method for treating or preventing diseases based on the expression of MCP-1 , CX3CR1 and p40.
• MCP-1 Monocyte Chemotactic Protein-1
• MCP-1 Monocyte Chemotactic Protein-1
• T lymphocytes T lymphocytes
• mastocytes T lymphocytes
• basophils Rollins BJ. , Chemokines, Blood 1997; 90: 909-928; M.
• chemokines belonging to the ⁇ subfamily are, for example, MCP-2 (Monocyte Chemotactic Protein-2), MCP-3, MCP-4, MIP-1 ⁇ and MIP-1 ⁇ , RANTES.
• the ⁇ subfamily differs from the ⁇ subfamily in that, in the structure, the first two cysteines are adjacent for the ⁇ subfamily, whereas they are separated by an intervening amino acid for the ⁇ subfamily.
• MCP-1 is produced by various types of cells (leukocytes, platelets, fibroblasts, endothelial cells and smooth muscle cells).
• MCP-1 shows the highest specificity for monocytes and macrophages, for which it constitutes not only a chemotactic factor but also an activation stimulus, consequently inducing processes for producing numerous inflammatory factors (superoxides, arachidonic acid and derivatives, cytokines/chemokines) and amplifying the phagocytic activity.
• Monocytes are the main precursors of macrophages and dendritic cells, and play a critical role as mediators of inflammatory processes.
• CX3CR1 with its ligand CX3CL1 (fractalkine), represents a key factor in regulating the migration and adhesiveness of monocytes.
• CX3CR1 is expressed in monocytes, whereas CX3CL1 is a transmembrane chemokine in endothelial cells.
• Genetic studies in man and in animal models have demonstrated an important role in the physiopathology of inflammatory diseases of CX3CR1 and CX3CL1.
• CX3CR1 fractalkine receptor
• CX3CR1 is indicated as a critical factor in the process of infiltration and accumulation of monocytes in the vascular wall, and CX3CR1 polymorphism in man is associated with a reduced prevalence of atherosclerosis, coronary disorders and restenosis (Liu P. et al., "Cross-talk among Smad, MAPK and integrin signalling pathways enhances adventitial fibroblast functions activated by transforming growth factor-1 and inhibited by Gax" Arterioscler. Thromb. Vase. Biol. 2008; McDermott D. H.
• IL-12 and IL-23 are members of a small family of proinflammatory heterodimeric cytokines. Both cytokines share a common subunit, p40, which is covalently bonded either to the p35 subunit to produce the mature form of IL-12, or to the p19 subunit to produce the mature form of IL-23.
• the receptor for IL-12 is constituted by the subunits IL-12R ⁇ 1 and IL-12R ⁇ 2, while the receptor for IL-23 is constituted by the subunits IL-12R ⁇ 1 and IL-23R.
• IL-12 and IL-23 are mainly expressed by activated dendritic cells and by phagocytes. The receptors for the two cytokines are expressed on the T and NK cells, and NK T cells, but low levels of complexes of the receptor for IL-23 are also present in monocytes, macrophages and dendritic cells.
• Psoriasis is a chronic inflammatory skin disease that affects 3% of the world's population (Koo J. Dermatol. Clin. 1996; 14:485-96; Schon M. P. et al., N. Engl. J. Med. 2005; 352: 1899-912).
• a type-1 aberrant immune response has been correlated with the pathogenesis of psoriasis, and the cytokines that induce this response, such as IL-12 and IL-23, may represent suitable therapeutic objects.
• Crohn's disease is a pathology associated with a Th1 cell-mediated excessive activity of cytokines.
• IL-12 is a key cytokine in the initiation of the inflammatory response mediated by Th1 cells.
• Crohn's disease is characterized by increased production of IL-12 by cells presenting the antigen in intestinal tissue, and of gamma-interferon (IFN- ⁇ ) and TNF ⁇ by lymphocytes and intestinal macrophages. These cytokines induce and support the inflammatory process and thickening of the intestinal wall, which are characteristic signs of the pathology.
