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WO2010091543A1 - Nouveaux dérivés d'hydrazinocyclobut-3-ène-1,2-dione comme antagonistes de cxcr2 - Google Patents

Nouveaux dérivés d'hydrazinocyclobut-3-ène-1,2-dione comme antagonistes de cxcr2 Download PDF

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WO2010091543A1
WO2010091543A1 PCT/CN2009/070387 CN2009070387W WO2010091543A1 WO 2010091543 A1 WO2010091543 A1 WO 2010091543A1 CN 2009070387 W CN2009070387 W CN 2009070387W WO 2010091543 A1 WO2010091543 A1 WO 2010091543A1
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alkyl
hydrogen
halogen
compound
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Shu-Hui Chen
Hao Wu
Jingchao Dong
Shilan Liu
Yinhui Niu
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Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
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Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/20—Hydrazines having nitrogen atoms of hydrazine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/22—Hydrazines having nitrogen atoms of hydrazine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved cysteine motif.
  • the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the CXC, CC and CX 3 C families.
  • the CXC and CC families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues.
  • the CX 3 C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues.
  • the CXC chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (TL-8) and neutrophil-activating peptide 2 (NAP-2).
  • TL-8 interleukin-8
  • NAP-2 neutrophil-activating peptide 2
  • the CC chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils. Examples include human monocyte chemotactic proteins 1-3 (MCP-I, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MP-I ⁇ and MIP-I ⁇ ).
  • the CX3C chemokine also known as fractalkine is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCRl, CCR2, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRI l (for the CC family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the CXC family) and CX 3 CRl for the CX 3 C family.
  • These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above. There remains a need for compounds that are capable of modulating activity at
  • CXC-chemokine receptors For example, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cell subsets into the inflammatory site and growth of tumors) would benefit by compounds that are inhibitors of IL- 8 receptor binding.
  • the present invention relates to novel hydrazino-cyclobut-3-ene-l,2-dione compounds encompassed by Formula (I) as selective CXCR2 antagonists, pharmaceutical compositions containing the novel compounds, as well as methods for treating or preventing chemokine mediated diseases or conditions in human and non-human animals using these novel compounds:
  • the present invention describes compounds of Formula (I) and pharmaceutically acceptable salts thereof:
  • A is selected from the group consisting of:
  • B is selected from the group consisting of: (1) hydrogen,
  • Ci -8 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of:
  • heteroaryl optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -8 alkyl, (b) halogen, and (c) -OR b ,
  • n 0, 1, 2, or 3
  • aryl optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -8 alkyl, (b) halogen, and (c) -OR b , and
  • heteroaryl optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -8 alkyl, (b) halogen, and (c) -OR b ;
  • C is selected from the group consisting of
  • W is selected from the group consisting of -CH 2 - and -NH-;
  • X is selected from the group consisting of hydrogen, Ci -8 alkyl, C 3-8 cycloalkyl, Ci -8 alkoxy, halogen, -CN, -CF 3 , and -OCF 3
  • Y is selected from the group consisting of hydrogen, Ci -8 alkyl, C 3-8 cycloalkyl, Ci -8 alkoxy, halogen, -CN, -CF 3 , and -OCF 3
  • each occurrence of Rl and R2 is independently selected from the group consisting of:
  • each of the Ci-S alkyl, C3_8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci -8 alkyl, halogen, and -OR a ; or Rl or R2 taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 1 nitrogen and 0 to 3 additional heteroatoms selected from the group consisting of O, S, and N; and each occurrence of R a and R b is independently selected from the group consisting of:
  • alkyl means both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci -8 alkyl means branched- or straight-chain saturated aliphatic hydrocarbon groups having 1 to 8 carbon atoms.
  • Non-limiting examples of suitable alkyl groups include methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tert-buty ⁇ (t-Bu), isopentyl, and isohexyl.
  • alkoxy means an alkyl-O-group wherein alkyl is as defined above.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • aryl means an aromatic monocyclic or multicyclic ring system, wherein at least one ring is aromatic, comprising about 6 to about 14 carbon atoms, or more specifically, about 6 to about 10 carbon atoms, or even more specifically, about 6 to about 8 carbon atoms.
