WO2005039583A1 - Methode permettant de traiter l'arthrite rhumatoide a l'aide d'inhibiteurs de nf-kb - Google Patents

Methode permettant de traiter l'arthrite rhumatoide a l'aide d'inhibiteurs de nf-kb Download PDF

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WO2005039583A1
WO2005039583A1 PCT/US2003/030339 US0330339W WO2005039583A1 WO 2005039583 A1 WO2005039583 A1 WO 2005039583A1 US 0330339 W US0330339 W US 0330339W WO 2005039583 A1 WO2005039583 A1 WO 2005039583A1
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carbon atoms
compounds
alkyl
aryl
heteroaryl
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PCT/US2003/030339
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Douglas Carl Harnish
Christopher Cyril Chadwick
James Carl Keith, Jr.
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Wyeth
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Priority to PCT/US2003/030339 priority Critical patent/WO2005039583A1/fr
Priority to AU2003278955A priority patent/AU2003278955A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • This invention relates to methods of treatment of rheumatoid arthritis by modulating NF B transcription with ligands that interact with the estrogen receptor, preferably, in the absence of classic estrogenic activity.
  • a common component of these chronic inflammatory conditions is polymorphonuclear leukocyte and monocyte infiltration into the site of damage through increased expression of cytokines and adhesion molecules responsible for their recruitment.
  • Overproduction of the cytokine interleukin (IL-6) has been associated with states of chronic inflammation (Bauer M. A., Herrmann F., Ann. Hematol. 1991, 62, 203).
  • Synthesis of the IL-6 gene is induced by the transcription factor nuclear factor KB (NF-KB). Interference at this step in the inflammatory process can effectively regulate the uncontrolled proliferative process that occurs in these chronic conditions.
  • E2 17 ⁇ -estradiol
  • RA Rheumatoid arthritis
  • Microbial or self antigens are presented to T lymphocytes, a process that leads to chronic activation of the immune system.
  • Interleukin 1 E -1
  • Tumor Necrosis Factor- ⁇ TNF- ⁇
  • IFN- ⁇ Interferon- ⁇
  • metalloproteinases mediate the inflammation of the joints.
  • Biochemical and histological changes in synovial tissue, cartilage, and bone have been documented in various animal models of arthritis. See Houri JM and O'Sullivan FX. 1995, Current Opinion in Rheumatology 7:201-205; Van de Loo AAJ, Arntz OJ, Bakker AC, Lent PLEM, Jacobs MJM, van den Berg WB. 1995, American Journal of Pathology 146 (No. 1) 239-249; O'Byrne EM, Blancuzzi V, Wilson DE, Wong M, Jeng AY.
  • the present invention concerns methods of treating rheumatoid arthritis comprising the steps of identifying a person is need of such treatment for rheumatoid arthritis and administering a therapeutically effective amount of a ligand which modulates NF-kB transcription factor by interaction with estrogen receptor ER- ⁇ , estrogen receptor ER- ⁇ , or both ER- ⁇ and ER- ⁇ estrogen receptors, preferably with a substantial absence of creatine kinase stimulation.
  • the administration is with a substantial absence of uterotropic activity.
  • Some preferred ligands interact with both ER ⁇ and ER ⁇ receptors.
  • the present invention provides methods for the treatment of rheumatoid arthritis.
  • Compounds useful in the present invention preferably block interleukin-l ⁇ (IL- l ⁇ ) induced nuclear factor kB (NF-kB) luciferase reporter activity or interleukin-6 (IL-6) expression in an ER dependent fashion in human endothelial cells.
  • Particularly preferred ligands are devoid of the proliferative effects on uterine and breast tissue associated with estrogen in vivo. This lack of estrogen side effects is confirmed in vitro by the lack of expression of creatine kinase (CK); a classic estrogen responsive gene.
  • CK creatine kinase
  • the selective anti-inflammatory compounds described herein are expected to prove useful for the treatment and prevention of chronic inflammatory diseases without stimulating uterine and breast cell proliferation as found with classic estrogens.
  • One family of compounds useful in the instant invention are substituted 4-(lH-indazol-3-yl)phenols represented by the general formula I and substituted 4-(2 ⁇ - indazol-3-yl)phenols represented by formula II. Such compounds have been found to be useful for the treatment of the inflammatory component of diseases and particularly in treating rheumatoid arthritis.
  • Rg, R7, Rg, and R9 are each, independently, hydrogen, alkyl, alkenyl, hydroxy, alkoxy, aryloxy, halogen, trifluoromethyl, -CO2R11, aryl, arylalkyl, or a heterocyclic ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
  • Rl is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3- 8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a heterocyclic ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S;
  • R2, R3, R4, and R5, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, aryloxy of 6- 20 carbon atoms, halogen, trifluoromethyl, -CN, -NO2, -CHO, or -CO2R11;
  • Rg, R7, Rg, and RQ are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of
  • the compounds of formula I and formula II can be converted to salts, in particular pharmaceutically acceptable salts using art recognized procedures.
  • the compounds of formulas I and II that have a basic center can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic, or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids,
  • Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the compounds of formula I having at least one acid group can form salts with bases.
  • Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri- lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine.
  • Some preferred 4-(l-H-indazol-3-yl)phenols useful in this invention include those of Group A in which: Rl is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, or a heterocyclic ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S; R2 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, or halogen; R7 and R9, are each, independently, hydrogen, alkyl of 1-6 carbon atoms, hydroxy, halogen, trifluoromethyl
  • Rj is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, or cycloalkenyl of 4-8 carbon atoms
  • R2 is hydrogen, alkyl of 1-6 carbon atoms, halogen, or hydroxy
  • R9 is alkyl of 1-6 carbon atoms, halogen, trifluoromethyl, -CO2R11, aryl of 6-20 carbon atoms, arylalkyl of 7-26 carbon atoms, or a heterocyclic ring system of 4-14 atoms, containing 1-4 heteroatoms selected from N, O, and S
  • RjO is hydrogen; where the remaining substituents are as defined above.
