US20060247297A1 - Chiral arylketones in the treatment of neutrophil-dependent inflammatory diseases - Google Patents

Chiral arylketones in the treatment of neutrophil-dependent inflammatory diseases Download PDF

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US20060247297A1
US20060247297A1 US10/537,824 US53782403A US2006247297A1 US 20060247297 A1 US20060247297 A1 US 20060247297A1 US 53782403 A US53782403 A US 53782403A US 2006247297 A1 US2006247297 A1 US 2006247297A1
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phenyl
methyl
oxo
isobutylphenyl
benzoyl
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Marcello Allegretti
Riccardo Bertini
Cinzia Bizzarri
Maria Cesta
Francesco Colotta
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07F9/4056—Esters of arylalkanephosphonic acids
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Definitions

  • the present invention relates to chiral arylketones, a process for their preparation, and pharmaceutical compositions containing them, which are useful in the prevention and treatment of tissue damage due to the exacerbated recruitment of polymorphonucleate neutrophils in the inflammatory sites.
  • R-2-arylpropionic acid amides and N-acylsulfonamides useful in the prevention and treatment of tissue damage due to the exacerbated recruitment of polymorphonucleate neutrophils in the inflammatory sites, have been described in WO 01/58852 and WO 00/24710 respectively.
  • the compounds of the invention are generally known compounds and disclosed in Belstein Handbook of Organic Chemistry.
  • the present invention relates to chiral arylketones of general formula I: wherein:
  • a ⁇ -ketoester of formula Ia and Ic may optionally be dealkoxydecarboxylated to the corresponding arylketone of formula I by simply heating in an aprotic solvent (preferably dimethylsulfoxide) in the presence of small amounts of water and, optionally, of small amounts of electrolytes, such as NaCl, NaCN, LiCl, LiI (according to J. P. Krapcho, Synthesis 805 and 893, 1982, and references cited herein).
  • an aprotic solvent preferably dimethylsulfoxide
  • electrolytes such as NaCl, NaCN, LiCl, LiI (according to J. P. Krapcho, Synthesis 805 and 893, 1982, and references cited herein).
  • a compound of formula Ia can be converted into another compound of formula I by removal of any protective groups that may be present, or by saponification of carboxyl groups, or by conversion of nitriles into carboxyamides.
  • the compounds of formula IV are obtained in a conventional way, conserving their enantiomeric integrity, starting from the individual enantiomers of the 2-aryl-propionic acids of formula IVa: which are known compounds and can be obtained from the individual racemates using known methods of optical resolution.
  • the preparation of the carbanions of formula V consists in a process of C-acylation in virtually neutral conditions, fully described in the literature (see, for example, D. W. Brooks et al., Angew. Chem. Int. Ed. Engl., 18, 72, 1979), as well as monoesters of malonic acids and of monosubstituted malonic acids, also on sulfinylacetic acids, sulfonylacetic acids and phosphonoacetic acids. All these acids are known in the literature or can be prepared using known methods, such as monosaponification of diesters of which are known compounds and can be obtained from the individual racemates using known methods of optical resolution.
  • the preparation of the carbanions of formula V consists in a process of C-acylation in virtually neutral conditions, fully described in the literature (see, for example, D. W. Brooks et al., Angew. Chem. Int. Ed. Engl., 18, 72, 1979), as well as monoesters of malonic acids and of monosubstituted malonic acids, also on sulfinylacetic acids, sulfonylacetic acids and phosphonoacetic acids.
  • sulfinylacetic and sulfonylacetic acids may be obtained by oxidation of ethers of thioglycolic acid.
  • lithium enolates of formula V obtained by reaction of lithium alkyls with known alkyl esters of alkylphosphonates (see, for example, N. Mongelli et al., Synthesis, 310, 1988) or with esters of acetic acid (according to D. H. Harris et al., Tetrah. Lett., 28, 2837, 1987).
  • the compounds of formula I are powerful inhibitors of the chemiotaxis of the neutrophils induced by IL-8 and inhibit the amplification of the production of TNF- ⁇ stimulated by lipopolysaccharides and by hydrogen peroxide.
  • An exacerbated production of hydrogen peroxide is notoriously the final consequence of the neutrophilic activation consequent upon a chemiotactic stimulus.
  • Examples of ⁇ -ketoesters of formula I are methyl R( ⁇ )-4-[(4′-isobutyl)phenyl]-3-oxopentanoate and methyl R( ⁇ )-4-[(3′-benzoyl)phenyl]-3-oxopentanoate, which, at the concentration of 10 ⁇ 8 M, inhibit the chemiotaxis of human neutrophils to an extent higher than 50% as compared to control values.
  • 2-aryl-alkan-3-one is R( ⁇ )-3-[(4′-isobutyl)phenyl]butan-2-one for which an IC 50 of 5.10 ⁇ 10 M has been calculated in the same in vitro inhibition assay.
  • polymorphonucleated blood cells were used obtained from heparinized blood of healthy adult volunteers by means of sedimentation on dextran.
  • the mononucleated cells were removed by means of Ficoll/Hypaque, whilst the red blood cells were eliminated by treatment with hypotonic solutions.
  • the cell vitality of the polymorphonucleated leucocytes (PMNs) was calculated by means of exclusion with Turk and Trypan Blue whilst after staining with Diff Quinck the percentage of the PM-nucleates on the cytocentrifugate was estimated (for details of the experimental techniques used see W. J. Ming et al., J. Immunol., 138, 1469, 1987).
