WO2010138421A1 - Amides inverses d'hexahydrocyclopentyl[f]indazole et leurs dérivés comme modulateurs sélectifs du récepteur des glucocorticoïdes - Google Patents

Amides inverses d'hexahydrocyclopentyl[f]indazole et leurs dérivés comme modulateurs sélectifs du récepteur des glucocorticoïdes Download PDF

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Publication number
WO2010138421A1
WO2010138421A1 PCT/US2010/035793 US2010035793W WO2010138421A1 WO 2010138421 A1 WO2010138421 A1 WO 2010138421A1 US 2010035793 W US2010035793 W US 2010035793W WO 2010138421 A1 WO2010138421 A1 WO 2010138421A1
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Prior art keywords
methyl
hexahydrocyclopenta
indazol
fluorophenyl
phenylethyl
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PCT/US2010/035793
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English (en)
Inventor
Helen J. Mitchell
Danielle M. Hurzy
Robert S. Meissner
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Merck Sharp & Dohme Corp.
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Publication of WO2010138421A1 publication Critical patent/WO2010138421A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Intracellular receptors are a class of structurally related proteins involved in the regulation of gene expression.
  • the steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of endogenous steroids such as estradiol, progesterone, and Cortisol.
  • Endogenous steroids such as estradiol, progesterone, and Cortisol.
  • Man-made ligands to these receptors play an important role in human health and, of these
  • the glucocorticoid receptor has an essential role in regulating human physiology and immune response.
  • Steroids that interact with the glucocorticoid receptor have been shown to be potent anti-inflammatory agents.
  • the present invention is directed to a novel class of compounds that are selective glucocorticoid receptor modulators that have potent anti-inflammatory and immunosuppressive activity and possess advantages over steroidal glucocorticoid ligands with
  • the present invention encompasses compounds of Formula I:
  • the present invention encompasses a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof: MRL-BRE-00008
  • X is H or halogen
  • Ci_6alkyl optionally substituted with one to three halogens or -OR7,
  • R3 is selected from the group consisting of:
  • each of items (b) to (e), items (p) to (q), the aryl portions of items (f) to (h), and the HET portions of items (i) to (k), and the alkyl portions of items (1) and (o) above is optionally substituted with one to three substituents independently selected from the group consisting of: 5 (i) halogen,
  • Ci_6alkyl (ii) Ci_6alkyl, (iii) C3-6cycloalkyl, (iv) -Cl-6alkyl-OR7, (v) -ORV,
  • each of Rl and R2 is independently selected from the group consisting of:
  • each of R4, R5, R6, and R7 is independently selected from the group consisting of:
  • each of Ra and Rb is independently selected from the group consisting of: 10 (1) hydrogen,
  • each of items (2) to (5), the alkyl portion of item (6), the aryl portion of item (7), the HET portion of item (8), and items (10) to (11) is optionally substituted with one to three substituents selected from the group consisting of:
  • X is hydrogen or halogen.
  • X is halogen.
  • X is selected from the group consisting of fluoro, chloro, bromo, and iodo.
  • X is fluoro.
  • Y is carbon or nitrogen.
  • X is hydrogen and Y is nitrogen. In yet another embodiment, X is fluoro and Y is carbon.