  • Yet other preferred compounds of this invention include those of C in which: Rj is alkyl of 1-6 carbon atoms or alkenyl of 2-7 carbon atoms; R9 is alkyl of 1-6 carbon atoms, halogen, or trifluoromethyl, where the remaining substituents are as defined above.
  • the reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • Ri is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkyloxy;
  • R 2 , R 3 , R , R 5 , R 6 , R , R 8 , and R 9 are as previously defined;
  • P is a phenol protecting group, preferably but not limited to methyl, benzyl or t- butyldiphenylsilyl .
  • compounds of formula III preferably are treated with sodium hydride in a suitable solvent such as 4-dimethylaminopyridine (DMAP). When the gas evolution ceases, the alkyl halide is added and the solution is heated at 50°C overnight.
  • DMAP 4-dimethylaminopyridine
  • 2-Fluorobenzophenones of compound VI can be reacted directly with optimally substituted hydrazines where Ri is alkyl or aryl, which are either commercially available or readily prepared by common procedures known to those skilled in the art.
  • a mixture of the benzophenones of compound VI are combined with the hydrazines in a suitable solvent such as methanol in the presence of ethyl acetate.
  • the intermediate hydrazone either spontaneously cyclizes to the compounds of formula IV or can be isolated by concentration of the reaction mixture.
  • the isolated hydrazone is heated neat to temperatures of up to 190°C.
  • the residues are purified by chromatography to provide compounds of formula IV.
  • X is preferably but not limited to Br.
  • Compounds of formula VJJI are either commercially available or readily prepared by one skilled in the art.
  • One suitable solvent is tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the Weinreb amides of formula VII can are generated by the reaction of an appropriately substituted 2-fluorobenzoic acid with N,O-dimethylhydroxylamine and N,N-carbonyldiimidazole in a suitable solvent such as DMF ( Robertson et.al., J. Med. Chem.
  • Ri, R 2> R 3 , and R are as defined above; and halo is CI or Br.
  • halo is CI or Br
  • compounds of formula IV where R 9 is aryl, heteroaryl, heterocycle, and alkenyl can be prepared by the Suzuki coupling of LX with an appropriately substituted boronic acid in a suitable solvent such as dioxane, in the presence of an aqueous base such as potassium carbonate, in the presence of 1 to 5 mol% of palladium catalyst such as tetrakis(triphenylphoshine)palladium (0).
  • the mixture is typically heated at 80 °C for a period of 1 to 24 hours (see Miyaura, N.
  • the substituted hydrogen phosphates of compounds of formulas I and II can be prepared as described by Rodriguez, M. J. et al., Bioorg. Med.
  • R 10 is H substituted dichlorophosphate and lithium hexamethyldisilazide in a suitable solvent such as THF is stirred for 1 hour at ambient temperature. The reaction mixture is quenched with H 2 O and purified by reversed phase HPLC, known by one skilled in the art.
  • Other useful compounds of the invention are dihydrophenanthridinesulfonamide compounds of formulae (XI) or (XII):
  • R55 is hydrogen, R 67 , monofluoroalkyl, monofluoroalkenyl, aryl-R 66 -, heteroaryl-R 66 -, hydroxyalkyl, HO-R 66 -, R 67 -X-R 66 -, HS-R 66 -, -C(O)R', -CO 2 R', or -C(O)N(R') 2 ; or R 55 may be linked with either R 56 or R 57 and linked with an -alkylene- or -X-alkylene- group;
  • R 56 is hydrogen, R 6 , monofluoroalkyl, monofluoroalkenyl, aryl-R 66 -, heteroaryl-R 66 -, hydroxyalkyl, HO-R 66 -, R 67 -X-R 66 -, HS-R 66 -, -C(O)R', -CO 2 R ⁇ or -C
  • R 6 7 is alkyl, aryl, heteroaryl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkenyl-X-alkylene-, cycloalkenyl-X-alkylene-, or perfluoroalkyl;
  • R' is, independently, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, monofluoroalkyl, perfluoroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy-(C 2 -C 6 )alkyl, alkoxyalkyl, alkylthioalkyl, formyl, acyl, alkoxycarbonyl, -C(O)NH 2 , alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminoalkyl, or dialkylaminoalkyl; or when an atom contains two R' groups, the R' groups may be linked with an -alkylene- group;
  • X is O, -NR'-, -S(O) m -, -C(O)-, -OC(O)-, -C(O)O-, -NR'C(O)-, or -C(O)NR'-;
  • m is O, l, or 2;
  • p is 52, 53, 56, 57, 58, 59, 62, 63, or 64;
  • R 5 is hydrogen, R 67 , monofluoroalkyl, monofluoroalkenyl, aryl-R 66 -, heteroaryl-R 66 -, hydroxyalkyl, HO-R 66 -, R 6 7-Y-R 6 6-, HS-R 66 -, -C(O)R', -CO 2 R', or -C(O)N(R') 2 ; or R 25 - may be linked with either R 76 or R 7 by an -alkylene- or -Y-alkylene- group;
  • R 6 is hydrogen, R 67 , monofluoroalkyl, monofluoroalkenyl, aryl-R 66 -, heteroaryl-R 66 -, hydroxyalkyl, HO-R 66 -, R 6 7-Y-R 6 6-, HS-R 66 -, -C(O)R', -CO 2 R', or -C(O)N(R') 2 ; or R 76 may be linked with either R 25 or R 2 by an -alkylene- or -Y-alkylene- group;
  • R 82 is R', R 67 -Y-R 66 -, R 67 -S(O)-, R 67 -S(O) 2 -, -SO 3 R', -S(O) 2 N(R') 2 , or D-glucuronidate;
  • Y is O, -NR'-, -S(O) n -, -C(O)-, -OC(O)-, -C(O)O-, -NR'C(O)-, or -C(O)NR'-; n is O, 1, or 2; q is 72, 73, 76, 77, 78, 79, 82, 83, or 84; or pharmaceutically acceptable salts thereof.
