EP1390348A1 - Derives de 5-cyano-1h-indole antagonistes des recepteurs de l'interleukine-8 - Google Patents

Derives de 5-cyano-1h-indole antagonistes des recepteurs de l'interleukine-8

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Publication number
EP1390348A1
EP1390348A1 EP02738246A EP02738246A EP1390348A1 EP 1390348 A1 EP1390348 A1 EP 1390348A1 EP 02738246 A EP02738246 A EP 02738246A EP 02738246 A EP02738246 A EP 02738246A EP 1390348 A1 EP1390348 A1 EP 1390348A1
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Prior art keywords
formula
compounds
compound
cyano
pharmaceutically acceptable
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English (en)
French (fr)
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Martine Barth
Pierre Dodey
Jean-Luc Paquet
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Laboratories Fournier SAS
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Laboratories Fournier SAS
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to new derivatives of 5-cyano-iH-indole, the pharmaceutical compositions containing them, as well as their use for the preparation of medicaments intended for treating diseases dependent on the interleukin-8 receptor.
  • IL-8 is a protein of 72 amino acids belonging to the superfamily of proteins capable of attracting leukocytes, also qualified as CXC or CC cytokines intercrine cytokines or more recently chemokines (Oppenheim et al, Annu Rey Immunol, 1991, 9, 617-648). Different names have been assigned to interleukin-8 such as NAP-1 (from English "neutrophil activating peptide-1"), NAF (from English "neutrophil activating factor”) and "T-cell lymphocyte chemotactic factor ". Many members of the chemokine family have been described to be involved in inflammatory processes and the migration of leukocytes.
  • chemokines The family of chemokines is made up of two distinct sub-families: alpha- and beta-chemokines.
  • Alpha-chemokines such as IL-8, NAP-2 (from the English “Neutrophil activating peptide-2"), MGSA / Gro, or Gro-alpha (from the English “melanoma growth stimulatory activity” ), and ENA-78 (from the English “Epithelial cell derived neutrophil activating protein 78"), all have effects on the attraction and activation of leukocytes and more particularly neutrophils.
  • This subfamily also includes PF-4 (from English "Platelet Factor-4"), beta-thromboglobulin and CTAPII (from English "connective tissue activating protein ⁇ I”), which do not have effect on neutrophils.
  • IL-8 was originally identified by its ability to attract and activate polymorphonuclear leukocytes (neutrophils). More recently, it has been shown that dTL-8 expression is rapidly induced in different tissues or cells such as macrophages, fibroblasts, endothelial and epithelial cells and even neutrophils, in response to pro-inflammatory cytokines such as IL-l alpha or beta or TNF alpha (from the English "Tumor necrosis factor”) or other pro-inflammatory agents such as LPS (from the English "Lipopolysacharid”) (Nan Damme J., Interleukin-8 and related chemotactic cytokines; 1994; The Cytokines Handbook, 2 nd Ed.
  • Gro-alpha, Gro-beta, Gro-gamma and ⁇ AP-2 belong to the family of chemokines and, like IL-8, these proteins have also been called by different terms. So, Gro-alpha, beta and gamma! were called respectively MGSA (from the English "Melanoma Growth Stimulatory Activity") a, b and g (Richmond and Thomas, J. Cell Physiol, 1986, 129, 375-384; Cheng et al, J. Immunol., 1992 , 148, 451-456). All these chemokines belong to the group of alpha-chemokines which have an ELR motif (Aspartate-Leucine-Arginate) upstream of the characteristic CXC motif; this subgroup. These chemokines all bind to the type 2 receptor or CXCR2. •
  • IL-8RA IL-8 type A receptor
  • CXCR1 which binds with a strong affinity IL-8 and GCP-2 (from the English “granulocyte chemoattractant protein 2,”
  • TL-8RB 1TL-8 type B receptor
  • CXCR2 which has specific ligands IL-8, GCP-2, Gro-alpha, Gro-beta, Gro-gamma and NAP-2 (Pon'ath, Exp. Opin. Invest. Drugs, 1998, 7, 1-18).
  • LTL-8 seems to be involved in the phenomena of ischemia-reperfusion; lung (Sekido et al, Nature, 1993, 365, 654-657).