  • Z is selected from the group consisting of:
  • Z is C-R , wherein R3 is selected from the group consisting of:
  • each of items (b) to (e), items (p) to (q), the aryl portions of items (f) to (h), and the HET portions of items (i) to (k), and the alkyl portions of items (1) and (o) above is optionally substituted with one to three substituents independently selected from the group consisting of: 5 (i) halogen,
  • R3 is selected from the group consisting of:
  • each of items (a) to (c), items (k) to (1), the aryl portions of (d) to (e), and the 30 HET portions of (f) to (g) above is optionally substituted with one to three substituents independently selected from the group consisting of: (i) halogen, ( ⁇ ) Cl-6alkyl, (iii) C3-6cycloalkyl, 35 (iv) -ORV, MRL-BRE-00008
  • R3 is selected from the group consisting 5 of:
  • each of items (a) to (b), items (g) to (h), the aryl portion of (c), and the HET 15 portion of (d) above is optionally substituted with one to three substituents independently selected from the group consisting of:
  • R3 is selected from the group consisting of:
  • Ci_6alkyl (i ⁇ ) Cl-6alkyl-OR7, (iv) -ORV, (v) -NRaRb,
  • HET optionally substituted with one to three halogens; and wherein each occurrence of HET is independently selected from the group consisting of: pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, isooxazole, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine, benzimidazolyl, 15 benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, iso
  • each of Rl and R2 is independently selected from the group consisting of:
  • each of R 1 and R2 is independently selected from the group consisting of:
  • Rl is hydrogen
  • R2 is selected from the group consisting of:
  • each of R4, R5, R6 ? and R7 is 20 independently selected from the group consisting of:
  • each of R4, R5, R6 ? and R7 is independently hydrogen, Cl-6alkyl or Cl-6cycloalkyl.
  • each of R4, R5, and R7 is hydrogen; and R6 is methyl or cyclopropyl.
  • each of R a and Rb is independently selected from the group consisting of:
  • each of items (2) to (5), the alkyl portion of item (6), the aryl portion of item (7), the HET portion of item (8), and items (10) to (11) is optionally substituted with one to three 10 substituents selected from the group consisting of:
  • each of R a and Rb is independently selected 20 from the group consisting of:
  • each of items (2) to (4), the alkyl portion of item (5), the phenyl portion of item (6), the HET portion of item (7), and items (9) to (10) is optionally substituted with one to three substituents selected from the group consisting of:
  • each of R a and Rb is independently selected from the group consisting of:
  • each occurrence of aryl is independently selected from phenyl and naphthyl. In another embodiment, aryl is phenyl.
  • HET is a 5- or 6-membered aromatic 30 or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N.
  • HET is a 9- or 10-membered aromatic or partially aromatic bicyclic ring containing 1- 3 heteroatoms selected from O, S, and N.
  • each occurrence of HET is independently selected from the group consisting of: pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, 35 oxazole, isooxazole, benzo furan, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, MRL-BRE-00008
  • each occurrence of HET is independently selected from the group consisting of: pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole,
  • the instant invention encompasses a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:
  • X is H or halogen
  • Y is carbon or nitrogen, provided that when Y is nitrogen, then X is hydrogen; each of Rl and R2 is independently selected from the group consisting of:
  • R3 is selected from the group consisting of:
  • each of R a and Rb is independently selected from the group consisting of: 5 (1) hydrogen,
  • each of items (2) to (4), the alkyl portion of item (5), the phenyl portion of item (6), the HET portion of item (7), and items (9) to (10) is optionally substituted with one to three substituents selected from the group consisting of:
  • the compound of Ia has chemical structure of Formula Ib: MRL-BRE-00008
  • X is fluoro and Y is carbon. In another embodiment of compounds of Formula Ia or Ib, X is hydrogen and Y is nitrogen.
  • Rl is hydrogen
  • R2 is selected from the group consisting of:
  • each of items (1) to (3), items (8) to (9), the phenyl portions of items (4) to (5), and the HET portions of items (6) to (7) above is optionally substituted with one to three substituents independently selected from the group consisting of:
  • R3 is selected from the group consisting of: 25 (a) Cl- 6 alkyl,
  • each of items (a) to (b), items (g) to (h), the phenyl portion of (c), and the 5 HET portion of (d) above is optionally substituted with one to three substituents independently selected from the group consisting of: (i) halogen, ( ⁇ ) Cl-6alkyl, (i ⁇ ) Cl-6alkyl-OR7, 10 (iv) -ORV,
  • phenyl optionally substituted with one to three halogens
  • HET optionally substituted with one to three halogens
  • each occurrence of HET is independently selected from the group consisting of: pyridine, 15 pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, isooxazole, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine, benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, iso
  • each of R a and Rb is 30 independently selected from the group consisting of:
  • each of items (2) to (4), the phenyl portion of item (5), the HET portion of item (6), and items (8) to (9) is optionally substituted with one to three substituents selected from the group consisting of:
  • each occurrence of HET is
  • azetidinyl 1 ,4-dioxanyl, furanyl, hexahydroazepinyl, isooxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thiazolyl, thiophenyl, thiazolyl, and thienyl.