• IFN- ⁇ gamma-interferon
• TNF ⁇ gamma-interferon
• Preclinical and clinical evidence has demonstrated that inhibition of IL-12 is effective in controlling the inflammatory response in models of intestinal inflammation and/or in patients suffering from Crohn's disease.
• IL-23 has been identified as a cytokine associated with cancer and, in particular, the expression of IL-23 is significantly high in samples of human carcinomas when compared with normal adjacent tissues. In addition, the absence of a significant expression of IL-23 in the normal adjacent tissues suggests an over-regulation of IL-23 in tumours, reinforcing its role in tumour genesis.
• European patent EP-B-O 382 276 describes a number of 1-benzyl-3- hydroxymethylindazole derivatives endowed with analgesic activity.
• European patent EP-B-O 510 748 describes, on the other hand, the use of these derivatives for preparing a pharmaceutical composition that is active in the treatment of autoimmune diseases.
• European patent EP-B-1 005 332 describes the use of these derivatives for preparing a pharmaceutical composition that is active in treating diseases derived from the production of MCP-1.
• European patent application EP-A-1 458 687 relates to the use of pyrimidine derivatives for treating diseases related to an overproduction of IL-12.
• European patent application EP-A-1 819 341 relates to the use of nitrogenous heterocyclic compounds, for instance pyridine, pyrimidine and triazine derivatives, for inhibiting the production of IL-12 (or of other cytokines, such as IL-23 and IL- 27 which stimulate the production of IL-12).
• European patent application EP-A- 1 827 447 relates to the use of pyrimidine derivatives for treating diseases related to an overproduction of IL-12, IL-23 and IL-27.
• R 9 and Ri 0 which may be identical or different each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms or an alkoxy group having from 1 to 3 carbon atoms,
• R 11 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, or R 11 together with R 12 forms a 4- to 7-membered heterocycle,
• R 12 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, COR', COOR', C0N(R')(R") with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms, or R 12 together with R 11 , forms a 4- to 7-membered heterocycle,
• R 13 and R 15 which may be identical or different, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms or an alkoxy group having from 1 to 3 carbon atoms,
• R 14 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, COR', COOR', C0N(R')(R") with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms,
• X 2 may be an alkyl group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms
• X 3 may be OH, NH 2 , NHOH or NHNH 2 ,
• the present invention relates to the use of a compound of formula (I)
• R 11 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, or R 11 together with R 12 forms a 4- to 7-membered heterocycle,
• R 12 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, COR', COOR', CON(R')(R") with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms, or R 12 together with R 11 , forms a 4- to 7-membered heterocycle, R 13 and R 15 , which may be identical or different each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms or an alkoxy group having from 1 to 3 carbon atoms,
• X 2 may be an alkyl group having from 1 to 5 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 5 carbon atoms or one or more alkoxy groups having from 1 to 3 carbon atoms,
• R 1 and R 2 which may be identical or different each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms or an alkoxy group having from 1 to 3 carbon atoms
• R 3 , R 4 and R 3 which may be identical or different each other, may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, -OH, -N(R')(R"), -N(R')C0R", -CN, -CONR'R", -SO 2 NR 1 R", -SO 2 R', nitro and trifluoromethyl; with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms,
• R 5 may be hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom, -OH, - N(R')(R"), -N(R')C0R", nitro and trifluoromethyl, or R 5 together with one from among R 6 and R 7 forms a ring having 5 or 6 carbon atoms; with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 5 carbon atoms, and
• residue A is represented by the group Xi Or X 1 -OC(R 9 )(Ri 0 ), where Xi is an alkyl group having from 1 to 3 carbon atoms, optionally substituted with one or more alkyl groups having from
• residue A is represented by the group Xi or X 1 - OC(R 9 )(R 10 ), where X 1 is the group CH 2 , the group CH 2 CH 2 or the group C(CH 3 ) 2 , and R 9 and R 10 , which may be identical or different each other, are hydrogen or a CH 3 group.