  • Preferred dihydrophenanthridinesulfonamides compounds useful in the invention include those of the Groups A-F detailed below.
  • Group A compounds are those of formula (XII),where the remaining substituents are as defined above.
  • Group B compounds include those of group A where R 32 > is hydrogen and the remaining substituents are as defined above.
  • the compounds of group C include those of group B in which: R 71 , R 72 , R 73 , R 74 , R 77 , R 78 , R 79 , R 80 , R 81 , R 83 , R 84 , and R 85 are each, independently, hydrogen, R 67 , aryl-R 66 _ R 6 -Y-R 66 -, hydroxyalkyl, HO- R 66 -, halogen, -OR', -COR', or -CO 2 R'; R 5 and R 6 are each, independently, hydrogen or R 67 ; R g6 is -alkylene-; R 67 is alkyl, aryl, heteroaryl, or perfluoroalkyl; R' is hydrogen or alkyl; and where the remaining substituents are as defined above.
  • Group D compounds include those in which the compound is of formula (I) and the remaining substituents are as defined above.
  • the compounds of group E include the compounds of group D where R poison is hydrogen and the remaining substituents are as defined above.
  • Group F compounds include those of group E in which: R 5 ⁇ , R 52 , R 53 , R 54 , R 57 , R 58 , R59, R ⁇ o, R ⁇ i, R ⁇ 2, R ⁇ 4, and R 65 are each, independently, hydrogen, R 67 , aryl-R 66 _, R 6 -X-R 66 -, hydroxyalkyl, HO- R 66 -, halogen, -OR', -COR', or -CO 2 R'; R 55 , and R 56 , are each, independently, hydrogen or R • R g6 is -alkylene-; R 67 is alkyl, aryl, heteroaryl, or perfluoroalkyl; R' is hydrogen or
  • R 1 and R 2 are each independently hydrogen, halo, alkyl, alkoxy, nitro, cyano, thioalkyl, CF 3 , OCF 3 , or hydroxy;
  • R 3 is H, alkyl, allyl, benzyl, alkenyl, cycloalkyl methyl, or heteroaryl methyl;
  • R 4 is NR 95 R 96 , morpholinyl, thiomorpholinyl, t-butylamino,
  • Z is O or S; and w is o-aryl, O-heteroaryl, NH-aryl, or NH-heteroaryl;
  • R 5 and R 6 are each, independently, alkyl, heteroaryl methyl, aryl methyl, or cycloalkyl; and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R 1 and R 2 are each independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, nitro, cyano, thioalkyl, CF 3 , OCF 3 , or hydroxy;
  • R 93 is H, alkyl of 1 to 6 carbon atoms, allyl, benzyl, alkenyl of 2 to 7 carbon atoms, cycloalkyl methyl, or heteroaryl methyl;
  • R 9 is NR 95 R 96 , morpholinyl, thiomorpholinyl, t-butylamino,
  • R 5 and R 96 are each, independently, alkyl of 1 to 6 carbon atoms, heteroaryl methyl, aryl methyl, or cycloalkyl of 3 to 8 carbon atoms.
  • R 1 and R 92 are each independently hydrogen, halo, alkyl, alkoxy, nitro, cyano, thioalkyl, CF 3 , OCF 3 , or hydroxy;
  • R 93 is H, alkyl, allyl, benzyl, or alkenyl, cycloalkyl methyl, or heteroaryl methyl;
  • R 4 is NR 5R96, t-butylamino, where W is O-heteroaryl, O-aryl, NH-aryl, or NH-heteroaryl,
  • R 91 and R 9 are independently hydrogen, halo, alkyl, alkoxy, CF 3 , OCF 3 , or hydroxy;
  • R 93 is H, alkyl, allyl, benzyl, alkenyl, or aryl methyl, or heteroaryl methyl;
  • R 9 is NR 95 R 9 6,
  • W is O-aryl, 4-benzyl piperazinyl, 4-heteroarylmethyl piperazinyl, 4-arylmethyl piperazinyl, heteroarylpiperazine, arylpiperazine, heteroaryl tetrahydropyridine, aryl tetrahydropyridine, heteroarylpiperidine, arylpiperidine, or OR 96 ; and R 9 5 and R 96 are each independently alkyl, benzyl, heteroaryl methyl, aryl methyl or cycloalkyl.
  • alkyl employed alone, is defined herein as, unless otherwise stated, either a ( -C ⁇ ) straight chain or (C 3 -C 20 ) branched-chain monovalent saturated hydrocarbon moiety.
  • saturated hydrocarbon alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, isobutyl, sec-butyl; higher homologs such as n-pentyl, ?z-hexyl, n-heptyl, n-octyl, and the like.
  • alkenyl employed alone, is defined herein as, unless otherwise stated, either a (C -C 20 ) straight chain or (C 3 -C 20 ) branched-chain monovalent hydrocarbon moiety containing at least one double bond.
  • Such hydrocarbon alkenyl moieties may be mono or polyunsaturated, and may exist in the E or Z configurations.
  • the compounds of this invention are meant to include all possible E and Z configurations.
  • Examples of mono or polyunsaturated hydrocarbon alkenyl moieties include, but are not limited to, chemical groups such as vinyl, 2-propenyl, isopropenyl, crotyl, 2-isopentenyl, butadienyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), and higher homologs, isomers, and the like. It is preferred that straight chain alkenyl moieties have 2-7 carbon atoms, and branched alkenyl moieties have 3-8 carbon atoms.