  • IL-8 seems to play a major role in alterations due to myocardial hypoxia / reperfusion (Kukielka et al., J. Clin. Invest., 1995, 95, 89-103).
  • mice deficient in interleukin-8 receptors were generated by elimination of the gene coding for the murine IL-8 receptor homologous to the human type 2 receptor (CXCR2) (Cacalano et al, Science, 1994 , 265, 682-684). Although these mice are healthy, the characteristics of their neutrophils are modified. In fact, their capacity to migrate • into the peritoneum is reduced in response to an intraperitoneal injection of thioglycolate. All these results demonstrate that the chemokines of the IL-8 family are important mediators of the migration and activation of neutrophils and other cell types such as endothelial cells under certain inflammatory conditions.
  • CXCR2 human type 2 receptor
  • chemokines of the IL-8 family have been described as playing an important role in tumor growth, metastasis and tumor angiogenesis in many types of cancer (Hébert and Baker, Cancer Invest., 1993, 11, 743-750; Richards et al, Am. J. Surg., 1997, 174, 507-512).
  • WO 96/18393 discloses derivatives of lj-benzyl-2-indolecarboxylic acid, capable of binding to some TL-8 receptors with! an inhibitory effect. More recently, according to WO 99/06354, compounds derived from urea or thiourea have also been presented as IL-8 receptor antagonists.
  • R 'i b represents a cyano group in position 5 is described.
  • the invention provides new non-peptide compounds, derived from
  • 5-cyano-1H-indole which have the property of binding to the CXCR2 receptor for] L-8 and other chemokines of the same family such as NAP-2, Gro-alpha or ENA-78 behaving as antagonists.
  • a subject of the present invention is therefore the new 5-cyano-iH-indole derivatives of formula (I):
  • - Rj and R represent, each independently of one another, a hydrogen atom, a halogen atom or a group (C ⁇ -C 3 ) alkyl, (C 1 -C 3 ) alkoxy, trifluoromethyl, trifluoromethoxy , cyano or nitro,
  • - n is equal to 2 or 3, as well as their pharmaceutically acceptable salts, solvates and hydrates.
  • alkyl is meant a monovalent, hydrocarbon, saturated, linear or branched radical.
  • (Cj-C 3 ) alkyl is meant an alkyl radical comprising from 1 to 3 carbon atoms.
  • halogen atom is meant a fluorine, iodine, chlorine or chromium atom, fluorine and chlorine being preferred.
  • the currently preferred compounds 1 are compounds of formula (Ia):
  • R 1s R 2 and n are as defined for (I), as well as their pharmaceutically acceptable salts, solvates and hydrates.
  • the preferred compounds of formula (I), (la) and (Ib) are those for which Ri and R 2 represent, each independently, a hydrogen, chlorine or fluorine or a group (C ⁇ -C 2 ) alkyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano or nitro, n being equal to 2 or 3, as well as their pharmaceutically acceptable salts, solvates and jhydrates. '
  • R 1 and R 2 represent, each independently, a hydrogen, chlorine or fluorine atom or a methyl group, n being equal to 2 or 3, as well as their salts, pharmaceutically acceptable solvates and hydrates. !
  • - R] represents a chlorine or fluorine atom, as well as their pharmaceutically acceptable salts, solvates and hydrates.
  • the compounds of formula (I), (la) and (Ib) can be salified with a pharmaceutically acceptable mineral or organic base, according to techniques well known to those skilled in the art.
  • mineral base includes hydroxides of alkali metals such as sodium hydroxide, potassium hydroxide, lithine, or alkaline earth metals such as lime.
  • organic base is meant primary, secondary or tertiary amines, amino alcohols, certain non-toxic nitrogen heterocycles, as well as their basic amino acids.
  • the sodium or potassium salts are preferred, and the lysine, arginine or 2-amino-2-methyl-1,3-propanediol salts.
  • the compounds of formula (I) according to the invention are, for example, prepared according to SCHEME 1 below, in which Ri, R 2 , X and n are as defined for (I), R 3 represents a group ( Cj-C) alkyl, and Y represents a bromine or iodine atom.