  • the invention encompasses a pharmaceutical composition
  • Another embodiment of the invention encompasses a method for treating a glucocorticoid receptor mediated disease or condition in a mammalian patient in need of such treatment comprising administering to the patient a compound of Formula I, Ia or Ib in an amount
  • the glucocorticoid receptor mediated disease or condition is selected from the group consisting of: tissue rejection, leukemias, lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of
  • myeloid cell lines immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, obesity, metabolic syndrome, inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa,
  • uveitis hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, cirrhosis, inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, 5 pemphigus vulgaris, buflous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type I reactive leprosy, capillar
  • Another embodiment of the invention encompasses a method of selectively modulating the activation, repression, agonism and antagonism effects of the glucocorticoid receptor 15 in a mammal comprising administering to the mammal a compound of Formula I, Ia, or Ib in an amount that is effective to modulate the glucocorticoid receptor.
  • halogen or halo includes F, Cl, Br, and I.
  • alkyl means linear or branched structures and combinations thereof, 20 having the indicated number of carbon atoms.
  • Cl-6alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkoxy means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms.
  • Cl-6alkoxy for example, includes
  • alkenyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond.
  • C2-6 a lkenyl for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.
  • alkynyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond.
  • C3- galkynyl for example, includes, propenyl, 1-methylethenyl, butenyl and the like.
  • cycloalkyl means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, the indicated number of carbon atoms. Examples of cycloalkyl MRL-BRE-00008
  • groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo[4.4.0]decyl, and the like.
  • aryl is defined as a mono- or bi-cyclic aromatic ring system and includes, for example, phenyl, naphthyl, and the like. 5
  • optionally substituted means "unsubstituted or substituted," and therefore, the generic structural formulas described herein encompass compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent. Each variable is independently defined each time it occurs within the generic structural formula definitions.
  • HET is defined as a 5- to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, containing 1-4 heteroatoms selected from O, S and N, and optionally substituted with 1-2 oxo groups.
  • HET is a 5- or 6-membered aromatic or non-aromatic monocyclic ring containing 1-3 heteroatoms selected from O, S and N, for example, pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole, oxazole, isooxazole and the like, or
  • HET is a 9- or 10-membered aromatic or partially aromatic bicyclic ring containing 1-3 heteroatoms selected from O, S, and N, for example, benzofuran, benzothiophene, indole, pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine and the like.
  • "HET” also includes the following: benzimidazolyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl,
  • dihydrobenzoxazolyl dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl.
  • each reference to a group is independent of all other references to the same group when referred to in the Specification.
  • Rl and R2 are HET
  • the definitions of HET are independent of each other and Rl and R2 may be different HET groups, for example furan and pyridine.
  • treating encompasses not only treating a patient to relieve the patient of
  • asymptomatic patient to prevent the onset of the disease or condition or preventing, slowing or reversing the progression of the disease or condition.
  • amount effective for treating is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, 5 veterinarian, medical doctor or other clinician.
  • the term also encompasses the amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers.
  • the present invention includes all stereoisomers of Formula I, Ia, and Ib and pharmaceutically acceptable salts thereof.
  • Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general Formula I, Ia, or Ib may be obtained by stereospecific
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • pharmaceutically acceptable nontoxic bases including inorganic bases and organic bases.
  • Salts derived from such inorganic bases 5 include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources.
  • Pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources.
  • salts include, for example, arginine, betaine, caffeine, choline, N 5 N - dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine,
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids.
  • Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic,
  • the present invention includes within its scope solvates of compounds of Formula I 5
  • solvate refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula Ia) or a pharmaceutically acceptable salt thereof and a solvent that does not interfere with the biological activity of the solute.
  • solvents include, but are not limited to water, ethanol, and acetic acid. When the solvent is water, the solvate is known as
  • hydrates include, but are not limited to, hemi-, mono, sesqui-, di- and trihydrates.
  • the present invention includes within its scope the use prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds of this 35 invention which are readily convertible in vivo into the required compound.
  • administering shall encompass the treatment of the various conditions described with a compound of Formula I, Ia, or Ib, or with a compound which may not be a compound of Formula I, Ia, or Ib, but which converts to a compound of Formula I, Ia, or Ib in vivo after administration to the patient.
  • Conventional procedures for the selection and 5 preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.
  • compositions of the present invention comprise a compound of Formula I, Ia, or Ib as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable
  • organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,
  • basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morph
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,
  • glutamic, hydrobromic, hydrochloric, isethionic lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • references to the compounds of Formula I, Ia, or Ib are meant to also include the pharmaceutically acceptable salts.
  • prophylactic or therapeutic dose of a compound of Formula I, Ia, or Ib will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a
  • the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain from about 1 mg to about 2 g of an active
  • 10 ingredient typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • the compound of Formula I, Ia, or Ib may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable
  • parenteral includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc.
  • the compound of the invention is effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding
  • agents for example starch, gelatin or acacia
  • lubricating agents for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique MRL-BRE-00008
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium 5 phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water- miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium 5 phosphate or kaolin
  • water- miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents
  • compositions may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
  • compositions of the invention may also be in the form of an oil- in- water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be
  • fatty acids and hexitol anhydrides for example sorbitan monooleate
  • condensation products of the said partial esters with ethylene oxide for example polyoxy ethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, 5 propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents water, Ringer's solution and isotonic sodium chloride solution.
  • Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at
  • Topical formulations may generally be
  • 25 comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • the compounds of Formula I, Ia, or Ib to selectively modulate glucocorticoid receptors makes them useful for treating, preventing or reversing the progression of a variety of inflammatory and autoimmune diseases and conditions.
  • the compounds of the formula I, Ia, or Ib to selectively modulate glucocorticoid receptors makes them useful for treating, preventing or reversing the progression of a variety of inflammatory and autoimmune diseases and conditions.
  • present invention are useful to treat, prevent or ameliorate the following diseases or conditions: inflammation, tissue rejection, auto-immunity, various malianancies, such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, stroke and
  • adrenal insufficiency secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, obesity and metabolic syndrome.
  • the compounds of the present invention are also useful for treating, preventing or reversing the progression of disease states involving systemic inflammation such as inflammatory 5 bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis, juvenile rheumatoid arthritis, uveitis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstructive pulmonary disease, asthma, tendonitis, bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, and cirrhosis.
  • systemic inflammation such as inflammatory 5 bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheuma
  • the compounds of the present invention are useful for treating, preventing or reversing the progression of a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, buflous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory
  • vasculitis 15 vasculitis, sarcoidosis, Sweet's disease, type I reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma.
  • the compounds of the present invention are also useful in treating, preventing or reversing the progression of disease states associated with Human Immunodeficiency Virus (HIV),
  • 20 cell apoptosis, and cancer including, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, IIL-I expression, natural killer cell development, lymphocytic leukemia, and treatment of retinitis pigmentosa.
  • Cogitive and behavioral processes are also susceptible to glucocorticoid therapy where antagonists would potentially be useful in the treatment of processes such as cognitive performance, memory and learning
  • the invention also encompasses a method for treating a glucocorticoid receptor mediated disease comprising concomitantly administering to a patient in need of such treatment a compound of Formula I, Ia, or Ib and one or additional more agents.