  • suitable aryl groups include phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, and fiuorenyl.
  • cycloalkyl means a monocyclic saturated carbocyclic ring, having the specified number of carbon atoms, for example, 3, 4, 5, 6, 7 or 8 carbon atoms for C 3- S cycloalkyl.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 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.
  • the terms "halo” or “halogen” refer to fluoro, chloro, bromo and iodo unless otherwise noted. In one embodiment, the term “halogen” refers to fluoro or chloro.
  • heteroaryl means an aromatic monocyclic or multi cyclic ring system comprising 5 to 14 ring atoms, or more specifically, 5 to 10 ring atoms, or even more specifically, 5 to 6 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example, nitrogen, oxygen or sulfur, alone or in combination.
  • suitable heteroaryls contain 5 to 6 ring atoms.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl,
  • A is selected from the group consisting of:
  • A is .
  • X is selected from the group consisting of (a) hydrogen, (b) Ci-S alkyl, (c) C3_8 cycloalkyl, (d) Ci -8 alkoxy, (e) halogen, (f) -CN, (g) -CF 3 , and (h) -OCF 3 .
  • X is selected from the group consisting of (a) hydrogen and (b) Ci-6 alkyl.
  • X is selected from the group consisting of (a) hydrogen and (b) Ci -4 alkyl.
  • X is hydrogen.
  • Y is selected from the group consisting of
  • Y is selected from the group consisting of (a) hydrogen and
  • Y is selected from the group consisting of (a) hydrogen and (b) C 1-4 alkyl. In yet another subset, Y is hydrogen. In another subset of this embodiment, each occurrence of R 1 and R 2 is independently selected from the group consisting of:
  • Ci -8 alkyl C 3-8 cycloalkyl, and (4) aryl, wherein each of the Ci -8 alkyl, C 3-8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -8 alkyl, (b) halogen, and (c) -0R a ; or
  • Rl or R2 taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 1 nitrogen and 0 to 3 additional heteroatoms selected from the group consisting of O, S and N.
  • each occurrence of R 1 and R 2 is independently Ci -6 alkyl. In another subset, each occurrence of R 1 and R 2 is independently Ci -4 alkyl. In yet another subset, each occurrence of R 1 and R 2 is methyl or ethyl.
  • R a is selected from the group consisting of:
  • each of the Ci -8 alkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -8 alkyl, (b) halogen, (c) hydroxy, and (d) Ci -8 alkoxy.
  • R a is selected from the group consisting of (a) hydrogen and (b) Ci -6 alkyl.
  • R a is selected from the group consisting of (a) hydrogen and (b) Ci -4 alkyl.
  • R a is hydrogen.
  • Formula I are compounds wherein B is selected from the group consisting of: (1) hydrogen,
  • Ci -8 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of:
  • n 0, 1, 2, or 3
  • aryl optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -8 alkyl, (b) halogen, and (c) -OR b , and
  • B is selected from the group consisting of:
  • Ci -6 alkyl optionally substituted with 1 to 3 substituents selected from the group consisting of:
  • heteroaryl optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -6 alkyl, (b) halogen, and (c) -OR b , O
  • aryl optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -6 alkyl, (b) halogen, and (c) -OR b , and
  • heteroaryl optionally substituted with 1 to 3 substituents selected from the group consisting of (a) Ci -6 alkyl, (b) halogen, and (c) -OR b .
  • B is selected from the group consisting of:
  • n is 0, 1, or 2
  • R is selected from the group consisting of: (a) hydrogen, (b) Ci -6 alkyl, and (c) halogen.
  • n is 0 or 1.
  • R b is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, chloro, and fiuoro. J , (7)
  • C is selected from the group consisting of (1) hydrogen and (2) Ci -6 alkyl.
  • C is selected from the group consisting of (1) hydrogen, (2) methyl, (3) ethyl, (4) n-propyl, and (5) n-butyl.