  • SCHEME 1 SCHEME 1 below, in which Ri, R 2 , X and n are as defined for (I), R 3 represents a group ( Cj-C) alkyl, and Y represents a bromine or iodine atom.
  • Ri, R 2 , X and n are as defined for (I) and R 3 represents a (C ⁇ -C 4 ) alkyl group, in particular a methyl or ethyl group.
  • the compounds (II) are new intermediates and form an integral part of the invention.
  • hydrolysis of the compounds (H) to acid (I) is carried out according to techniques well known to those skilled in the art, for example by the action of a (hydroalcoholic solution of sodium hydroxide.
  • the compounds of formula (H) can be prepared according to the following process: a) either by transformation of the compound of formula (m):
  • R ]; R 2 , X and n are as defined for (I), R 3 represents a (C ⁇ -C 4 ) alkyl group and Y represents a bromine or iodine atom, by the action of a cyanide, b) either by a Suzuki coupling between the bromine derivative of formula (V):
  • n is as defined for (I) and R represents a! (C] -C) alkyl group, and boronic acid of formula (2):
  • a palladium catalyst such as tetrakis (triphenylphosphine) palladium.
  • cuprous cyanide in the presence of N-methyl-2-pyrrolidone. It is also possible to use potassium cyanide, in the presence of a palladium catalyst. In this case, one will operate, for example, in the presence of tetrakis (triphenylphosphine) palladium and copper iodide in a solvent such as tetrahydrofuran. !
  • the step described in b) is preferably carried out in the presence of lithium chloride and sodium carbonate.
  • the compounds of formula (m) are, for example, obtained by a Fischer reaction between the compound of formula (TV):
  • n, RR 2 and X are as defined for (I), and R 3 represents a (C ⁇ -C 4 ) alkyl group, with a phenylhydrazine of formula (1):
  • Y represents a bromine or iodine atom.
  • This Fischer reaction is carried out for example in the presence of zinc dichlprure in acetic acid, at a temperature between 20 and 80 ° C.
  • the compounds of formula (1) are commercial or obtained according to techniques well known to those skilled in the art.
  • the compounds (IN) can be obtained for example: a) either by esterification, according to a reaction well known to man! in the art, by the action of alcohol R 3 OH in which R 3 represents a; (C ⁇ -C) alkyl group, on the acid of formula:
  • Rj, R and X are as defined for (I), in the presence of a Lewis acid; one could for example operate in the presence of aluminum trichloride in a solvent such as dichloromethane, b) either directly by a Friedel and Craft type reaction between an acid chloride of formula:
  • the compounds of formula (VI) are, for example, prepared from the halogen derivative of formula:
  • Y represents a bromine or iodine atom, preferably iodine, by the action of a cyanide such as potassium cyanide, in the presence of a palladium catalyst.
  • a cyanide such as potassium cyanide
  • the compounds (VU) can be prepared according to a method analogous to that used for the preparation of the compounds (UJ), namely a Fiscjher reaction between a hydrazine (1) and an aldehyde of formula: HC (O) (CH 2 ) n + ⁇ -COOR 3 ; (7) in which n is as defined for (I) and R 3 represents a (C ⁇ -C 4 ) alkyl group.
  • the boronic acids used (2) are commercial or known compounds.
  • HEK 293 cells are maintained in culture in DMEM medium (from the English “Dulbecco modified eagle's medium”) (GH3CO) containing 4.5 g / 1 of glucose, 10% of fetal calf serum, 1% of Glutamax, 1% of non-essential amino acids, 1 mM of! sodium pyruvate, 100 IU / ml of penicillin and 100 ⁇ g / ml of streptomycin.
  • DMEM medium from the English “Dulbecco modified eagle's medium” (GH3CO) containing 4.5 g / 1 of glucose, 10% of fetal calf serum, 1% of Glutamax, 1% of non-essential amino acids, 1 mM of! sodium pyruvate, 100 IU / ml of penicillin and 100 ⁇ g / ml of streptomycin.
  • K-562 and THP-1 cells are kept in culture in RPMI1640 medium (GL3CO) containing 10% fetal calf serum, 1% non-essential amino acids, 1 mM sodium pyruvate, 100 IU ml of penicillin and 100 ⁇ g / ml streptomycin. The cells are used when the cultures have reached 80% confluence.