  • a method for treating a glucocorticoid receptor mediated disease comprising concomitantly administering to a patient in need of such treatment a compound of Formula I, Ia, or Ib and one or additional more agents.
  • the compounds of Formula I may be combined with one or more agents selected from the group consisting of: O-agonists (e.g., salmeterol), theophylline, anticholinergics (e.g., atropine and ipratropium bromide), cromolyn, nedocromil and leukotriene modifiers (e.g., montelukast).
  • O-agonists e.g., salmeterol
  • theophylline e.g., anticholinergics (e.g., atropine and ipratropium bromide)
  • cromolyn e.g., nedocromil
  • leukotriene modifiers e.g., montelukast
  • montelukast e.g., montelukast
  • 35 a non-steroidal antiinflammatory drug, including indomethacin, sulindac, mefenamic, MRL-BRE-00008
  • the compound of Formula I, Ia, or Ib may also be used in combination with bisphonates such as alendronate to treat a glucocorticoid mediated disease and simultaneously inhibit osteoclast-mediated bone resorption.
  • melting points are uncorrected and M' indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
  • NMR data when given, NMR data is in the form of delta ( ⁇ ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, 10 determined at 500 MHz or 600 MHz using the indicated solvent, conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; and br. Broad.
  • ppm parts per million
  • Tr tetramethylsilane
  • reaction schemes and examples below illustrate the methods employed in the synthesis of the compounds of the present invention. In some cases the order of carrying out the 15 reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the synthesis of the novel compounds which are the subject of this invention may be accomplished by one or more of several similar routes. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. 20
  • Step B (7 ⁇ 'SV7 ⁇ '-Methyl-5'-oxo-2'.3'.5'.6'.7'.7 ⁇ '-hexahvdrospi ⁇ )ri.3-dioxolane-2.1'- indenel-6'-carbaldehvde (1-3):
  • Step D (4 ⁇ R.5 S)-I -(4-Fluorophenyl)-4 ⁇ -methyl-lA4 ⁇ .5.6.7- hexahydrocyclopentarflindazole-S-carbaldehyde (1-6):
  • Step F JV- ⁇ (l£)-2-r(4 ⁇ R.5R)-l-(4-Fluorophenyl)-4 ⁇ -methyl-1.4.4 ⁇ .5.6.7- hexahydrocyclopenta[/]indazol-5-yllethylidene
  • Step G j2- ⁇ (4aR.5R)- 1 -(4-Fluorophenyl)-4 ⁇ -methyl- 1.4.4 ⁇ .5.6.7- hexahvdrocvclopentar/iindazol-5-yll- 1 -phenylethyll -2-methylpropane-2-sulfinamide
  • Phenylmagnesium bromide (0.58 mL, 0.58 mmol, 1 M solution in THF) was added to 10 a cooled solution of M (0.12 g, 0.29 mmol) in anhydrous CH 2 Cl 2 (10 mL) at -78 0 C. The mixture was stirred for 1 hour at -78 0 C and then warmed to room temperature and stirred for 1 hour. The reaction was quenched by the addition of an aqueous solution of ammonium chloride and then extracted with CH 2 Cl 2 and washed with a saturated solution of brine. The combined organic extracts were dried over anhydrous MgSO4 and the solvent removed in vacuo. Purification by flash
  • Step H r(4 ⁇ R.5R)-l-(4-Fluorophenyl)-4 ⁇ -methyl-1.4.4 ⁇ .5.6.7- hexahydrocyclopenta[/1indazol-5 -yl "
  • Step I j2- ⁇ (4aR.5R)- 1 -(4-fluorophenyl)-4 ⁇ -methyl- 1.4.4 ⁇ .5.6.7- hexahvdrocvclopentar/iindazol-5-yll- 1 -phenylethyll acetamide (Ex. 1 ) :
  • Acetyl chloride (7.34 ⁇ l, 0.103 mmol) was added to a stirred solution of 1-10 (40 mg, 0.103 mmol) and triethylamine (14.39 ⁇ l, 0.103 mmol) in anhydrous CH 2 Cl 2 (1 mL) at 0 0 C.
