WO2001079209A2 - Antagonistes des recepteurs d'il-8 a base de diazafluorenone - Google Patents

Antagonistes des recepteurs d'il-8 a base de diazafluorenone Download PDF

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Publication number
WO2001079209A2
WO2001079209A2 PCT/US2001/006817 US0106817W WO0179209A2 WO 2001079209 A2 WO2001079209 A2 WO 2001079209A2 US 0106817 W US0106817 W US 0106817W WO 0179209 A2 WO0179209 A2 WO 0179209A2
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Prior art keywords
tetraaza
cyclopenta
oxa
fluoren
oxo
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PCT/US2001/006817
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English (en)
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WO2001079209A3 (fr
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Larry Don Bratton
David Thomas Connor
Steven Robert Miller
Bharat Kalidas Trivedi
Paul Charles Unangst
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Millennium Pharmaceuticals, Inc.
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Priority to AU2001240021A priority Critical patent/AU2001240021A1/en
Publication of WO2001079209A2 publication Critical patent/WO2001079209A2/fr
Publication of WO2001079209A3 publication Critical patent/WO2001079209A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to diazafluorenone derivatives that are pharmaceutical agents useful in the treatment of a mammal, including a human, by virtue of their IL-8 receptor antagonist properties.
  • IL-8 is a 72 amino acid protein which is a member of the superfamily of leukocyte chemoattractant proteins which have been referred to as intercrines, C-X-C or C-C cytokines or, more recently as chemokines (Oppenheim J.J. et al., "Properties of the novel proinflammatory supergene "intercrine” cytokine family.” Annu. Rev. Immunol., 1991;9:617-648). Many members of the chemokine family appear to be involved in the inflammatory process and in the trafficking of leukocytes.
  • the chemokine superfamily is composed of two branches: the ⁇ - and the ⁇ -chemokines.
  • the ⁇ -chemokine branch includes IL-8, neutrophil activating peptide-2 (NAP-2), melanoma growth stimulatory activity (MGSA/gro or GRO ⁇ ), and ENA-78, all of which have attracting and activating effects predominantly on neutrophils.
  • This branch also includes PF4, ⁇ -thromboglobulin, and CTAPIII, which do not affect neutrophils.
  • IL-8 was originally identified by its ability to both attract and activate polymorphonuclear leukocytes (neutrophils) and has now been shown to be rapidly induced in a wide variety of cell and tissue types in response to pro- inflammatory cytokines such as IL-lb or TNF ⁇ . Additionally, there is data demonstrating high systemic levels of IL-8 in certain neutrophil-mediated inflammatory diseases, suggesting the IL-8 and closely related factors may be the principal endogenous mediators of neutrophil activation.
  • mice that lack the murine IL-8 receptor homolog
  • Science, 1994;265(5172):682-4 Issn: 0036-8075 Although these mice appear healthy, their neutrophils are greatly impaired, as compared to wild-type mice, in their ability to migrate to the peritoneum in response to intraperitoneal thioglycollate injection. All of these results suggest that IL-8 is an important mediator of neutrophil migration and activity in some inflammatory settings. Antagonists to the receptors for IL-8 are useful as anti-inflammatory agents.
  • IL-8 is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies (Hebert et al., Cancer Invest., 1993;11 :743 and Richards et al., American Journal of Surgery, 1997; 174:507).
  • IL-8 receptor antagonists that are IL-8 receptor antagonists. They can be used in the treatment of psoriasis, or atopic dermatitis, disease associated with pathological angiogenesis (i.e., cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, or allograft rejections in a mammal, including a human.
  • pathological angiogenesis i.e., cancer
  • asthma chronic obstructive pulmonary disease
  • adult respiratory distress syndrome arthritis
  • inflammatory bowel disease Crohn's disease
  • ulcerative colitis gastric ulcer
  • septic shock endotoxic shock
  • gram-negative sepsis toxic shock syndrome
  • the present invention relates to diazafluorenone derivatives which are IL-8 receptor antagonists useful as pharmaceutical agents, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to methods of treating a chemokine-mediated disease state in a mammal, including a human. More particularly, the diazafluorenones of the present invention are useful in the treatment of chemokine-mediated diseases such as, for example, psoriasis or atopic dermatitis, disease associated with pathological angiogenesis (i.e., cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease,
  • chemokine-mediated diseases such as, for example, psoriasis or atopic dermatitis, disease associated with pathological angiogenesis (i.e., cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease,
  • the present invention is a compound of Formula I
  • X is O or S
  • R ⁇ , R2, and R3 are independently hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, (CH 2 ) n OC(O)CH 3 ,
  • the present invention is also a method of treating a chemokine-mediated disease state in a mammal, including a human, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or 2-oxa- 1 ,3 ,4, 10-tetraaza- cyclopenta[b]fluoren-9-one or a pharmaceutically acceptable salt thereof.