• residue A is chosen from the group comprising a group CH 2 , a group CH 2 CH 2 , a group C(CH 3 ) 2 , a group CH 2 CH 2 OCH 2 , a group CH 2 CH 2 OC(CHs) 2 and a group CH 2 CH 2 CH 2 OC(CHa) 2 .
• residue Y is represented by the group N(R 11 )(R 12 ), N(R 13 )N(R 14 )(R 15 ), N(R 13 )-X 2 -N(R 14 )(R 15 ) or N(R 13 )-X 2 -CO-X 3 .
• R 11 is represented by a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, or R 11 together with R 12 forms a 5- or 6- membered heterocycle.
• Ri 2 is represented by a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, CON(R')(R") with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 3 carbon atoms, or R 12 together with R 11 forms a 5- or 6-membered heterocycle.
• R 12 is represented by a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a heteroaryl group, CON(R')(R") with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 3 carbon atoms, or R 12 together with R 11 forms a 5- or 6-membered heterocycle.
• R- 1 3 and R 15 which may be identical or different each other, are represented by a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or an alkoxy group having 1 or 2 carbon atoms.
• R 13 and R 15 which may be identical or different each other, are represented by a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, or an alkoxy group having 1 or 2 carbon atoms.
• R 14 is represented by a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, an aryl group, a heteroaryl group, an alkylaryl group, an alkylheteroaryl group, COR', COOR', CON(R')(R") with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 3 carbon atoms.
• R 14 is represented by a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an aryl group or CON(R')(R") with R' and R", which may be identical or different each other, represented by hydrogen and an alkyl group having from 1 to 3 carbon atoms.
• X 2 is represented by an alkyl group having from 1 to 3 carbon atoms, optionally substituted with one or more alkyl groups having from 1 to 3 carbon atoms or one or more alkoxy groups having 1 or 2 carbon atoms.
• X 3 is represented by the groups OH, NH 2 , NHOH or NHNH 2 .
• R 5 is represented by a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a halogen atom, an OH group, or R 5 , together with one from among R 6 and R 7 , forms a ring having 5 or 6 carbon atoms.
• the compound of formula (I) according to the present invention may be an asymmetric carbon atom and may then be in the form of stereoisomers and enantiomers.
• Suitable physiologically acceptable organic acids are acetic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-toluenesulfonic acid, benzenesulfonic acid, succinic acid, tannic acid and tartaric acid.
• Suitable physiologically acceptable mineral bases are hydroxides, carbonates and hydrogen carbonates of ammonium, calcium, magnesium, sodium and potassium, for instance ammonium hydroxide, calcium hydroxide, magnesium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
• pharmaceutically acceptable and “physiologically acceptable” are intended to define, without any particular limitation, any material suitable for preparing a pharmaceutical composition to be administered to a living being.
• the compounds according to formula (I) of the present invention may be used for the preparation of a pharmaceutical composition that is active in the treatment of diseases (or pathologies) based on the expression of the chemokine MCP-1 , the cytokine p40, the subunit p40 (involved in the production of cytokines IL-12 and IL-23) and the receptor CX3CR1.
• the pathologies associated with the expression of MCP-1 and CX3CR1 are articular diseases, renal diseases, cardiovascular diseases, metabolic syndrome, obesity, diabetes, insulin resistance and cancer.
• the pathologies associated with the expression of MCP-1 are rheumatoid arthritis, arthritis induced by viral infections, psoriatic arthritis, arthrosis, lupus nephritis, diabetic nephropathy, glomerulonephritis, polycystic kidney disease, interstitial lung disease, fibrosis, multiple sclerosis, Alzheimer's disease, HIV-associated dementia, atopic dermatitis, psoriasis, vasculitis, restenosis, atherosclerosis, myocardial infarction, angina, acute coronary diseases, adenomas, carcinomas and metastases, metabolic diseases and complications following surgical interventions such as, for example, angioplasty, arterectomy, circulation recovery techniques, transplants, organ replacements, tissue replacements and prosthesis implants.