  • Step A 1 - ⁇ (4aR,5R)- 1 -(4-Fluorophenyl)-4 ⁇ -methyl- 1.4.4 ⁇ .5.6.7- hexahvdrocvclopentar/1indazol-5-vnpropan-2-one (4-1):
  • Methylmagnesium bromide (6.44 ml, 19.33 mmol) was added to a stirred solution of 1-8 (3.0 g, 9.67 mmol) in anhydrous THF (100 mL) at -78 0 C. The mixture was stirred at this temperature for 30 min and warmed to RT and stirred for 30 min. The mixture was cooled,
  • Step D N- ( l- ⁇ (4aR,5R)- 1 -(4-FluorophenylM ⁇ -methyl- 1 A4 ⁇ .5.6.7- hexahydrocvclopentar/iindazol-S-yll-l-methvtoropan-l-vUacetamide (Ex. 4):
  • Acetyl chloride (0.16 rnL, 2.03 mmol) was added to a stirred solution of 4 ⁇ 3 (0.68 g, 2.03 mmol) and triethylamine (0.28 mL, 2.03 mmol) in anhydrous CH 2 Cl 2 (10 mL) at 0 0 C.
  • TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM beta-mecaptoethanol,
  • Wash Buffer 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA.
  • Molybdate Molybdic Acid (Sigma, M 1651)
  • HeLa 10 ATCC
  • RPMI 1640 Gibco 11835-055
  • human insulin Sigma, 1-0259
  • FBS FBS
  • 20 ug/ml of Gentamicin Gibco# 15710-072
  • Phenol red-free Trypsin-EDTA is diluted in the same PBS 1 :10.
  • the cell layers are rinsed with IX Trypsin, extra Trypsin is poured out, and the cell layers are incubated at 37 0 C for ⁇ 2 min.
  • the flask is tapped and checked for signs of cell detachment. Once the cells 15 begin to slide off the flask, the complete media is added. The cells are counted at this point, then diluted to the appropriate concentration and split into flasks or dishes for further culturing (Usually 1 :3 to 1 :6 dilution).
  • the cells When the cells are 70 to 85% confluent, they are detached as described above, and collected by centrifuging at 1000 g for 10 minutes at 4 0 C. The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate, pH 7.2). After the final wash, the cells are resuspended in TEGM at a concentration of 107 cells/mL. The cell suspension is snap frozen in liquid nitrogen or ethano I/dry
  • the test compound can be prepared in 50 ⁇ L of the TEGM buffer.
  • Ix TEGM buffer is prepared, and the isotope-containing assay mixture is prepared in the following order: EtOH (2% final concentration in reaction), 3H-DEX (Amersham Biosciences) and Ix TEGM. [e.g. For 100 samples, 200 ⁇ L (100 x 2) of EtOH + 4.25 ⁇ L of 1 :10 3H-Dex stock + 2300 ⁇ L (100 x 23) Ix TEGM]. The compound is serially diluted, e.g., if starting final cone, is 1 MRL-BRE-00008
  • 25 ⁇ L of 3H-DEX (6 nM) trace and 25 ⁇ L compound solution are first mixed together, followed by addition of 50 ⁇ L receptor solution.
  • the reaction is gently mixed, spun 5 briefly at about 200 rpm and incubated at 4 0 C overnight.
  • 100 ⁇ L of 50% HAP slurry is prepared and added to the incubated reaction which is then vortexed and incubated on ice for 5 to 10 minutes.
  • the reaction mixture is vortexed twice more to resuspend HAP while incubating reaction.