  • the present invention is also a method of treating a chemokine-mediated disease state in a mammal, including a human, wherein the chemokine binds to an IL-8a (CXCR1) or IL-8b (CXCR2) receptor, which comprises administering to said mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or 2-oxa- 1,3 ,4,10-tetraaza- cyclopenta[b]fluoren-9-one or a pharmaceutically acceptable salt thereof.
  • CXCR1 IL-8a
  • CXCR2 IL-8b
  • the present invention is also a compound selected from: 6-Hydroxy-4,5-dimethyl-indan- 1 -one; Benzoic acid 6,7-dimethyl-3-oxo-indan-5-yl ester; (l-Oxo-indan-5-yloxy)-acetic acid methyl ester; Benzoic acid 3-oxo-indan-5-yl ester;
  • the compounds of Formula I or 2-oxa-l,3,4,10-tetraaza-cyclopenta[b]fluoren-9-one can be used as pharmaceutical agents for treating psoriasis or atopic dermatitis, disease associated with pathological angiogenesis (i.e., cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, atherosclerosis, cardiac and renal reperfusion injury, glomerulonephritis, or thrombosis, Alzheimer's disease, graft versus host reaction, or allograft rejections in a mammal, including a human.
  • pathological angiogenesis i.e., cancer
  • asthma chronic obstructive pulmonary disease
  • adult respiratory distress syndrome arthritis
  • inflammatory bowel disease Crohn's disease
  • ulcerative colitis gastric
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I or 2-oxa-l,3,4,10-tetraaza-cyclopenta[b]fluoren-9-one in unit dosage form in admixture with a pharmaceutically acceptable excipient, diluent, or carrier.
  • the present invention is diazafluorenone IL-8 receptor antagonists that are useful as pharmaceutical agents in the treatment of chemokine-mediated diseases.
  • a preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein X is O.
  • Another preferred embodiment of the present invention is a compound of
  • Another preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein n is 1.
  • Another preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein R ⁇ is halogen, lower alkyl, lower alkoxy, (CH 2 ) n OC(O)CH 3 , O(CH 2 ) n CO 2 R4,
  • Another preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein R ⁇ is
  • R4 is lower alkyl or O(CH 2 ) n R-g wherein R is unsubstituted phenyl, substituted phenyl, or heteroaryl.
  • Another preferred embodiment of the present invention is a compound of
  • a more preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein X is O;
  • R ⁇ is halogen, lower alkyl, lower alkoxy, (CH 2 ) n OC(O)CH 3 , O(CH2)nCO 2 R4,
  • a still more preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein X is O; Ri is halogen, lower alkyl, lower alkoxy, (CH 2 ) n OC(O)CH 3 ,
  • R6 is unsubstituted phenyl, substituted phenyl, or heteroaryl
  • R7 and Rg are lower alkyl; and n is i.
  • a still more preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein X is O; R 1 is (CH 2 )nOC(O)CH 3 , O(CH 2 ) n CO 2 R4,
  • R7 and Rg are lower alkyl; and n is 1.
  • a still more preferred embodiment of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof wherein X is O;
  • R ⁇ is O(CH 2 ) n CO 2 R4 wherein R4 is lower alkyl or
  • Rg is heteroaryl selected from:
  • the present invention is also a method of treating a chemokine-mediated disease state in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of Formula I wherein X is O.
  • Another preferred embodiment of the present invention is a method of treating a chemokine-mediated disease state in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of Formula I wherein X is S.
  • a more preferred embodiment of the present invention is a method of treating a chemokine-mediated disease state in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of Formula I wherein:
  • X is O
  • R! is (CH 2 ) n OC(O)CH 3 , O(CH 2 ) n CO 2 R4,
  • R7 and Rg are lower alkyl; and n is 1 to 3.