  • the membranes are prepared according to the protocol previously described (Bastian et al, Br. J. Pharmacol. 1997, 122, 393-399) except the homogenization buffer which has been replaced by a saline solution buffered to pH 8.0 containing 20 mM Tris (tris (hydroxymethyl) aminomethane), 1.2 mM MgSO (magnesium sulfate), 0.1 mM EDTA (ethylenediaminetetraacetic acid) and 25 'mM NaCl (sodium chloride).
  • the competition experiments are carried out in 96-well plates of 1 ml, at room temperature, in a final volume of 10.25 ml. i
  • Tris-HCl buffered to pH 8.0 containing 1.2 mM MgSO 4, 10, l mM EDTA 25 mM NaCl and 0.03% CHAPS (3 - [(cholamidopropyl) - dimethylammonio ] -l-propanesulfonate) are incubated with decreasing concentrations of the test compound (from 100 ⁇ M to 0.01 nM) and 150 ⁇ M of [ 125 I] -IL-8.
  • Non-specific binding is determined in the presence of 300 nM unlabeled IL-8.
  • the affinities of the compounds described in the present invention were also determined by a whole cell binding test.
  • the transfected THP-1 or K-562 cells are suspended in the! PBS binding test buffer (of “buffered saline phosphate”) without calcium or magnesium containing 0.5% BSA (weight / volume), pH 7.4 at 2.5 x 10 6 cells / ml.
  • the competition experiments are carried out in 1-well 96-well plates in a final volume of 0.25 ml. 0.5 x 10 6 cells are incubated with decreasing concentrations of the test compound (100 ⁇ M at 0.01 nM) and 150 ⁇ M of [ 125 I] -IL-8.
  • Non-specific binding is determined in the presence of 300 nM of non-radionuclear chemokine.
  • the reaction is stopped by rapid filtration under vacuum on a Whatman GF / C filter previously incubated for 1 hour in a 3% polyethyleneimine solution (weight / volume).
  • the filters are washed with a PBS solution at pH 7.4 containing 0.5 M NaCl.
  • the radioactivity contained in the filters is measured in a gamma counter.
  • THP-1 cells expressing the recombinant CXCR2 receptors U937 cells differentiated with DMSO (dimethyl sulfoxide) at 1% (volume / volume) or Eol3 cells are incubated in the presence of a fluorescent indicator, Fura-2 AM, at a concentration of 5 ⁇ M for 1 hour at 37 ° C.
  • DMSO dimethyl sulfoxide
  • Fura-2 AM a fluorescent indicator
  • the cells are washed and suspended at the concentration of 1 ⁇ 10 6 cells / ml in a saline solution containing: 136 mM NaCl, 4.7 nM KC1, 1.2 mM MgSO 4 , 1.6 mM CaCl 2 , 1.2 mM KH 2 PO 4 , 11 mM glucose, 5 mM HEPES (N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid]), pH 7.4.
  • a saline solution containing: 136 mM NaCl, 4.7 nM KC1, 1.2 mM MgSO 4 , 1.6 mM CaCl 2 , 1.2 mM KH 2 PO 4 , 11 mM glucose, 5 mM HEPES (N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid]), pH 7.4.
  • the cell suspension (2 ml) is placed in a quartz tank and the fluorescence intensity at 510 nm is measured, on a spectrofluorimeter of the LS50B type (Perkin-El er) after excitations alternately at 340 nm and 380 nm.
  • K d represents the affinity constant of the Fura-2 and calcium complex
  • Rmax is the maximum fluorescence intensity determined after addition of 1 ⁇ M of the Bromo-A23187 ionophore
  • Rmin is the minimum ratio determined after addition of
  • the compounds of formula (I) described in the present invention inhibit the release of calcium induced by IL-8 or Gro-alpha.
  • the subject of the invention is also the compounds (I), as well as their pharmaceutically acceptable salts, solvates and hydrates, for their use as a medicament.