  • alkynyl employed alone, is defined herein as, unless otherwise stated, either a (C 2 -C 20 ) straight chain or (C 3 -C 20 ) branched-chain monovalent hydrocarbon moiety containing at least one triple bond.
  • alkynyl moieties include, but are not limited to, chemical groups such as ethynyl, 1-propynyl, l-(2- propynyl), 3-butynyl, and higher homologs, isomers, and the like. It is preferred that straight chain alkynyl moieties have 2-7 carbon atoms, and branched alkynyl moieties have 3-8 carbon atoms.
  • Preferred alkylene chains have 2-7 carbon atoms.
  • cycloalkyl employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbon moiety of 3-10 carbon atoms, wherein the carbon atoms are located inside or outside of the ring system.
  • the ring comprises 3-8 carbon atoms. Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure.
  • cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]decanyl, and homologs, isomers, and the like.
  • cycloalkenyl employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent unsaturated hydrocarbon moiety of 3-10 carbon atoms containing at least one double bond, wherein the carbon atoms are located inside or outside of the ring system.
  • the ring has 4-8 carbon atoms. Any suitable ring position of the cycloalkenyl moiety may be covalently linked to the defined chemical structure.
  • cycloalkenyl moieties include, but are not limited to, chemical groups such as cyclopropenyl, cyclopropenylmethyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexenylmethyl, cyclohexenylethyl, cycloheptenyl, norbornenyl, and homologs, isomers, and the like.
  • cycloalkylene employed alone, is defined herein as, unless otherwise stated, a bivalent moiety of 3-10 carbon atoms derived from a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro hydrocarbon.
  • the ring has 4-8 carbon atoms.
  • Such hydrocarbon cycloalkylene moieties may be fully saturated, or mono or polyunsaturated, and may exist in the E or Z configurations.
  • the compounds of this invention are meant to include all possible E and Z configurations. Any suitable ring position of the cycloalkylene moiety may be covalently linked to the defined chemical structure.
  • saturated and unsaturated hydrocarbon cycloalkylene moieties include, but are not limited to, bivalent chemical groups such as cyclopropylene, cyclopentylene, cyclohexylene, cyclohexenylene, trans- decahydronaphthalenylene, spiro[3.3]heptenylene, and higher homologs, isomers, and the like.
  • halo or halogen, employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • monofluoroalkyl employed alone, is defined herein as, unless otherwise stated, either a ( - o) straight chain or (C 3 -C 10 ) branched-chain monovalent saturated hydrocarbon moiety containing only one fluorine atom.
  • monofluoroalkyl moieties include, but are not limited to, chemical groups such as - CH 2 F, -CH 2 CH 2 F, -CH(CH 3 )CH 2 CH 2 F, and higher homologs, isomers, and the like.
  • Preferred chain lengths are from 1-6 carbon atoms for straight chains and from 3-8 carbon atoms for branched chains.
  • monofluoroalkenyl employed alone, is defined herein as, unless otherwise stated, either a (C 2 -C 10 ) straight chain or (C 3 - 0 ) branched-chain monovalent unsaturated hydrocarbon moiety, containing only one fluorine atom and at least one double bond.
  • Preferred chain lengths are from 2-7 carbon atoms for straight chains and from 3-8 carbon atoms for branched chains.
  • perfluoroalkyl employed alone or in combination with other terms, is defined herein as, unless otherwise stated, either a (Ci- o) straight chain or
  • aryl employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an aromatic carbocyclic moiety of up to 20 carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. Any suitable ring position of the aryl moiety may be covalently linked to the defined chemical structure.
  • aryl moieties include, but are not limited to, chemical groups such as phenyl, 1-naphthyl, 2- naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl.
  • arylalkyl groups have 7 to 26 carbon atoms.
  • arylalkyl moieties include, but are not limited to, chemical groups such as benzyl, 1- phenylethyl, 2-phenylethyl, diphenylmethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl, and homologs, isomers, and the like.
  • heterocyclic ring system is defined as being 4 to 14 carbon atoms, he rings may contain from one to four hetero atoms selected from nitrogen (N), oxygen (O), or sulfur (S), wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally substituted or quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.
  • the ring may be saturated, unsaturated, or partially unsaturated.
  • Heterocyclic rings may comprise a single ring or a multiple ring system comprising up to three rings.
  • heteroaryl employed alone or in combination with other terms, is defined herein as, unless otherwise stated, an aromatic heterocyclic ring system, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently.
  • the rings may contain from one to four hetero atoms selected from nitrogen (N), oxygen (O), or sulfur (S), wherein the nitrogen or sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally substituted or quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.
  • heteroaryl moieties include, but are not limited to, heterocycles such as furan, thiophene, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, imidazole, N-methylimidazole, oxazole, isoxazole, thiazole, isothiazole, lH-tetrazole, 1-methyltetrazole, 1,3,4-oxadiazole, lH-l,2,4-triazole, 1- methyl-l,2,4-triazole, 1,3,4-triazole, l-methyl-l,3,4-triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzoxazole, benzisoxazole, benzothiazole, benzofuran, benzothiophene, thianthrene, dibenzo[b,d]furan, dibenzo[b,d]thiophene, benzimid
  • heteroarylalkyl employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a heteroaryl group, as herein before defined, suitably substituted on any open ring position with an alkyl moiety, wherein the alkyl chain is either a (Ci-C ⁇ ) straight or (C 2 -C 7 ) branched-chain saturated hydrocarbon moiety.
  • heteroarylalkyl moieties include, but are not limited to, chemical groups such as furanylmethyl, thienylethyl, indolylmethyl, and the like.