  • C is methyl or ethyl.
  • Formula I are compounds wherein W is selected from the group consisting of -CH 2 - and -NH-. In another embodiment, W is -CH 2 -.
  • X is selected from the group consisting of (1) hydrogen and (2) Ci -6 alkyl. In yet another embodiment, X is hydrogen. In one embodiment of Formula I are compounds wherein Y is selected from the group consisting of:
  • Y is selected from the group consisting of (1) hydrogen and (2) Ci -6 alkyl. In yet another embodiment, Y is hydrogen.
  • each occurrence of Rl and R2 is independently selected from the group consisting of (1) hydrogen, (2) Ci -8 alkyl, (3) C 3-8 cycloalkyl, and (4) aryl, wherein each of the Ci -8 alkyl, C 3-8 cycloalkyl, and aryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci -8 alkyl, halogen, and -OR a ; or Rl or R2 taken together with the nitrogen they are attached to form an unsubstituted or substituted saturated or unsaturated 4-8 membered ring, wherein the 4-8 membered ring contains 0 to 3 heteroatoms selected from the group consisting of O, S and N.
  • each occurrence of Rl and R2 is independently selected from the group consisting of (1) hydrogen, (2) Ci -6 alkyl, and (3) C 3-6 cycloalkyl. In yet another embodiment, each occurrence of Rl and R2 is independently selected from the group consisting of (1) hydrogen and (2) Ci -4 alkyl. In still another embodiment, each occurrence of Rl and R2 is independently methyl or ethyl.
  • each occurrence of R a and R b is independently selected from the group consisting of (1) hydrogen, (2) Ci -8 alkyl, (3) halogen, (4) aryl, and (5) heteroaryl, wherein each of the Ci -8 alkyl, aryl, and heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci-S alkyl, halogen, hydroxy, and Ci -8 alkoxy.
  • each occurrence of R a and R b is independently selected from the group consisting of (1) hydrogen, (2) Ci -6 alkyl, and (3) halogen. In yet another embodiment, each occurrence of R a and R b is independently selected from the group consisting of (1) hydrogen, (2) methyl, and (3) ethyl, (4) n-propyl, (5) chloro, and (6) fiuoro.
  • R a is hydrogen. In another embodiment, R b is hydrogen, methyl, or fiuoro.
  • B is selected from the group consisting of (1) hydrogen, (2) Ci -6 alkyl, optionally
  • each occurrence of Rl and R2 is independently selected from the group consisting of (1) methyl, (2) ethyl, (3) n-propyl, and (4) n-butyl.
  • each occurrence of R a and R b is independently selected from the group consisting of (1) hydrogen, (2) Ci -6 alkyl, and (3) halogen.
  • Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers.
  • bonds to the chiral carbon are depicted as straight lines in the formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formulas.
  • the present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers.
  • the above Formula I is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I 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 F£PLC column. Further, any enantiomer or diastereomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from such inorganic bases 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.
  • organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • 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, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • solvates of compounds of Formulas I.
  • the term "solvate” refers to a complex of variable stoichiometry formed by a solute (i.e., a compound of Formula I) 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.
  • the solvent is water, the solvate is known as hydrate; hydrates include, but are not limited to, hemi-, mono, sesqui-, di- and trihydrates.
  • Prodrugs The present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various conditions described with a compound of formula I or with a compound which may not be a compound of formula I, but which converts to a compound of formula I in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.
  • Compounds of the present invention are potent antagonists of the CXCR2 receptors, and as such are useful in treating or preventing diseases, disorders or conditions mediated by the activation of CXCR2 receptors.
  • one aspect of the present invention provides a method for the treatment, control or prevention of such diseases, disorders, or conditions in a mammal which comprises administering to such mammal a therapeutically effective amount of a compound of Formula I.
  • mammal includes human and non- human animals such as dogs and cats and the like.