  • human recombinant IL-8 (Pepro Tech.) was used as stimulant: the liophilized protein was dissolved in HBSS (Hank's balanced salts solution) at a concentration of 100 ng/mL and was used after dilution in HBSS down to concentrations of 10 ng/mL in the chemiotaxis experiments and at the concentration of 25-50 ng/mL in the evaluation of the modifications of [Ca 2+ ].
  • PVP filters were used having a porosity of 5 ⁇ m and a Plexiglas microchamber suitable for making 48 replications.
  • the microchamber consists of a block of Plexiglas containing 48 wells, each having a capacity of 25 ⁇ L and is provided with a lid, which in turn contains 48 pores arranged in such a way that, once the lid has been set in place and screwed to the underlying part, it comes to form the top compartments of the microchamber, each having a capacity of 50 ⁇ L.
  • the compounds under study were added at one and the same concentration in the wells of higher level, which contain the suspension of PMNs and in the wells of lower level, which contain the vehicle to which IL-8 (or a different stimulant) has been added or not.
  • the compounds of the invention prevent the increase in the intracellular concentration of Ca 2+ induced by IL-8.
  • the compounds of the invention are characterized by their capacity for inhibiting in vitro the chemiotaxis of the human PMN leucocytes (PMNs) stimulated by interleukin 8, also known as “monocyte-derived neutrophil-activating protein” (NAP/IL-8 or more simply IL-8). Said inhibition is dose-dependent, with values of IC 50 (dose inhibiting 50% of the effect) in the 10 ⁇ 7 to 10 ⁇ 9 -M range; the inhibiting effect is selective and specific in regard to the chemiotactic stimulus induced by IL-8.
  • Concentrations higher by one or two orders of magnitude are needed to inhibit the chemiotaxis stimulated in vitro by other chemiotactic factors (C5a, formylpeptides of bacterial origin or synthetic origin, such as f-LMP).
  • C5a formylpeptides of bacterial origin or synthetic origin, such as f-LMP.
  • the specificity of the compounds of the invention is moreover demonstrated by their capacity to inhibit the increase in the intracellular concentration [Ca 2+ ] i in human PMNs, an increase that is associated to the activation of the human PMNs themselves by IL-8 [J. H. Liu et al., J. Infect. Dis., 166, 1089 (1992)].
  • the compounds of the invention are without significant effects on cyclooxygenasis and on the production of PG.
  • the compounds of the invention (evaluated in the range of concentration of 10 ⁇ 5 to 10 ⁇ 7 M) show an inhibition of the production of PGE 2 which, albeit frequently at the limit of statistical significance, is never higher than 10 to 15% of the basal value.
  • the above minor inhibition of the synthesis of PGE 2 involves the advantage, unlike what occurs for certain 2-aryl-propionic acids, of not constituting a stimulus that is likely to amplify the synthesis of TNF- ⁇ by the murine macrophages themselves (once they have been stimulated by LPS).
  • the amplification of the synthesis of TNF- ⁇ is considered to concur, in turn, in amplifying the activation and chemiotaxis of the neutrophils and the synthesis of IL-8.
  • these effects of non-amplification of the synthesis of TNF- ⁇ are shown also in regard to the synthesis of TNF- ⁇ stimulated by hydrogen peroxide.
  • interleukin 8 and the correlated cytokines are the most important modulators of the infiltration of the neutrophils in diseases such as psoriasis (B. J. Nickoloff et al., Am. J. Pathol., 138, 129, 1991), rheumatoid arthritis (M. Selz et al., J. Clin. Invest. 87, 463, 1991), ulcerative cholitis (Y. R. Mahkla et al., Clin. Sci., 82, 273, Nickoloff et al., Am. J. Pathol., 138, 129, 1991), rheumatoid arthritis (M. Selz et al., J. Clin.
  • the compounds of the invention are also conveniently used for the prevention and the treatment of damages caused by ischemia and reperfusion, in particular in connection with organ transplantation.
  • compositions of the invention can be administered via intramuscular injection, via intravenous route, as a bolus, in preparations for dermatological use (creams, lotions, sprays and ointments), as well as via oral route in the form of capsules, tablets, syrup, controlled-release formulations, and the like.
  • the mean daily dosage will depend upon various factors, such as the severity of the illness and the conditions of the patient (age, sex and weight).
  • the dose will vary generally from one mg or a few mg up to 1500 mg of the compounds per day, optionally divided into multiple administrations. Higher dosages, as well as more prolonged treatment times, can be administered also by virtue of the low toxicity of the compounds of the invention.
  • the reaction mixture Upon completion of the dripping step, the reaction mixture is kept, under stirring, for 1 h at ⁇ 70° C. and then for 1 h at room temperature. The mixture is then cooled to ⁇ 10° C., and 1.8 mL of glacial acetic acid is added dropwise. The solvent is removed under vacuum, the residue is diluted with water, and the mixture is repeatedly extracted with dichloromethane (4 ⁇ 50 mL).
  • butyllithium (1.6 M in hexanes, 0.75 mL; 1.21 mmol)) is added to the mixture and, after 30′, a solution of R( ⁇ )-2-(4′-isobutylphenyl)propionyl chloride (0.27 g; 1.21 mmol)in dry THF (10 mL) is added dropwise. At the end of the adding, the ice-water bath is removed and the solution is left under stirring overnight at room temperature.
  • Carbonyldiimidazole (0.18 g) is added to a solution of (S) 2-(3′-phenoxy-phenyl)-propionic acid (0.24 g) in anhydrous THF (5 mL) and is stirred for at least 1 h to form the corresponding imidazolide (Sol. A).
  • magnesium ethylate (2.3 g) is added, under stirring, to a solution of 4.2 g of the monoamide of malonic acid in 15 mL of THF. After the total dissolution of the reagents, the solution of the imidazolide is added, and the mixture is stirred for 24 h at room temperature.