  • the invention relates to the use of the i compounds of formula (I), or of one of their pharmaceutically acceptable salts, solvates or [hydrates] for the preparation of a medicament intended for the preventive treatment or curative in mammals, in particular in humans, of diseases dependent on an activation of the CXCR2 receptor of 1TL-8 and chemokines of the same family, and which are generally characterized by a massive invasion of neutrophils.
  • the invention therefore relates to the use of a compound of formula (I), or of a pharmaceutically acceptable salt, solvate or hydrate thereof, for the preparation of a medicament intended for the preventive or curative treatment of atopic dermatitis, l osteoarthritis, rheumatoid arthritis, asthma, chronic obstruction of the lungs, acute respiratory distress syndrome, inflammation of the colon, Crohn's disease, ulcerative colitis, stroke myocardial infarction, septic shock, multiple sclerosis, endotoxic shock, psoriasis, gram-negative septicemia, toxic shock syndrome, cardiac, pulmonary or reperfusion ischemia and reperfusion phenomena, glomerulo-nephritis, thrombosis, graft versus host reaction, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, non physiological release e of bone marrow stem cells, diseases caused by respiratory viruses, herpes viruses
  • the compounds of formula (I) must be administered in an amount sufficient to antagonize TIL-8 by binding competitively to its receptors .;
  • the dose of active ingredient depends on the method of administration and the type of pathology and is generally between 0.01 and 10 mg / kg.
  • the compounds of formula (I) can also be combined with another active principle. ! In the context of their therapeutic use, the compounds of formula (I) will generally be administered in various forms, in combination with the excipients commonly used. Also, the present invention also relates to
  • the formulation used may be an oral form, such as for example capsules, tablets containing the solid active principle in a sprayed or micronized form, a syrup or a solution containing the active principle in solution, in suspension, in emulsion or in micro -emulsion. ;
  • the formulation can also be presented in a form which can be administered for topical use, for example a cream or a lotion or a device. transdermal such as an adhesive patch.
  • the active principle can also be formulated for a mode of administration by subcutaneous, intramuscular or intravenous injection.
  • a suspension of 2.59 g of aluminum chloride in 4 ml of dichloromethane is prepared.
  • the mixture is cooled to -5 ° C. and a mixture of 0.97 ml of fluorobenzene and 1.31 ml of methyl ester of 6-chlorb-6-oxohexanoic acid in 3 ml of dichloromethane is gradually added.
  • the temperature between -4 and -7 ° C.
  • the temperature is then allowed to rise to 20 ° C. and, after 15 hours, it is hydrolyzed on acidified ice water.
  • the mixture is extracted i with dichloromethane and the organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure.
  • a suspension of 5 g of 3,4-dichloro- ⁇ -oxo-benzenepentanoic acid in 60 ml of ethanol is prepared and 1 ml of pure sulfuric acid is added.
  • the residue obtained in b) is added dropwise to a solution of sodium ethylate obtained from 206 mg of sodium in 4 ml of ethanol.
  • the reaction mixture is heated at reflux for 45 minutes then is cooled to 40 ° C. and 1.28 ml of ethyl 4-bromobutyrate are added at this temperature.
  • the reaction mixture is heated at reflux for 4 hours 30 minutes. After returning to room temperature, the reaction mixture is filtered and washed with ethanol. After extraction with ethyl acetate, the solvents are evaporated under reduced pressure.
  • the residue obtained is purified by chromatography on silica gel, eluting with a petroleum ether / ethyl acetate mixture, 95/5 then 9/1, v / v.
  • a mixture of 1.6 g of compound III.1, 2.66 g of puyrous cyanide and 7 ml of N-methyl-2-pyrrolidone is prepared, which is heated at reflux for 16 hours.
  • the reaction mixture is then cooled and 30 ml of water are added.
  • the mixture is kept stirring at room temperature for 15 minutes and then 20 ml of ethylenediamine are added.
  • the mixture is then extracted with twice 40 ml of toluene and the combined organic phases are washed with three times 30 ml of a saturated solution of sodium chloride and then dried over magnesium sulfate. After filtration, the solvents are evaporated under reduced pressure.
  • the evaporation residue is dissolved in ethyl acetate then a few drops of cyclohexane are added.