  • the diseases, disorders or conditions for which compounds of the present invention are useful in treating or preventing include, but are not limited to, (1) asthma, (2) COPD, (3) autoimmune disease, (4) allergic rhinitis, (5) psoriasis, (6) rheumatoid arthritis, (7) cardiovascular disease, and (8) cancer.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • oral, topical, parenteral, ocular, pulmonary, and nasal may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of Formula I are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • compositions include compositions suitable for oral, intravesical, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.01 percent of active compound. The percentage of active compound in these compositions may be varied and may conveniently be between about 0.01 percent to about 30 percent, or more specifically, about 0.05 to about 20 percent, or even more specifically, about 0.1 to about 10 percent, of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of Formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • a compound of Formula I may be used in combination with a second active agent that is useful for the treatment of chemokines mediated diseases.
  • Suitable second active agents include, but are not limited to, an antirheumatic agent, a nonsteroidal anti-inflammatory agent, a COX-2 selective inhibitor, a COX-I inhibitor, an immunosuppressive agent, a steroid, and a biological response modifier.
  • the second active agent may be administered contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical unit dosage form may contain the second active agent in addition to a compound of Formula I.
  • pharmaceutical compositions of the present invention include those that also contain one or more of the second active agents, in addition to a compound of Formula I.
  • the compounds of Formula I of the present invention can be prepared according to the procedures of the following Schemes and Examples using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the Examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described previously hereinabove.
  • the free amine bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, and potassium hydroxide, and extraction of the liberated amine free base into an organic solvent followed by evaporation.
  • the amine free base isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation, or crystallization. All temperatures are degrees Celsius unless otherwise noted.
  • Mass spectra (MS) were measured by electron-spray ion-mass spectroscopy.
  • HPLC High Performance Liquid Chromatography
  • MPLC Medium Pressure Liquid Chromatography
  • prep TLC preparative Thin Layer Chromatography
  • flash chromatography with silica gel or reversed-phase silica gel ion-exchange chromatography; and radial chromatography. All temperatures are degrees Celsius unless otherwise noted. Throughout the application, the following terms have the indicated meanings unless otherwise noted:
  • EDAC (or EDC) 1 -Ethyl-3 -[3 -(dimethylamino)propyl]-carbodiimide
  • TBS (or TBDMS) 7ert-butyldimethylsilyl tBu Tert-buty ⁇
  • 3-(2-ethoxy-3,4-dioxocyclobut-l-enylamino)-2-hydroxy-N,N- dimethy benzamide (1-1) is commercially available or may be prepared from readily available 3,4-diethoxy-3-cyclobutene-l,2-dione(diethyl squarate) and the corresponding 3-amino-2- hydroxy-N,N-dimethylbenzamide via a substitution reaction, for example using the method as published by Dwyer et al., J. Med. Chem. 49, 7603-7606 (2006).
  • the mono -alkylated 1-4 can be further N-alkylated (wherein R b is an alkyl) or acylated (wherein R b is an acyl) to give 1-5 under reaction conditions with or without a base, using a solvent that can dissolve the reactants and at a temperature between - 7O 0 C to 12O 0 C.
  • the base can be either an inorganic or an organic base.
  • R b is an alkyl
  • X can be Cl, Br, I, Ms, or Tosy
  • the base can be an inorganic base such as K2CO3, NaC ⁇ 3, NaH, and NaOH, or an organic base such as Et 3 N, DBU 5 PhNEt 2 , NaOEt, and KOt-Bu.
  • the reaction temperature can be -70 0 C to 120 0 C and suitable solvents can be EtOH, MeOH, BuOH, t-BuOH, DMSO, DMF, DCM, THE, and dioxane.
  • R b is an acyl
  • X can be Cl, Br and F
  • the base can be organic amines and pyridines such as Et 3 N, DBU, PhNEt 2 , and pyridine.
  • Suitable solvents can be non-proton solvents such as DMSO, DMF, DCM, THF, dioxane, and ether.
  • hydrazine H-I can react with 1-1 under conditions with or without a base, using a solvent that can dissolve the reactants and at a temperature between -2O 0 C to 12O 0 C.