  • the samples in 96-well format are then washed in wash buffer using The FilterMateTM Universal Harvester plate washer (Packard).
  • the washing process transfers HAP pellet containing ligand- 10 bound expressed receptor to Unifilter-96 GF/B filter plate (Packard).
  • the HAP pellet on the filter plate is incubated with 50 ⁇ L of MICRO SCINT (Packard) scintillint for 30 minutes before being counted on the TopCount micro scintillation counter (Packard).
  • IC50S are calculated using DEX as a reference.
  • This assay assesses the ability of test compounds to control transcription from the MMTV-LUC reporter gene in lung adenocarcinoma A549 cells or HeLa cells, a human breast cancer cell line that naturally expresses the human GR.
  • the assay measures induction of a modified MMTV LTR/promoter linked to the LUC reporter gene.
  • the routine transient assay consists of plating 7,000-25,000 cells/well of a white, clear-bottom 96-well plate. Alternatively, 384-well plates can be used at a cell concentration of 10,000 /well.
  • the media that the cells are plated in is "exponential growth medium" which consists of phenol red-free RPMI1640 containing 10%FBS, 4mM L-glutamine, 2OmM HEPES, lOug/mL human insulin, and 20ug/mL gentamicin. Incubator conditions are 37 0 C and 5% C ⁇ 2- The
  • 25 transfection is done in batch mode.
  • the cells are trypsinized and counted to the right cell number in the proper amount of fresh media. It is then gently mixed with the FuGene6/DNA mix and plated onto the 96 or 384-well plate, all the wells receive 100 uL or 4OuL, respectively, of medium + lipid/DNA complex then incubated 37 0 C overnight.
  • the transfection cocktail consists of serum- free OptiMEM, FuGene ⁇ reagent and DNA. The manufacturer's (Roche Biochemical) protocol for
  • the lipid to DNA ratio is approximately 2.5:1 and the incubation time is 20 min at room temperature.
  • the cells are treated with dexamethasone to a final concentration of 1OnM as well as the compound of interest, such that final DMSO (vehicle) concentration is equal to or less than 1%.
  • Each plate also contains samples that are treated with 1OnM dexamethasone alone, which is used as the 100% activity control.
  • the cells are
  • Activity of test compounds is calculated as the E ma ⁇ relative to the activity obtained with 300 nM dexamethasone.
  • Activity of test compounds is calculated as the E ma ⁇ relative to the activity obtained with 300 nM DEX.
  • the exemplified tissue selective glucocorticoid receptor modulators of the present invention display agonist activity in this assay of greater than 5% and less than 100%, and maximal transactivation activity less then maximal transrepression activity.
  • Anti-GRAMMER an antagonist mode in which the cells are treated with medium containing an agonist such as 10 nM DEX and the ability to agents to inhibit the activation by an agonist is measured.
  • TNF ⁇ - ⁇ -lactamase reporter gene in U937 cells a human myelomonocytic leukemia cell line that naturally expresses the human GR.
  • the assay measures compound dependent-repression of the TNFa promoter linked to a reporter gene.
  • U937 cells contain an endogenous glucocorticoid receptor (GR).
  • GR glucocorticoid receptor
  • Cells are maintained in RPMI 1640 Growth medium (Gibco Cat#l 1875-093) containing 25mM HEPES, 10% FBS, 2mM L-Glutamine, ImM Sodium pyruvate, 25 ⁇ g/ml Gentamicin (Gibco Cat#15710-064), 1 :1000 2-Mercaptoethanol (Gibco Cat#21985-023) and 0.8 mg/ml G418 (Gibco Cat#10131-027).
  • the density of the cells in the flask needs to be about 1X106
  • the cells are split to 1.2-1.4x105 /ml (1 : 10) 3 days prior to the assay.
  • 50,000 cells/well are plated in 96 well black-walled plates the day of assay.
  • Test compounds are added 10 ⁇ L/well, and cells are incubated at 37oC for 30-45 min.