  • a still more preferred embodiment of the present invention is a method of treating a chemokine-mediated disease state in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of Formula I wherein:
  • a still more preferred embodiment of the present invention is method of treating a chemokine-mediated disease state in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of Formula I selected from the list of components recited above.
  • Another preferred embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier with a compound of Formula I wherein X is O.
  • Another preferred embodiment of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier with a compound of Formula I wherein X is S.
  • a more preferred embodiment of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier with a compound of Formula I wherein: X is O; R is (CH 2 ) n OC(O)CH 3 ,
  • n 1 to 3.
  • a still more preferred embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier with a compound of Formula I wherein:
  • X is O;
  • R ⁇ is O(CH 2 ) n R6 wherein R5 is heteroaryl selected from:
  • a still more preferred embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent, or carrier with a compound of Formula I selected from the list of compounds recited above.
  • Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts,” J. ofPharma. Sci., 1977;66:1).
  • the acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge supra., 1977).
  • the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.
  • the free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration.
  • the present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti,
  • EMA Delta-Anti-Value
  • Z Delta-Value
  • the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid that is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 1 to 1000 mg, preferably 10 to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the pharmaceutical method of this invention can be administered at the initial dosage of about 1 to about 100 mg/kg daily.
  • a daily dose range of about 25 mg to about 75 mg/kg is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the (9-Oxo-9H-2-oxa- 1 ,3,4, 10-tetraaza-cyclopenta[b]fluoren-6-yloxy)- acetic acid methyl ester, lactose, and cornstarch (for mix) are blended to uniformity.
  • the cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
  • Such tablets can be administered to a human from one to four times a day for treatment of chemokine-mediated disease.
  • lower alkyl means a straight or branched saturated hydrocarbon group or radical having from 1 to 6 carbon atoms, also known as a C -C alkyl.
  • Illustrative examples of a straight or branched alkyl group or radical having from 1 to 4 carbon atoms, also known as a C1-C4 alkyl include groups defined for C1-C3 alkyl and 1 -butyl, 2-butyl, 2-methyl- 1-propyl, and 1,1-dimethylethyl.
  • 6 carbon atoms also known as a Cj-Cg alkyl, include groups defined for C1-C4 alkyl and 1-pentyl, 2-pentyl, 3-pentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3 -hexyl, and 4-methyl- 1 -pentyl.
  • lower alkoxy means an alkyl-O- group or radical wherein alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms as defined above.
  • alkyl is a straight or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms as defined above.
  • Illustrative examples of a straight or branched alkoxy group or radical having from 1 to 3 carbon atoms, also known as a C1-C3 alkoxy include methoxy, ethoxy, 1-propoxy, and 2-propoxy.
  • Illustrative examples of a straight or branched alkoxy group or radical having from 1 to 4 carbon atoms, also known as a C1-C4 alkoxy include groups defined for
  • Ci -Cg alkoxy straight or branched alkoxy group or radical having from 1 to 6 carbon atoms
  • Ci -Cg alkoxy include groups defined for C1-C4 alkoxy and 1-pentoxy, 2-pentoxy, 3-pentoxy, 2,2-dimethylpropoxy, 1 -hexoxy, 2-hexoxy, 3 -hexoxy, and 4-methyl- 1 -pentoxy.
  • phenyl means a cyclic aromatic group or radical having 6 carbon atoms, which group may be optionally substituted with from 1 to 3 substituents selected from: Ci-C ⁇ alkyl, OH, O-CH2F, O-CHF2, O-CF3, O-(C ⁇ -C 6 alkyl), F, Cl, Br, I, NH 2 , N(H)-(C!-C 6 alkyl), N-(C ⁇ -C 6 alkyl) 2 , NO 2 , CF3, CN, C ⁇ CH, C ⁇ C-(C ⁇ -C 6 alkyl), CH(OH)-(C ⁇ -C 6 alkyl), CH OH,
  • monocyclic heteroaryl include 2- or 3-thienyl;
  • 2- or 3-furanyl 1-, 2-, or 3-pyrrolyl; 1-, 2-, or 4-imidazolyl; 1-, 3-, or 4-pyrazolyl; 2-, 4-, or 5-oxazolyl; 2-, 4-, or 5-thiazolyl; 3-, 4-, or 5-isoxazolyl; 3-, 4-, or 5-isothiazolyl; 1-, 3-, or 5-(l,2,4-triazolyl); 1-, 2-, or 5-(l,3,4-triazolyl);
  • bicyclic heteroaryl examples include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl; 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl; 2-, 4-, 5-, 6-, or 7-benzofuran; 2-, 4-, 5-, 6-, or
  • Preferred heteroaryl groups are 5- or 6-membered monocyclic and 9- or 10-membered bicyclic heteroaryl groups.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • the compounds of Formula I may be prepared by applying synthetic methodology known in the art and synthetic methodology outlined in Schemes 1 to 3.