  • the base can be either an inorganic base such as K 2 CO 3 , Na 2 CO 3 , NaH or NaOH, or an organic base such as Et 3 N, DBU, PhNEt 2 , NaOEt or KOt-Bu.
  • R can be an alkyl or aryl and R b can be an alkyl or acyl.
  • Suitable solvents can be EtOH, MeOH, BuOH, t-BuOH, DMSO, DMF, DCM, THF or dioxane.
  • the protected (for example, Boc- or Cbz-protected) alkyl hydrazine H-2 can react with 1-1 to give 1-6 under conditions with or without a base, using a solvent that can dissolve the reactants and at a temperature between -2O 0 C to 12O 0 C.
  • the base can be either an inorganic base or an organic base.
  • Suitable inorganic bases include, but are not limited to, K 2 CO 3 , Na 2 CO 3 , NaH and NaO.
  • Suitable organic bases include, but are not limited to, Et 3 N, DBU, PhNEt 2 , NaOEt and KOt-Bu.
  • Suitable solvents include, but are not limited to, EtOH, MeOH, BuOH, t-BuOH, DMSO, DMF, DCM, THF or dioxane.
  • de-protection of 1-6 followed by alkylation, acylation or sulfonylation of 1-7 can give 1-8 using well known methods.
  • PG of 1-6 when PG of 1-6 is Boc, it can be removed using, for example, HCl in Et 2 O or EtOAc or 2 equivalents TFA in CH 2 Cl 2 , to give I- 7.
  • PG of 1-6 when PG of 1-6 is Cbz, it can be removed by hydrogenation using palladium catalysts such as Pd/C or Pd(OH) 2 /C in alcohol to give 1-7.
  • 1-7 can be converted to 1-8 under similar conditions as those for the conversion from 1-4 to 1-7 in Scheme 1.
  • R can be alkyl or aryl
  • R b can be alkyl or acyl
  • R c can be alkyl or aryl. Suitable aryls include, but are not limited to, aromatic heterocycles.
  • PG protection group such as Boc or Cbz
  • Step 3 3 -(2-Ethoxy-3 ⁇ -dioxocyclobut- 1 -enylamino V2-hydroxy-N.N- dimethylbenzamide
  • Step 4 3-(2-Hydrazinyl-3.4-dioxocyclobut-l-enylamino)-2-hydroxy-N.N-dimethyl benzamide
  • Step 5 3-(2-(2-Ethylidenehydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2-hydroxy-
  • the wavy bond " - ⁇ > ⁇ - " represents the cis-isomer, the trans-isomer, or a mixture of the cis-isomer and the trans- isomer.
  • Step 6 3-(2-(2-EthylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2-hydroxy-N.N- dimethyl benzamide
  • the wavy bond " " ⁇ " represents the cis-isomer, the trans-isomer, or a mixture of the cis-isomer and the trans- isomer.
  • N'-Ethyl-hydrazinecarboxylic acid tert-butyl ester 500 mg, 3.13 mmol was dissolved in anhydrous CH 2 Cl 2 (20 mL), then 4-fluoro-benzoyl chloride (500 mg 3.16 mmol) was added.
  • Anhydrous pyridine (0.74 g, 93.7 mmol) was added at 0 0 C. After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 4 hours successively. Then the mixture was extracted with ethyl acetate. The combined organic phases were dried over Na 2 SO 4 , then filtrated. The filtrate was concentrated to give N'-Ethyl-N'-(4-fiuoro-benzoyl)- hydrazinecarboxylic acid tert-butyl ester (1 g).
  • N'-Ethyl-N'-(4-fiuoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester 200 mg, 0.8 mmol was dissolved in Et 2 OZHCl (5 mL, 2N), and stirred at room temperature. After 1 hour 10 mL of NaHCOs (sat.) was added to adjust pH to 10. The mixture was extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na 2 SO 4 , and concentrated to give compound 4-fiuoro-benzoic acid N-ethyl-hydrazide (120 mg).