  • For assaying compounds first dilute 1 : 10 in DMSO to make 1 mM, then further dilute 1 : 100 in medium to make 1OX stock prior to adding to the cells. Add 50ng/ml PMA (Sigma, cat# P8139) 10 ⁇ L/well to a final
  • This assay assesses the ability of test compounds to modulate the transcription of endogenously expressed genes in a variety of cell types including but not limited to A549, HeLa or U937 cells. All cell culture reagents were purchased from Invitrogen Life Tech, Carlsbad CA. A549 cells were grown in phenol red-free DMEM/F12 medium supplemented with 10% FBS. Cells were grown at 37oC with 5% CO2. Using the RNeasy Kit (Qiagen Corp, Valencia CA.), total
  • the Rosetta p value had to be less than 0.1 and the Rosetta fold change value had to be greater than 1.4 in at least one of the treatments.
  • Inter-ear thickness difference (etd) is used for the estimating the level of inflammation and effectiveness of the
  • 15 compounds is determined by their ability to reduce the increase the thickness of the inflamed ear.
  • Back of the rat skin thickness, spleen weight, serum insulin as well as the effects of gcs on the expression of molecular markers in skin inflammation, skin atrophy, muscle atrophy and glucose metabolism in liver are measured.
  • Data are analyzed by anova plus fisher plsd post-hoc test to identify intergroup differences.

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Abstract

La présente invention concerne des composés de formule I : I ou des sels ou des hydrates de ceux-ci pharmaceutiquement acceptables, qui sont utiles comme ligands sélectifs du récepteur de glucocorticoïdes pour traiter une variété de maladies ou d'états auto-immuns et inflammatoires. L'invention concerne également des compositions pharmaceutiques et des procédés d'utilisation.
PCT/US2010/035793 2009-05-27 2010-05-21 Amides inverses d'hexahydrocyclopentyl[f]indazole et leurs dérivés comme modulateurs sélectifs du récepteur des glucocorticoïdes WO2010138421A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013130013A1 (fr) * 2012-02-27 2013-09-06 Nanyang Polytechnic Nouveaux composés et utilisations de ceux-ci
WO2020152193A1 (fr) 2019-01-22 2020-07-30 Akribes Biomedical Gmbh Modificateurs sélectifs du récepteur de glucocorticoïdes pour le traitement de la mauvaise cicatrisation de plaies cutanées
EP3541431B1 (fr) * 2016-11-16 2024-04-17 The General Hospital Corporation Agents d'imagerie de myéloperoxydase

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008051532A1 (fr) * 2006-10-23 2008-05-02 Merck & Co., Inc. Dérives de 2-[1-phényl-5-hydroxy ou methoxy-4alpha-méthyl-hexahydroclopenta[f]indazol-5-yl]éthyle phényle utilises comme ligands de récepteur de glucocorticoide
US20080214641A1 (en) * 2006-12-21 2008-09-04 Markus Berger Chemical compounds 572

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008051532A1 (fr) * 2006-10-23 2008-05-02 Merck & Co., Inc. Dérives de 2-[1-phényl-5-hydroxy ou methoxy-4alpha-méthyl-hexahydroclopenta[f]indazol-5-yl]éthyle phényle utilises comme ligands de récepteur de glucocorticoide
US20080214641A1 (en) * 2006-12-21 2008-09-04 Markus Berger Chemical compounds 572

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013130013A1 (fr) * 2012-02-27 2013-09-06 Nanyang Polytechnic Nouveaux composés et utilisations de ceux-ci
EP3541431B1 (fr) * 2016-11-16 2024-04-17 The General Hospital Corporation Agents d'imagerie de myéloperoxydase
WO2020152193A1 (fr) 2019-01-22 2020-07-30 Akribes Biomedical Gmbh Modificateurs sélectifs du récepteur de glucocorticoïdes pour le traitement de la mauvaise cicatrisation de plaies cutanées

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