  • Substituted indan-1-ones 1 are commercially available or may be prepared by well-known methods, such as Cordi A.A., Lacoste J-M., Descombes J-J., Courchay C, Vanhoutte P.M., Laubie M., and Verbeuren T.J., J. Med. Chem., 1995;38:4056; Nilsson J.L.G., Selander H., Sievertsson H., and Skanberg I., Acta Chem. Scand., 1970;24:580; Cornelius L.A.M.
  • substituted indan-1-ones may be halogenated and the halogenated intermediates oxidized to yield indan-l,2,3-triones 2 or 2,2-dihydroxy-indan-l,3-diones 3, depending on the reaction conditions employed. See, for example, Heffner R.J. and Joullie M.M., Synthetic Communications, 1991;21 :2231 and Tatsugi J. and Izawa Y., Synthetic Communications, 1998;28:859.
  • indan-l,2,3-triones beginning with phthalate esters or indan-l,2-diones are also known (Joullie M.M., Thompson T.R., and Nemeroff N.H., Tetrahedron, 1991;47:8791).
  • the indan-l,2,3-triones 2 or 2,2-dihydroxy-indan-l,3-diones 3 are reacted with furazan-3,4-diamine 4 (Zelenin A.K. and Trudell M.L., J Heterocyclic Chem., 1997;34:1057) under acidic conditions by the method of Eremeev AN., Andrianov V.G., and Piskunova I.
  • the diol intermediates 5 may be isolated.
  • certain 2-oxa-l,3,4,10-tetraaza-cyclopenta[b]fluorene-9-ones 6 may be formed as a mixture of regioisomers. Standard techniques such as chromatography and fractional crystallization may be employed in the separation of these isomer mixtures.
  • 2-Oxa-l,3,4,10-tetraaza-cyclopenta[b]fluorene-9-ones containing an esterified phenolic function (7, Scheme 2) are prepared by incorporating the ester function into the starting indan-1-one 1.
  • the esters are treated with ammonia in methanol or ethanol or cesium carbonate in tetrahydrofuran to give the phenolic derivatives 8.
  • the compounds of type 8 are alkylated with various alkylating agents, such as alkyl halides, alkyl tosylates, or alkyl bromoacetates to form the alkylated products 9.
  • the alkylation reactions may be conducted with cesium carbonate or potassium carbonate and the appropriate alkylating agents in acetonitrile, acetone or 2-butanone at 25° to 80° for 2 to 24 hours, or with sodium hydride in N,N-dimethylformamide at 25° to 80° for 2 to 24 hours.
  • the compounds of type 8 are also reacted with alcohols by the well-known Mitsunobu reaction (Hughes D.L., Organic Reactions, 1992;42:335) as another method of preparing the alkylated products 9.
  • Benzoic acid 2,2-dihydroxy-l,3-dioxo-indan-5-yl ester was reacted with furazan-3,4-diamine by the procedure described in Example 22 to give in 68% yield a mixture of the regioisomers benzoic acid 9-oxo-9-H-2-oxa- l,3,4,10-tetraaza-cyclopenta[t ]fluoren-6-yl ester and benzoic acid 9-oxo-9-H-2- oxa-l,3,4,10-tetraaza-cyclopenta[t ]fluoren-7-yl ester.
  • the isomer mixture was purified by flash chromatography (eluting with 20-100% ethyl acetate/hexane), followed by recrystallization from aqueous acetonitrile.
  • the above isomer mixture was reacted with cesium carbonate by the procedure described in Example 26. Recrystallization of the crude product from aqueous acetonitrile gave the pure
  • Acetic acid 2-(l,2,3-trioxo-indan-4-yl)-ethyl ester was prepared as an oil in 31% yield from acetic acid 2-(l-oxo-indan-4-yl)-ethyl ester (Nakada Y., Ohno S., Yoshimoto M., and Yura Y., Agric. Biol. Chem., 1978;42: 1365) by the procedure described in Example 17.