  • the expected product is filtered and dried under reduced pressure; Mp 158-160 ° C.
  • Compound VII.l is prepared from 4-iodo ⁇ henylhydrazine and from the methyl ester i of 6-oxohexanoic acid according to a procedure analogous to that described in PREPARATION 4.
  • ⁇ NMR 300 MHz, DMSO: 10.95 (s, 1H); 7.85 (s, 1H); 7.32 (dd, 1H); 7.19 (d, 1H); 7.13 (d, 1H); 3.59 (s, 3H); 2.66 (t, 2H); 2.35 (t, 2H); 1.85 (q, ' ⁇ H).
  • a mixture of 1.586 g of compound VII.l, 602 mg of potassium cyanide, 88 mg of copper iodide and 267 mg of tetrakis (triphenylphosphine) palladium in 6 ml of tetrahydrofuran is heated to reflux with stirring for 8 hours.
  • 88 mg of copper iodide and 267 mg of tetrakis (triphenylphosphine) palladium are added again, after 2 hours and 6 hours of stirring.
  • 200 ml of ethyl acetate are added and the mixture is filtered through celite. The organic phase is washed twice with water and with a saturated solution of sodium chloride and then dried over magnesium sulfate.
  • a solution 3 g of the compound VU in 125 ml of carbon tetrachloride is prepared and 2.56 g N-bromosuccinimide is added.
  • the reaction mixture is brought to reflux with stirring for 4 hours and then cooled to room temperature; 200 ml of ethyl acetate and 200 ml of hot water are added.
  • the organic phase is washed with hot water, then dried over magnesium sulfate.
  • the solvahts are evaporated under reduced pressure. The residue obtained is taken up in petroleum ether and
  • a mixture of 80 mg of compound II.1 is prepared in 3 ml of dio ⁇ ane. 1 ml of a 1N sodium hydroxide solution in water is added and; brings the reaction mixture to reflux for 1 hour 30 minutes. The solvent is then

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EP02738246A 2001-05-17 2002-05-16 Derives de 5-cyano-1h-indole antagonistes des recepteurs de l'interleukine-8 Withdrawn EP1390348A1 (fr)

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FR0106506A FR2824826B1 (fr) 2001-05-17 2001-05-17 Nouveaux derives de 5-cyano-1h-indole antagonistes des recepteurs de l'interleukine-8
FR0106506 2001-05-17
PCT/FR2002/001647 WO2002092568A1 (fr) 2001-05-17 2002-05-16 Derives de 5-cyano-1h-indole antagonistes des recepteurs de l'interleukine-8

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GB0422057D0 (en) * 2004-10-05 2004-11-03 Astrazeneca Ab Novel compounds
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EP3897833A1 (en) 2018-12-17 2021-10-27 Vertex Pharmaceuticals Incorporated Inhibitors of apol1 and methods of using same
JP7668804B2 (ja) 2020-01-29 2025-04-25 バーテックス ファーマシューティカルズ インコーポレイテッド Ａｐｏｌ１の阻害剤およびこれを使用する方法
KR20220151634A (ko) 2020-03-06 2022-11-15 버텍스 파마슈티칼스 인코포레이티드 Apol-1 의존성 국소 분절성 사구체경화증을 치료하는 방법
AU2021286728A1 (en) 2020-06-12 2023-01-19 Vertex Pharmaceuticals Incorporated Inhibitors of APOL1 and use of the same
CN115867532A (zh) * 2020-06-12 2023-03-28 弗特克斯药品有限公司 Apol1的抑制剂及其用途
PE20231106A1 (es) 2020-08-26 2023-07-19 Vertex Pharma Inhibidores de apol1 y metodos para usar los mismos

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FR2801585B1 (fr) * 1999-11-25 2002-02-15 Fournier Ind & Sante Nouveaux antagonistes des recepteurs de l'ii-8

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CA2447184A1 (fr) 2002-11-21
KR20030094255A (ko) 2003-12-11
JP2004534034A (ja) 2004-11-11
FR2824826A1 (fr) 2002-11-22
BR0207438A (pt) 2004-08-10
CZ20032260A3 (cs) 2003-11-12

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