  • Heteroaryl chemical groups, as herein before defined also include saturated or partially saturated heterocyclic rings.
  • saturated or partially saturated heteroaryl moieties include, but are not limited to, chemical groups such as azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl,
  • acyl moieties include, but are not limited to, chemical groups such as acetyl, propionyl, butyryl, 3,3- dimethylbutyryl, trifluoroacetyl, pivaloyl, hexanoyl, hexenoyl, decanoyl, benzoyl, nicotinyl, isonicotinyl, and homologs, isomers, and the like.
  • hydroxyalkyl employed alone or in combination with other terms, is defined herein as, unless otherwise stated, a (C o) straight chain hydrocarbon, terminally substituted with a hydroxyl group.
  • alkoxy employed alone or in combination with other terms, is defined herein as, unless otherwise stated, either a (Ci-Cio) straight chain or (C 3 -C 10 ) branched-chain hydrocarbon covalently bonded to an oxygen atom.
  • alkoxy moieties include, but are not limited to, chemical groups such as methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy, decanoxy, and homologs, isomers, and the like.
  • the alkoxy group has 1-6 carbon atoms.
  • aryloxy or “heteroaryloxy”, employed alone or in combination with other terms, or unless otherwise stated, are aryl or heteroaryl groups, as herein before defined, which are further covalently bonded to an oxygen atom.
  • aryloxy, or heteroaryloxy moieties include, but are not limited to, chemical groups such as C 6 H 5 O-, 4-pyridyl-O-, and homologs, isomers, and the like.
  • alkoxycarbonyl moieties include, but are not limited to, chemical groups such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, decanoxycarbonyl, and homologs, isomers, and the like.
  • alkylthio employed alone or in combination with other terms, is defined herein as, unless otherwise stated, either a (Ci-Cio) straight chain or
  • alkylthio moieties include, but are not limited to, chemical groups such as methylthio, ethylthio, isopropylthio, .sec-butylthio, tert-butylthio, decanylthio, and homologs, isomers, and the like. It is preferred that straight chain alkylthio moieties have 1-6 carbon atoms, and branched alkylthio moieties have 3-8 carbon atoms.
  • arylthio or “heteroarylthio”, employed alone or in combination with other terms, or unless otherwise stated, are aryl or heteroaryl groups, as herein before defined, which are further covalently bonded to a sulfur atom.
  • arylthio or heteroarylthio moieties include, but are not limited to, chemical groups such as C 6 H 5 S-, 4-pyridyl-S-, and homologs, isomers, and the like.
  • alkoxyalkyl or “alkylthioalkyl”, employed alone or in combination with other terms, are an alkoxy or alkylthio group, as herein before defined, which is further covalently bonded to an unsubstituted (Q- o) straight chain or unsubstituted (C 2 -C 10 ) branched-chain hydrocarbon.
  • alkoxyalkyl or alkylthioalkyl moieties include, but are not limited to, chemical groups such as , methoxymethyl, methylthioethyl, ethylthioethyl, isopropylthiomethyl, sec-butylthioethyl, -CH 2 CH(CH 3 )OCH 2 CH 3 , and homologs, isomers, and the like. It is preferred that straight chain alkoxyalkyl or alkylthioalkyl moieties have 1-6 carbon atoms, and branched alkoxyalkyl or alkylthioalkyl moieties have 3-8 carbon atoms.
  • aryloxyalkyl employed alone or in combination with other terms, or unless otherwise stated, are aryloxy, heteroaryloxy, arylthio, or heteroarylthio groups, as herein before defined, which are further covalently bonded to an unsubstituted ( - o) straight chain or unsubstituted (C 2 -C 10 ) branched-chain hydrocarbon.
  • aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, or heteroarylthioalkyl moieties include, but are not limited to, chemical groups such as C 6 H 5 OCH -, C 6 HsOCH(CH 3 )-, 4-pyridyl-O- CH 2 CH 2 -, C 6 H 5 SCH 2 -, C 6 H 5 SCH(CH 3 )-, 4-pyridyl-S -CH 2 CH 2 -, and homologs, isomers, and the like.
  • straight chain aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, or heteroarylthioalkyl moieties have 1-6 carbon atoms, and branched aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, or heteroarylthioalkyl moieties have 3-8 carbon atoms.
  • alkylamino employed alone or in combination with other terms, or unless otherwise stated, is a moiety with one alkyl group, wherein the alkyl group is an unsubstituted ( -C ⁇ ) straight chain hereunto before defined alkyl group or an unsubstituted (C 3 -C 8 ) hereunto before defined cycloalkyl group.
  • alkylamino moieties include, but are not limited to, chemical groups such as -NH(CH 3 ), - NH(CH 2 CH 3 ), -NH-cyclopentyl, and homologs, and the like.
  • dialkylamino employed alone or in combination with other terms, or unless otherwise stated, is a moiety with two independent alkyl groups, wherein the alkyl groups are unsubstituted ( -C ⁇ ) straight chain hereunto before defined alkyl groups or unsubstituted (C 3 -C 8 ) hereunto before defined cycloalkyl groups. Two groups may be linked to form an unsubstituted (CrC 6 ) -alkylene- group.
  • dialkylamino moieties include, but are not limited to, chemical groups such as -N(CH 3 ) 2 ,
  • alkylaminoalkyl employed alone or in combination with other terms, or unless otherwise stated, is an alkylamino moiety, as herein before defined, which is further covalently bonded to a straight chain alkyl group of 1-6 carbon atoms.
  • alkylaminoalkyl moieties include, but are not limited to, chemical groups such as -CH 2 NH(CH 3 ), -CH 2 CH 2 NH(CH 2 CH 3 ), -CH 2 CH 2 CH 2 NH(CH 2 CH 3 ), and homologs, and the like.