  • the crude product was purified by flash chromatography (eluting with 40% ethyl acetate/hexane).
  • the above ester was reacted with furazan-3,4-diamine by the procedure described in Example 43 to give the title compound in 35% yield.
  • the compounds of the present invention were evaluated in an IL-8 receptor binding assay.
  • Chemotaxis is movement of cells such as, for example, neutrophils to a site in response to a chemical agent, particularly a chemokine.
  • Agents such as, for example, IL-8 antagonists block chemokine- mediated activation of cells, which can be shown by their effect on chemotaxis.
  • chemotaxis buffer which is made of one part of RPMI 1640 medium, one part of Medium 199, and 0.5% BSA. The cells were incubated with or without compounds for 5 minutes. Similarly, rhIL-8 was incubated in a separate plate, then transferred into lower chambers of chemotaxis plate. Neutrophils were added onto the top chamber. The plates were incubated at 37°C for 30 minutes. The top chamber was then removed and the plate frozen at -80°C for 30 minutes. After thawing, migrated cells were stained with Cytoquant Cell Proliferation Assay Kit
  • IC50 is the concentration of inhibitor in micromolar required to inhibit binding by 50%.
  • Interleukin-8 is a CXC chemokine that activates neutrophils and serves as a strong chemotactic signal both in vitro and in vivo.
  • the recruitment of neutrophils in response to endogenously produced IL-8 is responsible for some of the acute inflammatory response in a variety of diseases (Matsushima K., Baldwin E., Mukaida N. "Interleukin-8 and MCAF: Novel leukocyte recruitment and activating cytokines.” In: Kishimoto T. (Ed.) Interleukins: Molecular Biology and Immunology, Basel. 1992:236.).
  • Compounds that inhibit IL-8 binding and the subsequent recruitment response would be expected to be useful pharmaceutical agents.

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Abstract

L'invention concerne des dérivés de diazafluorénone représentés par la formule (I), ou un sel pharmaceutiquement acceptable de ceux-ci. Dans la formule, X représente O ou S ; R1, R2, et R3 représentent indépendamment hydrogène, hydroxy, alkyle inférieur, alcoxy inférieur, halogène, (CH2)nOC(O)CH3, O(CH2)nCO2R4, O(CH2)nC(O)R4, où R4 représente alkyle inférieur, OC(O)R5 où R5 représente phényle substitué ou non substitué, O(CH2)nR6 où R6 représente phényle non substitué, phényle substitué ou hétéroaryle, un composé représenté par les formules II ou III dans lesquelles R7 et R8 sont alkyle inférieur ; et n est un nombre entier compris entre 1 et 3 ; à condition que lorsque X représente O, R1, et R2, et R3 ne soient pas tous hydrogène. L'invention concerne des antagonistes des récepteurs de IL-8 utiles comme agents pharmaceutiques, des compositions pharmaceutiques qui contiennent ces composés et un excipient pharmaceutiquement acceptable, et des méthodes permettant de traiter chez un mammifère, y compris l'être humain, des affections dépendant des chimiokines. Les diazafluorénones de l'invention sont utiles dans le traitement d'affections dépendant des chimiokines telles que, par exemple, le psoriasis ou la dermatite atopique, des maladies associées à une angiogenèse pathologique (cancer), l'asthme, la bronchopneumopathie obstructive chronique, le syndrome de détresse respiratoire de l'adulte, l'arthrite, les maladies inflammatoires intestinales, la maladie de Crohn, la rectocolite hémorragique, l'ulcère gastrique, le choc septique, le choc endotoxinique, la sepsie Gram-négative, le choc toxique staphylococcique, l'accident vasculaire cérébral, l'athérosclérose, les lésions cardiaques et rénales consécutives à une reperfusion, la glomérulonéphrite ou la thrombose, la maladie d'Alzheimer, la réaction du greffon contre l'hôte ou les rejets d'allogreffe chez un mammifère, y compris l'être humain.