  • Step 3 3-(2-(2-Ethyl-2-(4-fluorobenzoyl)hydrazinyl)-3.4-dioxocyclobut-l-enylamino)-
  • Step 3 N-Ethyl-N-(4-methoxy-phenylVhydrazine
  • Step 2 3-(2-(2-Ethyl-2-(pyridin-2-yl)hydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2- hydroxy-N.N- dimethylbenzamide
  • Step 3 3-(2-(2-acetyl-2-ethylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2-hydroxy- N.N- dimethyl benzamide
  • N-ethylacetohydrazide hydrochloride 200 mg, 1.46 mmol
  • 3-(2-ethoxy-3,4- dioxocyclobut-l-enylamino)-2 -hydroxy -N,N-dimethylbenzamide 440 mg, 1.46 mmol
  • DIEA 540 ⁇ L, 2.91 mmol
  • the reaction mixture was directly purified with preparative HPLC to give 3-(2-(2-acetyl-2-ethylhydrazinyl)-3,4- dioxocyclobut-1- enylamino)-2-hydroxy -N,N- dimethyl benzamide (45 mg, yield 8.6%).
  • N-ethylaniline (3.65 g, 30.12 mmol), 48 mL HCl (con.), and 12 g ice was placed in 50 mL three-necked flask, to which a solution Of NaNO 2 (2.1 g, 30.4 mmol) in 8.3 mL H 2 O was added during the course of 10 minutes below 5 0 C. After 1 hour, the mixture was extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na 2 SO 4 , then filtrated, the filtrate was concentrated to give N-ethyl-N-phenylnitrous amide (4.06 g, yield about 90%), which was used directly in the next step without further purification.
  • Step 3 3-(2-(2-Ethyl-2-phenylhydrazinyl)-3.4-dioxocyclobut-l-enylamino)-2-hydroxy-
  • Step 2 1 -ethyl- 1 -f 4-fluorophenvDhvdrazine
  • the warmed solution was filtered from the un-reacted Zn, which was washed with 5% HCl.
  • Step 3 3-(2-(2-emyl-2-(4-fluorophenv ⁇ hvdrazinylV3.4-dioxocvclobut-l- envlamino)-2-hvdroxv-N,N- dimethvlbenzamide
  • Step 1 rgrt-butyl-2-(2-(3-(dimethylcarbamoylV2-hydroxyphenylaminoV3.4- dioxocyclobut-1-enylV 2 -ethyl hydrazine carboxylate
  • Step 2 3-(2-(l-EthylhydrazinylV3.4-dioxocyclobut-l-enylaminoV2-hydroxy-N.N- dimethylbenzamide Tert-buty ⁇ -2-(2-(3 -(dimethyl carbamoyl)-2-hydroxyphenylamino)-3, 4- dioxocyclobut-l-enyl)-2-ethyl hydrazinecarboxylate (89 mg) was dissolved in TFA/DCM (1 :1).
  • novel compounds described herein were evaluated for their binding affinity according to the following assay methods.
  • Membrane preparation Membrane was prepared by nitrogen cavitation at 800 psi for up to 30 minutes on ice followed by differential centrifugation (100Og, lOmin and 16000Og,
  • Binding assay was done in a 96-well SPA-compatible incubation plate in a final volume of lOO ⁇ L containing lOOpM [ 125 I]IL8, 0.2mg PVT-WGA SPA beads (Amersham), plus or minus 0.5%(w/v) human serum albumin for the protein shift assay (Sigma #8763), 2 ⁇ L of compound competitor (in DMSO) and approximately l-3 ⁇ g membrane proteins (determined experimentally for each new membrane preparation) in assay buffer (25mM HEPES pH 7.4 (KOH), 3mM MgCl 2 , 0.001% (v/v) Tween-20).
  • assay buffer 25mM HEPES pH 7.4 (KOH), 3mM MgCl 2 , 0.001% (v/v) Tween-20.
  • Total and non-specific binding were determined in the presence of DMSO and 30 ⁇ M of methyl l-[(3- ⁇ [(Z)-[(2- bromophenyl)amino](cyanoimino)methyl]amino ⁇ -6-chloro-2-hydroxyphenyl)sulfonyl]-L- prolinate, respectively.