  • dialkylaminoalkyl employed alone or in combination with other terms, or unless otherwise stated, is a dialkylamino moiety, as herein before defined, which is further covalently bonded to a straight chain alkyl group of 1-6 carbon atoms.
  • dialkylaminoalkyl moieties include, but are not limited to, chemical groups such as -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 2 CH 3 ) 2 , -CH 2 CH 2 CH 2 NCH 3 (CH 2 CH 3 ), and homologs, and the like.
  • alkylaminocarbonyl or "dialkylaminocarbonyl”, employed alone, or unless otherwise stated, are alkylamino or dialkylamino moieties, as herein before defined, which are further bonded to a carbonyl group.
  • alkylaminocarbonyl or dialkylaminocarbonyl moieties include, but are not limited to, chemical groups such as -C(O)NH(CH 3 ), -C(O)N(CH 2 CH 3 ) 2 , -C(O)NCH 3 (CH 2 CH 3 ), and homologs, and the like.
  • Each of the above terms includes unsubstituted, monosubstituted, and polysubstituted forms of the indicated radical or moiety. Representative substituents for each type of moiety are provided below.
  • aryl or heteroaryl moieties employed alone or in combination with other terms, may be optionally mono-, di- or tri-substituted with substituents selected from the group consisting of -R', -OR', -SR', -C(O)R', -CO 2 R ⁇ -alkoxyalkyl, alkoxyalkyloxy, cyano, halogen, nitro, trifluoromethyl, trifluoromethoxy, -NR'R", alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, -S(O)R', -S(O) 2 R', -SO 3 R', - S(O) 2 NR'R", -CO2R', -C(O)NR'R", -OC(O)NR'R
  • a substantial absence of creatine kinease stimulation means the compound has an IC 50 value greater than 1 ⁇ mol with an efficacy of less than 30% compared to 17- ⁇ -estradiol.
  • the phrase "a substantial absence of uterotropic activity” means that no statistically significant uterine wet weight gain is observed.
  • a pro-drug is defined as a compound which is convertible by in vivo enzymatic or non-enzymatic metabolism (e.g. hydrolysis) to a compound of the invention.
  • the compounds of the present invention may contain an asymmetric atom, and some of the compounds may contain one or more asymmetric atoms or centers, which may thus give rise to optical isomers (enantiomers) and diastereomers. While shown without respect to the stereochemistry in Formula (I) or (JJ), the present invention includes such optical isomers (enantiomers) and diastereomers (geometric isomers); as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Optical isomers may be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diasteromeric salt formation, kinetic resolution, and asymmetric synthesis. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof, which may be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin- layer chromatography, and high-performance liquid chromatography. [0086]
  • the compounds of the present invention may contain isotopes of atoms for diagnostic, therapeutic, or metabolic purposes. Such isotopes may or may not be radioactive.
  • Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri- lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine.
  • Internal salts may furthermore be formed.
  • the term "providing,” with respect to providing a compound or substance covered by this invention means either directly administering such a compound or substance, or administering a pro-drug, derivative, or analog which will form the effective amount of the compound or substance within the body.
  • This invention also covers providing the compounds of this invention to treat the disease states disclosed herein that the compounds are useful for treating.
  • the terms “therapeutically effective amount” and “therapeutically effective dose” as applied to the active ingredient refers to the amount of the component in the composition or administered to the host that results in an increase in the therapeutic index of the host.
  • the "therapeutic index” can be defined for purposes herein in terms of efficacy, i.e., extent of reduction or inhibition of inflammation. Suitable doses of the active ingredient can be determined using well-known methods, a variety of which are known and readily available in the pharmaceutical sciences, including, for example, measurement of markers associated with the disorder, the biological effects of TNF- ⁇ , and decreased symptomatology. [0092] It is understood that the effective dosage of the active compounds of this invention may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated.
  • compounds of this invention will be administered at an oral daily dosage of from about 0.05 mg to about 30 mg per kilogram of body weight, preferably administered in divided doses two to six times per day, or in a sustained release form.
  • the total daily dosage is from about 3.5 mg to about 2100 mg, preferably from about 3.5 to about 5 mg. In the case of a 70 kg human adult, the total daily dose will generally be from about 3.5 mg to about 2100 mg and may be adjusted to provide the optimal therapeutic result.
  • the compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
  • the pharmaceutical carrier may be solid or liquid.
  • a solid carrier can include one or more substances which may also act as flavoring agents, sweetening agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • Solid dosage unit forms or compositions such as tablets, troches, pills, capsules, powders, and the like, may contain a solid carrier binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin.
  • a dosage unit form When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit.
  • Liquid carriers are used in preparing liquid dosage forms such as solutions, suspensions, dispersions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution); alcohols, including monohydric alcohols such as ethanol and polyhydric alcohols such as glycols and their derivatives; lethicins, and oils such as fractionated coconut oil and arachis oil.
  • the liquid carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • a liquid pharmaceutical composition such as a syrup or elixir may contain, in addition to one or more liquid carriers and the active ingredients, a sweetening agent such as sucrose, preservatives such as methyl and propyl parabens, a pharmaceutically acceptable dye or coloring agent, or a flavoring agent such as cherry or orange flavoring.
  • a sweetening agent such as sucrose
  • preservatives such as methyl and propyl parabens
  • a pharmaceutically acceptable dye or coloring agent such as cherry or orange flavoring.
  • a flavoring agent such as cherry or orange flavoring.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be administered intraocularly or parenterally, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy injectability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing a liquid carrier, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the liquid carrier may be suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Nuclear magnetic resonance data is reported as ⁇ in parts per million (ppm) downfield from the standard, tetramethylsilane; along with the solvent, nucleus, and field strength parameters.