PCT/US2001/006817 2000-04-13 2001-03-01 Antagonistes des recepteurs d'il-8 a base de diazafluorenone WO2001079209A2 (fr)

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AU2001240021A AU2001240021A1 (en) 2000-04-13 2001-03-01 Diazafluorenone il-8 receptor antagonists

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US19707300P 2000-04-13 2000-04-13
US60/197,073 2000-04-13

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002002562A2 (fr) * 2000-07-06 2002-01-10 Kinetek Pharmaceuticals, Inc. Inhibiteurs heteropolycycliques
WO2005007141A2 (fr) * 2003-07-11 2005-01-27 Proteologics, Inc. Inhibiteurs de l'ubiquitine ligase et methodes associees
WO2007005403A1 (fr) 2005-06-29 2007-01-11 Schering Corporation Oxadiazolopyrazines 5,6-di-substituées et thiadiazolopyrazines comme ligands récepteurs de cxc-chimiokine
US7202249B2 (en) 2002-08-27 2007-04-10 Bristol-Myers Squibb Company Antagonists of chemokine receptors
WO2007066200A2 (fr) * 2005-12-08 2007-06-14 Hybrigenics Sa Inhibiteurs innovants des cysteine-proteases, leurs compositions pharmaceutiques et leurs applications therapeutiques
EP1798232A1 (fr) 2005-12-08 2007-06-20 Hybrigenics S.A. Inhibiteurs de la cysteine protease, compositions pharmaceutiques et applications therapeutiques
EP1918292A1 (fr) * 2006-10-30 2008-05-07 Hybrigenics S.A. Inhibiteurs tetracycliques de cysteine proteases, des compositions pharmaceutiques et leur utilisation therapeutique
WO2008053301A2 (fr) * 2006-10-30 2008-05-08 Hybrigenics Sa Tetracyclic inhibitors of cysteine proteases, the pharmaceutical compositions thereof and their therapeutic applications
US7875613B2 (en) 2006-10-30 2011-01-25 Hybrigenics Sa Tetracyclic inhibitors of cysteine proteases, the pharmaceutical compositions thereof and their therapeutic applications
WO2012006104A2 (fr) * 2010-06-28 2012-01-12 Academia Sinica, Taiwan Composés et procédés destinés au traitement d'une infection par la tuberculose
US11291641B2 (en) * 2016-10-03 2022-04-05 The Children's Medical Center Corporation Prevention and treatment of diabetic nephropathy
WO2022108730A1 (fr) * 2020-11-18 2022-05-27 Texas Tech University System Thérapies pour le cancer à l'aide de petites molécules qui se lient à et inhibent des protéines interagissant avec ral
WO2023225558A1 (fr) * 2022-05-17 2023-11-23 Avesta76 Therapeutics, Inc. Inhibiteurs de rlip76

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WO1999042463A1 (fr) * 1998-02-23 1999-08-26 Warner-Lambert Company Derives de quinoxaline substitues utilises comme antagonistes du recepteur de l'interleukine-8
WO1999042464A1 (fr) * 1998-02-23 1999-08-26 Warner-Lambert Company ANTAGONISTES DU RECEPTEUR DE L'INTERLEUKINE-8 A BASE D'IMIDAZO[1,2-a;3,4-a']DIQUINOLINYLIUM SUBSTITUE

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WO1999042463A1 (fr) * 1998-02-23 1999-08-26 Warner-Lambert Company Derives de quinoxaline substitues utilises comme antagonistes du recepteur de l'interleukine-8
WO1999042464A1 (fr) * 1998-02-23 1999-08-26 Warner-Lambert Company ANTAGONISTES DU RECEPTEUR DE L'INTERLEUKINE-8 A BASE D'IMIDAZO[1,2-a;3,4-a']DIQUINOLINYLIUM SUBSTITUE

Cited By (28)

* Cited by examiner, † Cited by third party
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WO2002002562A3 (fr) * 2000-07-06 2002-05-02 Kinetek Pharmaceuticals Inc Inhibiteurs heteropolycycliques
US7196083B2 (en) * 2000-07-06 2007-03-27 Olt Inc. Heteropolycyclic inhibitors of protein kinases
WO2002002562A2 (fr) * 2000-07-06 2002-01-10 Kinetek Pharmaceuticals, Inc. Inhibiteurs heteropolycycliques