• CX3CR1 pathologies associated with the expression of CX3CR1 are rheumatoid arthritis, lupus nephritis, diabetic nephropathy, Crohn's disease, ulcerative colitis, coronary disorders, restenosis, atherosclerosis, myocardial infarction, angina, and complications following surgical interventions such as, for example, angioplasty, arterectomy and circulation recovery techniques.
• suitable dosage forms are tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; medicated plasters, solutions, pastes, creams and ointments for transdermal administration; suppositories for rectal administration and sterile solutions for injection or aerosol administration.
• the dosage forms may also contain other conventional ingredients such as: preserving agents, stabilizers, surfactants, buffers, osmotic pressure regulators, emulsifiers, sweeteners, colorants, flavourings and the like.
• the pharmaceutical composition of the present invention may contain other pharmacologically active ingredients whose simultaneous administration is useful.
• the amount of compound of formula (I) or of pharmaceutically acceptable salt, ester or prodrug thereof in the pharmaceutical composition of the present invention may vary within a wide range as a function of known factors, for instance the type of pathology to be treated, the severity of the disease, the body weight of the patient, the dosage form, the chosen route of administration, the number of daily administrations and the efficacy of the chosen compound of formula (I). However, the optimum amount may be determined simply and routinely by a person skilled in the art.
• the amount of compound of formula (I) or of pharmaceutically acceptable salt, ester or prodrug thereof in the pharmaceutical composition of the present invention will be such that it ensures a level of administration of between 0.001 and 100 mg/kg/day.
• the level of administration is between 0.05 and 50 mg/kg/day and even more preferably between 0.1 and 10 mg/kg/day.
• the dosage forms of the pharmaceutical composition of the present invention may be prepared according to techniques that are well known to pharmaceutical chemists, including mixing, granulation, compression, dissolution, sterilization and the like.
• the activity of the compounds of the present invention on MCP-1 and CX3CR1 was demonstrated in vitro in human monocytes via techniques of gene expression analysis with "real-time" RT-PCR and by protein production analysis via an immunoenzymatic test.
• the abovementioned experimental models are considered useful for checking the activity of the compounds with regard to the expression and production of MCP-1 and the expression of CX3CR1. Consequently, the abovementioned models may be considered as predictive of the activity in man for the treatment of pathologies characterized by the expression and production of MCP-1 , by the expression of CX3CR1 and by inflammatory conditions with the presence of infiltrates rich in monocytes and macrophages.
• the preparation of the compounds of general formula (I) may be performed according to one of the following procedures.
• Method A is performed according to conventional techniques.
• the alcohols of formula (III) are reacted, respectively, with the derivatives of formula (IV) in which Q is a leaving group preferably chosen from the group comprising a chlorine atom, a bromine atom and a methanesulfonyl group.
• the reaction is performed in the presence of a suitable base and in a suitable solvent.
• the bases that may preferably be used are NaH, butyllithium and lithium diisopropylamide, whereas the solvents that are suitable for this type of reaction are preferably polar aprotic solvents such as tetrahydrofuran, diethyl ether or 1 ,4-dioxane.
• the reaction temperature is preferably between room temperature and the reflux temperature of the solvent used. Reactions of this type may last from a few hours to a few days.
• Method B is performed according to conventional techniques.
• the alcohols of formula (Vl) are reacted, respectively, with the derivatives of formula (V) in which Q is a leaving group preferably chosen from the group comprising a chlorine atom, a bromine atom and a methanesulfonyl group.
• the reaction is performed in the presence of a suitable base and in a suitable solvent.
• the bases that may preferably be used are NaH, butyllithium and lithium diisopropylamide, whereas the solvents that are suitable for this type of reaction are preferably polar aprotic solvents such as tetrahydrofuran, diethyl ether or 1 ,4-dioxane.
• the reaction temperature is preferably between room temperature and the reflux temperature of the solvent used. Reactions of this type may last from a few hours to a few days.
• the aqueous phase was acidified with 2N HCI and the product was extracted with diethyl ether (3x100 ml). The organic phase was then concentrated under reduced pressure and the resulting crude residue was purified by double crystallization from a 1/1 hexane/ethyl acetate mixture.