  • the spin-spin homonuclear coupling constants are reported as J values in hertz; and the multiplicities are reported as a: s, singlet; d, doublet; t, triplet; q, quartet; quintet; or br, broadened. Italicized elements or groups are those responsible for the chemical shifts.
  • the yields given below are for informational purposes and may vary according to experimental conditions or individual techniques.
  • Step A A solution of (2-fluoro-3-substituted-phenyl)(4-methoxy-2-substituted- phenyl)methanone (1 equivalent), hydrazine hydrate (10 eq.) and DMAP (1 eq.) in pyridine was heated at 100°C for 24-48 hrs. The cooled reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na 2 SO ).
  • Step B A solution of the intermediate 3-(4-methoxyphenyl)-7-substituted-l- lH-indazole (1 eq.) in DMF was added in one portion sodium hydride (1 eq., 60 % in oil). After the gas evolution ceased, the alkyl halide was added and the reaction was stirred at ambient to 50 °C overnight. The cool reaction mixture was partitioned with EtO Ac and 1 N HCl. The organic phase was washed with brine and dried (Na 2 SO 4 ).
  • Step C A solution of 3-(4-methoxyphenyl)-7-substituted-(l or 2-substituted)- (1 ⁇ or 2 ⁇ )-indazole (1 eq.) in CH 2 C1 2 containing excess equivalents of cyclohexene at - 78 °C was treated with boron tribromide (4 eq.) and slowly allowed to warm to ambient temperature. The reaction was quenched by dropwise edition of CH 3 OH to the cooled reaction. The solvent was removed in vacuo and the residue partitioned with EtO Ac and 1 N HCl. The organic phase was washed with brine and dried (Na 2 SO ). Removal of the solvent in vacuo afforded the crude product. Pure product was obtained by crystallization or flash chromatography through water deactivated silica gel. Note: HPLC retention times were obtained using the following conditions:
  • Solvent System A: 95% lOmM NH4OAc/5% acetonitrile, B: 95% acetonitrile 5% lO mM NE OAc,
  • step B Prepared according to Example 1, step B from 3-(2,4-methoxyphenyl)-7- trifluoromethyl- IH-indazole 0.52 g, 1.6 mmol), sodium hydride (60% in oil, 0.065 g, 1.6 mmol) and allyl bromide (0.138 mL, 1.6 mmol) to give the title compound (0.26 g) as a white solid.
  • Step 2 4-[l-allyl-7-(trifluoromethyl)-l J H-indazol-3-yl]benzene-l,3-diol
  • step C from l-allyl-3-(2,4- dimethoxyphenyl)-7-(trifluoromethyl)-lH-indazole (0.065 g, 0.18 mmol), boron tribromide (0.136 mL, 1.4 mmol) and 1.0 mL of cyclohexene to give the product (0.066 g) as a white solid, mp 114-115 °C;
  • Step 1 N-(4'-FIuorobiphenyl-2-yl)acetamide
  • 2-iodoaniline 32.6 g, 149 mmol
  • 4- fluorophenylboronic acid 20.8 g, 149 mmol
  • tetrahydrofuran 1.5 L
  • [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (JJ) complex dichloromethane (2.20 g, 2.69 mmol) and a 5 ⁇ sodium hydroxide solution
  • the white solid (40.0 g) was suspended in toluene (350 mL) and treated with NN-dimethylformamide (6.0 mL) and thionyl chloride (22.0 mL, 298 mmol), and the resulting mixture was heated at 100 °C for twelve hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and the resulting oil solidified upon standing. The solidified oil was dissolved in ethyl acetate-hexane (1:4), filtered through a short column of silica gel, and the solvent removed in vacuo to yield the sulfonyl chloride as a white solid (34.8 g, 61%), m.p. 74-76 °C;
  • Step 4 Ethyl 4-[(8-fluoro-6-methylphenanthridin-5(6H)-yl)sulfonyl]phenyl carbonate [0110] A stirred solution of 8-fluoro-6-methylphenanthridine (8.00 g, 37.9 mmol) in tetrahydrofuran (152 mL) was treated with freshly crushed sodium borohydride (7.16 g, 189 mmol). Trifluoroacetic acid (11.7 mL, 152 mmol) was added drop-wise at a rate suitable to control gas evolution and exothermic reaction conditions.
  • the heterogeneous reaction mixture was stirred until the reaction returned to room temperature; then was re-heated to reflux for 14 hours. After cooling to room temperature, a saturated, aqueous, sodium bicarbonate solution (250 mL) was slowly added. The mixture was filtered through a plug of glass wool, and extracted with diethyl ether (4 x 75 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the dihydrophenanthridine as a light-brown paste.
  • the brown oil was triturated with hexane (25 mL) to afford a light- brown solid.
  • the light-brown solid was purified by crystallization from a mixture of ethyl acetate-hexane to yield a first crop of the desired product.
  • the mother liquor was concentrated in vacuo, and purified by filtration through a plug of silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop.
  • the combined crops afforded the title compound as a white, crystalline solid (15.2 g, 91%), m.p. 136-138 °C; MS [(+ESI), m/z]: 442 [M+H] + ;
  • Step 5 4-[(8-Fluoro-6-methylphenanthridin-5(6 T)-yl)s ⁇ lfonyl]phenol [0111]
  • a solution of ethyl 4-[(8-fluoro-6-methylphenanthridin-5(6H)- yl)sulfonyl]phenyl carbonate (0.45 g, 1.02 mmol) in methanol (5.0 mL) was treated with a 1 N sodium hydroxide (5.1 mL) solution, and heated at 75 °C for 14 hours. After cooling to room temperature, the methanol was evaporated in vacuo.
  • the resulting aqueous mixture was acidified with a 1 N hydrochloric acid solution, diluted with a saturated, aqueous, sodium chloride solution (100 mL), and extracted with dichloromethane (5 x 15 mL).