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RU2421213C1 (ru) * 2010-02-24 2011-06-20 Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) Применение 2-гидрокси-3-метил-6-(1-метилэтенил)циклогекс-3-енона в качестве анальгезирующего средства
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US20090203652A1 (en) 2009-08-13
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EP1581474B1 (en) 2008-08-27
HK1085721A1 (zh) 2006-09-01
JP5021169B2 (ja) 2012-09-05
AU2003289993A1 (en) 2004-06-30
DK1581474T3 (da) 2008-12-08
PT1581474E (pt) 2008-12-09
RU2345759C2 (ru) 2009-02-10
AU2003289993B2 (en) 2008-04-24
CN1732145A (zh) 2006-02-08
RU2005121554A (ru) 2006-01-20
EP1581474A1 (en) 2005-10-05
CA2507765A1 (en) 2004-06-24
JP2006509022A (ja) 2006-03-16
WO2004052830A1 (en) 2004-06-24
NO332223B1 (no) 2012-07-30
NO20053086L (no) 2005-06-23
CA2507765C (en) 2012-03-20
US9328057B2 (en) 2016-05-03
AU2003289993B8 (en) 2008-05-08
DE60323264D1 (de) 2008-10-09
CN100383110C (zh) 2008-04-23
SI1581474T1 (sl) 2009-02-28
CY1108596T1 (el) 2014-04-09

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