US7202249B2 (en) 2002-08-27 2007-04-10 Bristol-Myers Squibb Company Antagonists of chemokine receptors
WO2005007141A2 (fr) * 2003-07-11 2005-01-27 Proteologics, Inc. Inhibiteurs de l'ubiquitine ligase et methodes associees
WO2005007141A3 (fr) * 2003-07-11 2005-03-24 Proteologics Inc Inhibiteurs de l'ubiquitine ligase et methodes associees
US7659277B2 (en) 2003-07-11 2010-02-09 Proteologies, Ltd. Ubiquitin ligase inhibitors and methods related thereto
JP2009500328A (ja) * 2005-06-29 2009-01-08 シェーリング コーポレイション Ｃｘｃ−ケモカインレセプターリガンドとしての５，６−ジ−置換オキサジアゾロピラジンおよびチアジアゾロピラジン
WO2007005403A1 (fr) 2005-06-29 2007-01-11 Schering Corporation Oxadiazolopyrazines 5,6-di-substituées et thiadiazolopyrazines comme ligands récepteurs de cxc-chimiokine
US7897606B2 (en) 2005-06-29 2011-03-01 Schering Corporation 5,6-di-substituted oxadiazolopyrazines and thiadiazolopyrazines as CXC-chemokine receptor ligands
JP2009518383A (ja) * 2005-12-08 2009-05-07 ヒブリジェニクス・エスアー 新規のシステインプロテアーゼ阻害剤、その薬剤組成物および治療のためのその使用
WO2007066200A2 (fr) * 2005-12-08 2007-06-14 Hybrigenics Sa Inhibiteurs innovants des cysteine-proteases, leurs compositions pharmaceutiques et leurs applications therapeutiques
CN101365702B (zh) * 2005-12-08 2013-03-20 海布里詹尼克斯股份公司 半胱氨酸蛋白酶抑制剂、其药物组合物及其治疗应用
EP1798232A1 (fr) 2005-12-08 2007-06-20 Hybrigenics S.A. Inhibiteurs de la cysteine protease, compositions pharmaceutiques et applications therapeutiques
WO2007066200A3 (fr) * 2005-12-08 2007-09-07 Hybrigenics Sa Inhibiteurs innovants des cysteine-proteases, leurs compositions pharmaceutiques et leurs applications therapeutiques
US20090181972A1 (en) * 2005-12-08 2009-07-16 Philippe Guedat Novel Inhibitors of Cysteine Proteases, the Pharmaceutical Compositions Thereof and their Therapeutic Applications
EP1918292A1 (fr) * 2006-10-30 2008-05-07 Hybrigenics S.A. Inhibiteurs tetracycliques de cysteine proteases, des compositions pharmaceutiques et leur utilisation therapeutique
JP2010508258A (ja) * 2006-10-30 2010-03-18 ヒブリジェニクス・エスアー 新規のシステインプロテアーゼのテトラサイクリン阻害剤、その薬剤組成物および治療のためのその使用
US7875613B2 (en) 2006-10-30 2011-01-25 Hybrigenics Sa Tetracyclic inhibitors of cysteine proteases, the pharmaceutical compositions thereof and their therapeutic applications
WO2008053301A2 (fr) * 2006-10-30 2008-05-08 Hybrigenics Sa Tetracyclic inhibitors of cysteine proteases, the pharmaceutical compositions thereof and their therapeutic applications
WO2008053301A3 (fr) * 2006-10-30 2008-08-07 Hybrigenics Sa Tetracyclic inhibitors of cysteine proteases, the pharmaceutical compositions thereof and their therapeutic applications
CN101611036B (zh) * 2006-10-30 2013-04-24 海布里詹尼克斯股份公司 新的半胱氨酸蛋白酶四环抑制剂、其药物组合物和它们的治疗应用
WO2012006104A2 (fr) * 2010-06-28 2012-01-12 Academia Sinica, Taiwan Composés et procédés destinés au traitement d'une infection par la tuberculose
WO2012006104A3 (fr) * 2010-06-28 2012-04-12 Academia Sinica, Taiwan Composés et procédés destinés au traitement d'une infection par la tuberculose
US9073941B2 (en) 2010-06-28 2015-07-07 Academia Sinica Compounds and methods for treating tuberculosis infection
US11291641B2 (en) * 2016-10-03 2022-04-05 The Children's Medical Center Corporation Prevention and treatment of diabetic nephropathy
WO2022108730A1 (fr) * 2020-11-18 2022-05-27 Texas Tech University System Thérapies pour le cancer à l'aide de petites molécules qui se lient à et inhibent des protéines interagissant avec ral
WO2023225558A1 (fr) * 2022-05-17 2023-11-23 Avesta76 Therapeutics, Inc. Inhibiteurs de rlip76

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