• the combined organic phases were then extracted with 2N HCI (4x200 ml).
• the acidic phase was then brought to basic pH with 10N NaOH and again extracted with diethyl ether (4x200 ml).
• the combined organic phases were concentrated under reduced pressure and the crude residue was purified by crystallization from a 1/1 hexane/ethyl acetate mixture.
• the acidic phase was then brought to basic pH with 1 ON NaOH and extracted with diethyl ether (3x150 ml).
• the combined organic phases were concentrated under reduced pressure.
• the residue obtained was purified by crystallization from a 1/3 hexane/ethyl acetate mixture.
• the product obtained was suspended in water (100 ml) and NaOH (1.28 g, 0.032 mol) was added thereto. The mixture was stirred at 50 0 C for 16 hours, and then cooled and acidified with concentrated HCI. The solid thus obtained was purified by crystallization from ethanol.
• the product was prepared via the procedures described in the preparation of compound 9, using 2-[(1-benzyl-5-methoxy-1 H-indazol-3-yl)methoxy]-2- methylpropanoic acid as starting reagent.
• the product was obtained via the method described in Example 30a), using 3,4-chlorobenzyl chloride as reagent.
• the product obtained was purified by crystallization from a 1/1 hexane/ethyl acetate mixture.
• m.p. 1 18°-120°C 1H-NMR (CDCI 3 , ⁇ ppm): 3.1-3.3 (m, 1 H), 4.9-5.2 (m, 2 H), 5.38 (s, 2 H),
• LPS lipopolysaccharide
• the amplification was obtained in 96-well plates using the ABI Prism 7000 sequence detection system (Applied Biosystems), by applying the following temperature profile: 50 0 C for 2 minutes, 95°C for 10 minutes and 45 cycles at 95°C for 15 seconds and 60 0 C for 1 minute.
• a set of primers and probe specific for human MCP-1 was used (Applied Biosystems, RefSeq NM_002982.3).
• a set of primers and probe for ⁇ - actin was used in separate wells as an internal control of the samples for the purposes of normalization. Once the reaction had taken place, the fluorescence data were analysed using the ABI Prism 7000 SDS software, by calculating the threshold cycle (Ct) for each sample and subsequently performing a relative quantification via the ⁇ Ct method.
• Ct threshold cycle
• the compounds were capable of significantly inhibiting the LPS-induced expression of MCP-1 in a human monocyte line, and showed a reduction in the levels of specific mRNA between 20% and 99%.
• LPS lipopolysaccharide
• the amplification was obtained in 96-well plates using the ABI Prism 7000 sequence detection system (Applied Biosystems), by applying the following temperature profile: 50 0 C for 2 minutes, 95°C for 10 minutes and 45 cycles at 95°C for 15 seconds and 60 0 C for 1 minute.
• a set of primers and probe specific for human CX3CR1 was used (Applied Biosystems, RefSeq NM_001337.3).
• the compounds were capable of significantly inhibiting the LPS-induced expression of CX3CR1 in a human monocyte line, and showed a reduction in the levels of specific mRNA between 44% and 100%.
• LPS lipopolysaccharide
• the amplification was obtained in 96-well plates using the ABI Prism 7000 sequence detection system (Applied Biosystems), by applying the following temperature profile: 50 0 C for 2 minutes, 95°C for 10 minutes and 45 cycles at 95°C for 15 seconds and 60 0 C for 1 minute.
• a set of primers and probe specific for human p40 was used (Applied Biosystems, RefSeq NM_002187.2).
• a set of primers and probe for ⁇ - actin was used in separate wells as an internal control of the samples for the purposes of normalization. Once the reaction had taken place, the fluorescence data were analysed using the ABI Prism 7000 SDS software, by calculating the threshold cycle (Ct) for each sample and subsequently performing a relative quantification via the ⁇ Ct method.
• Ct threshold cycle
• the compounds were capable of significantly inhibiting the LPS-induced expression of p40 in a human monocyte line, and showed a reduction in the levels of specific mRNA between 33% and 96%.

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