  • the final concentration of DMSO was 2% and kept constant throughout the plate.
  • the incubation was conducted for Ih at room temperature with shaking and then counted for 1 minute in a Microbeta counter (Perkin Elmer). Percent residual specific binding was determined as ((cpm-average cpm for non-specific)/(average cpm for total binding-average cpm for non-specific ))*100.
  • K 1 was calculated by Inflection Point/1 +([radioligand]/K D ).
  • K D was determined by saturation analysis of the radioligand specific binding for CXCRl and CXCR2.
  • FLIPR Assay Method fIC ⁇ The FLIPR Assay was conducted according to the method described in the publications by Hamonmond M.E. et al, J. of Immunol., 155, 1428-1433 (1995) and Ahuja S.K et al., Nature Genet, 2 (1), 31-36. (1992).
  • Example 6 a close analog of Comparative Example b having one additional nitrogen in place of a carbon, exhibited CXCR2 binding affinity Ki of 120 nM.
  • Example 6 IC50 - 46 nM
  • Examples 5 and 8 had similar CXCR2 binding affinities (130 nM and 110 nM, respectively) as that of Example 6 (120 nM).
  • Examples 5 and 8 each having an ethylaryl hydrazine moiety instead of the diethyl hydrazine moiety of Example 6, showed about 40-fold selectivity, whereas Example 6 displayed about 80-fold selectivity.
  • Example 4 shows that while including an electron donating group (-0Me) for Example 4 on the phenyl ring of Example 8 had minimal effect on CXCR2 binding activity (180 nM), addition of an electron withdrawing group (-F) for Example 9 on the same phenyl ring in Example 8 resulted in about 5 -fold reduction in CXCR2 binding affinity (55O nM).
  • an electron donating group (-0Me) for Example 4 on the phenyl ring of Example 8 had minimal effect on CXCR2 binding activity (180 nM)
  • an electron withdrawing group (-F) for Example 9 on the same phenyl ring in Example 8 resulted in about 5 -fold reduction in CXCR2 binding affinity (55O nM).
  • Example 2 (7.2 ⁇ M), an analog of Example 9 having a /7-F-Bn group replacing /7-F-Ph group of Example 9 (550 nM), had about 12-fold drop in CXCR2 binding affinity.
  • Example 3 which has a benzoyl moiety replacing the corresponding benzyl linker in Example 2, displayed about 28-fold enhanced binding potency (260 nM) relative to

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Abstract

La présente invention porte sur de nouveaux composés d'hydrazinocyclobut-3-ène-1,2-dione de formule (I) comme antagonistes sélectifs de CXCR2, sur des compositions pharmaceutiques contenant les nouveaux composés, ainsi que sur des procédés de traitement ou de prévention de maladies ou affections à médiation par des chimiokines chez l'homme et des animaux non humains à l'aide des nouveaux composés (I).