  • the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a white solid.
  • the solid was purified by filtration through a short column of silica gel, eluting with ethyl acetate, to yield the title compound as a homogeneous, white, crystalline, solid (0.34 g, 89%), m.p. 188 °C;
  • the acid chloride is dissolved in dichloromethane (lOmL) this is added to a solution of l-(3,5-dimethoxy-phenyl)-piperazine (305mg, 1.36 mmol) and a crystal of DMAP in dichloromethane (15mL). This is followed by the dropwise addition of TEA (0.6mL, 4.27 mmol). The reaction is stirred overnight. The reaction mixture is diluted with dichloromethane (50mL), washed with aqueous HCl (lOmL 0.5N) then saturated NaHCO 3 (lOmL) and brine (lOmL). The sample is dried over NaSO 4 , filtered and concentrated in vacuo.
  • Example 7 Lewis Rat Studies [0115] Forty-two, male, 8-10 weeks old, Lewis rats were housed according to standard facility operating procedures. They received a standard regimen of food and water ad libitum. Each animal was identified by a cage card indicating the project group and animal number. Each rat number was marked by indelible ink marker on the tail. Freund's Adjuvant-Complete (Sigma Immuno Chemicals, St. Louis, MO) was used to induce arthritis. Each mL contained 1 mg Mycobacterium tuberculosis heat killed and dried, 0.85 mL mineral oil and 0.15 mL mannide monooleate Lot No. 084H8800.
  • the rats were injected intradermally with 0.1 mL of Freund' s Adjuvant- Complete at the base of the tail.
  • the animals were randomized to seven groups, each group containing six rats.
  • the groups received vehicle (2% Tween 80, 0.5% methylcellulose), the compound of Example 3 at l.Omg/kg, 0.3 mg/kg, O.lmg/kg or the compound of Example 6 at l.Omg kg, 0.3 mg/kg, O.lmg/kg orally each day. All rats began treatment on Day 8 after adjuvant injection.
  • the degree of arthritis severity was monitored daily in terms of the following disease indices: Hindpaw erythema, hindpaw swelling, tenderness of the joints, and movements and posture.
  • Fibroplasia a. No change 0 b. Fibroplasia present under lining cells. 1 c. small areas of areolar tissue replaced by fibrous tissue. 2 d. Replacement of areolar tissue by fibrous tissue. 3

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Abstract

L'invention concerne une méthode permettant de traiter l'arthrite rhumatoïde, qui consiste à diagnostiquer qu'une personne nécessite un traitement contre l'arthrite rhumatoïde, et à administrer une quantité thérapeutiquement efficace d'un ligand qui module le facteur de transcription NF-kB par interaction avec le récepteur d'oestrogène ER-?, le récepteur d'oestrogène ER-? ou les deux avec l'absence substantielle de stimulation de la créatine kinase. Dans certains modes de réalisation, l'administration s'effectue en l'absence substantielle d'activité utérotrope.
PCT/US2003/030339 2003-09-24 2003-09-24 Methode permettant de traiter l'arthrite rhumatoide a l'aide d'inhibiteurs de nf-kb WO2005039583A1 (fr)

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AU2003278955A AU2003278955A1 (en) 2003-09-24 2003-09-24 METHOD OF TREATING RHEUMATOID ARTHRITIS USING NF-kB INHIBITORS

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006526630A (ja) * 2003-04-30 2006-11-24 ワイス ２−シアノプロパン酸アミドおよびエステル誘導体ならびにそれらの使用法。
US7378427B2 (en) * 2004-06-18 2008-05-27 Wyeth Processes for preparing 6-alkyl-5-arylsulfonyl-dihydrophenanthridines
WO2009004104A1 (fr) * 2007-06-29 2009-01-08 Fundación Marqués De Valdecilla Utilisation d'un polymorphisme au niveau du gène card8 pour le pronostic de la polyarthrite rhumatoïde

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WO2002010137A2 (fr) * 2000-07-31 2002-02-07 Signal Pharmaceuticals, Inc. Derives d'indazole utilises comme inhibiteurs de jnk et compositions et methodes associees a ceux-ci
WO2002011765A1 (fr) * 2000-08-10 2002-02-14 Schering Aktiengesellschaft PREPARATIONS COMBINEES CONSTITUEES D'UN OESTROGENE SELECTIF DE L'ERβ ET D'UN SERM OU D'UN ANTI-OESTROGENE
US20030207927A1 (en) * 2001-12-13 2003-11-06 Wyeth Phenyl benzisoxazoles as estrogenic agents

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WO2002010137A2 (fr) * 2000-07-31 2002-02-07 Signal Pharmaceuticals, Inc. Derives d'indazole utilises comme inhibiteurs de jnk et compositions et methodes associees a ceux-ci
WO2002011765A1 (fr) * 2000-08-10 2002-02-14 Schering Aktiengesellschaft PREPARATIONS COMBINEES CONSTITUEES D'UN OESTROGENE SELECTIF DE L'ERβ ET D'UN SERM OU D'UN ANTI-OESTROGENE
US20030207927A1 (en) * 2001-12-13 2003-11-06 Wyeth Phenyl benzisoxazoles as estrogenic agents

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006526630A (ja) * 2003-04-30 2006-11-24 ワイス ２−シアノプロパン酸アミドおよびエステル誘導体ならびにそれらの使用法。
US7378427B2 (en) * 2004-06-18 2008-05-27 Wyeth Processes for preparing 6-alkyl-5-arylsulfonyl-dihydrophenanthridines
WO2009004104A1 (fr) * 2007-06-29 2009-01-08 Fundación Marqués De Valdecilla Utilisation d'un polymorphisme au niveau du gène card8 pour le pronostic de la polyarthrite rhumatoïde

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