PCT/CN2009/070387 2009-02-10 2009-02-10 Nouveaux dérivés d'hydrazinocyclobut-3-ène-1,2-dione comme antagonistes de cxcr2 Ceased WO2010091543A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7989497B2 (en) 2008-08-04 2011-08-02 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US9018261B2 (en) 2011-09-02 2015-04-28 Novartis Ag Choline salt of an anti-inflammatory substituted cyclobutenedione compound
CZ305538B6 (cs) * 2014-05-06 2015-11-25 Vysoká škola chemicko- technologická v Praze Benzothiazolem substituované cyklobut-3-en-1,2-dion-3-hydrazony a jejich použití k léčbě leukémií a nádorových onemocnění
US9809581B2 (en) 2015-11-19 2017-11-07 Chemocentryx, Inc. Inhibitors of CXCR2
US9834545B2 (en) 2015-11-19 2017-12-05 Chemocentryx, Inc. Modulators of chemokine receptors
WO2019165315A1 (fr) 2018-02-23 2019-08-29 Syntrix Biosystems Inc. Méthode de traitement du cancer à l'aide d'antagonistes de chimiokine seuls ou en combinaison
US10660909B2 (en) 2016-11-17 2020-05-26 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists
WO2021104506A1 (fr) * 2019-11-28 2021-06-03 中国医学科学院药物研究所 Composé sulfone cyclique et son procédé de préparation, composition pharmaceutique de celui-ci et son utilisation
US11207294B2 (en) 2018-01-08 2021-12-28 Chemocentryx, Inc. Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011418A1 (fr) * 2002-07-30 2004-02-05 Schering Corporation Cyclobutene-1, 2-diones 3,4-di-substitues utilises comme ligands du recepteur de chimiokine cxc

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004011418A1 (fr) * 2002-07-30 2004-02-05 Schering Corporation Cyclobutene-1, 2-diones 3,4-di-substitues utilises comme ligands du recepteur de chimiokine cxc

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YU YOUNONG ET AL.: "Synthesis and Structure-activity Relationships of Heteroaryl Ssubstituted-3,4-diamino-3-cyclobut-3-ene-1,2-dione CXCR2/CXCRIReceptor Antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS., vol. 18, 2008, pages 1318 - 1322 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7989497B2 (en) 2008-08-04 2011-08-02 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US8288588B2 (en) 2008-08-04 2012-10-16 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US8329754B2 (en) 2008-08-04 2012-12-11 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US8722925B2 (en) 2008-08-04 2014-05-13 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US9115087B2 (en) 2008-08-04 2015-08-25 Novartis Ag Squaramide derivatives as CXCR2 antagonist
US9018261B2 (en) 2011-09-02 2015-04-28 Novartis Ag Choline salt of an anti-inflammatory substituted cyclobutenedione compound
CZ305538B6 (cs) * 2014-05-06 2015-11-25 Vysoká škola chemicko- technologická v Praze Benzothiazolem substituované cyklobut-3-en-1,2-dion-3-hydrazony a jejich použití k léčbě leukémií a nádorových onemocnění
US10336736B2 (en) 2015-11-19 2019-07-02 Chemocentryx, Inc. Modulators of chemokine receptors
TWI724056B (zh) * 2015-11-19 2021-04-11 美商卡默森屈有限公司 Ｃｘｃｒ２抑制劑
EP3377059A4 (fr) * 2015-11-19 2019-03-20 ChemoCentryx, Inc. Inhibiteurs de cxcr2
US9809581B2 (en) 2015-11-19 2017-11-07 Chemocentryx, Inc. Inhibitors of CXCR2
US10370363B2 (en) 2015-11-19 2019-08-06 Chemocentryx, Inc. Inhibitors of CXCR2
US11945805B2 (en) 2015-11-19 2024-04-02 Chemocentryx, Inc Inhibitors of CXCR2
US11820759B2 (en) 2015-11-19 2023-11-21 Chemocentryx, Inc. Modulators of chemokine receptors
US9834545B2 (en) 2015-11-19 2017-12-05 Chemocentryx, Inc. Modulators of chemokine receptors
US10988464B2 (en) 2015-11-19 2021-04-27 Chemocentryx, Inc. Modulators of chemokine receptors
US11040960B2 (en) 2015-11-19 2021-06-22 Chemocentryx, Inc. Inhibitors of CXCR2
US10660909B2 (en) 2016-11-17 2020-05-26 Syntrix Biosystems Inc. Method for treating cancer using chemokine antagonists
US11207294B2 (en) 2018-01-08 2021-12-28 Chemocentryx, Inc. Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2
US11684606B2 (en) 2018-01-08 2023-06-27 Chemocentryx, Inc. Methods of treating generalized pustular psoriasis with an antagonist of CCR6 or CXCR2
WO2019165315A1 (fr) 2018-02-23 2019-08-29 Syntrix Biosystems Inc. Méthode de traitement du cancer à l'aide d'antagonistes de chimiokine seuls ou en combinaison
WO2021104506A1 (fr) * 2019-11-28 2021-06-03 中国医学科学院药物研究所 Composé sulfone cyclique et son procédé de préparation, composition pharmaceutique de celui-ci et son utilisation

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