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WO2007000337A1 - Derives bicycliques utilises en tant qu'inhibiteurs de p38 kinase - Google Patents

Derives bicycliques utilises en tant qu'inhibiteurs de p38 kinase Download PDF

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Publication number
WO2007000337A1
WO2007000337A1 PCT/EP2006/006253 EP2006006253W WO2007000337A1 WO 2007000337 A1 WO2007000337 A1 WO 2007000337A1 EP 2006006253 W EP2006006253 W EP 2006006253W WO 2007000337 A1 WO2007000337 A1 WO 2007000337A1
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Prior art keywords
tetrahydronaphthalen
formula
compound
alkyl
difluorophenylamino
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PCT/EP2006/006253
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German (de)
English (en)
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WO2007000337A8 (fr
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Carmen Almansa Rosales
Marina VIRGILI BERNADÓ
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Palau Pharma, S.A.
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Publication of WO2007000337A1 publication Critical patent/WO2007000337A1/fr
Publication of WO2007000337A8 publication Critical patent/WO2007000337A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a new series of bicyclic derivatives, to processes to prepare them, to pharmaceutical compositions comprising these compounds as well as to their use in therapy.
  • MAPK mitogen-activated protein kinases
  • MAPK activate their substrates by phosphorylation in serine and threonine residues.
  • MAPK are activated by other kinases in response to a wide range of signals including growth factors, pro-inflammatory cytokines, UV radiation, endotoxins and osmotic stress. Once they are activated, MAPK activate by phosphorylation other kinases or proteins, such as transcription factors, which, ultimately, induce an increase or a decrease in expression of a specific gene or group of genes.
  • the MAPK family includes kinases such as p38, ERK (extracellular- regulated protein kinase) and JNK (C-Jun N-terminal kinase).
  • p38 kinase plays a crucial role in cellular response to stress and in the activation pathway in the synthesis of numerous cytokines, especially tumor necrosis factor (TNF- ⁇ ), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8).
  • TNF- ⁇ tumor necrosis factor
  • IL-1 interleukin-1
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • IL-1 and TNF- ⁇ are produced by macrophages and monocytes and are involved in the mediation of immunoregulation processes and other physiopathological conditions.
  • elevated levels of TNF- ⁇ are associated with inflammatory and autoimmune diseases and with processes that trigger the degradation of connective and bone tissue such as rheumatoid arthritis, osteoarthritis, diabetes, inflammatory bowel disease and sepsis.
  • p38 kinase inhibitors can be useful to treat or prevent diseases mediated by cytokines such as IL-1 and TNF- ⁇ , such as the ones mentioned above.
  • p38 inhibitors inhibit other pro-inflammatory proteins such as IL-6, IL-8, interferon- ⁇ and GM-CSF (granulocyte-macrophage colony-stimulating factor). Moreover, in recent studies it has been found that p38 inhibitors not only block cytokine synthesis but also the cascade of signals that these induce, such as induction of the cyclooxygenase-2 enzyme (COX-2).
  • COX-2 cyclooxygenase-2 enzyme
  • One aspect of the present invention relates to the compounds of general formula I
  • A represents CRiR 2 or NR 3 ;
  • Ri and R 2 independently represent hydrogen or C 1-4 alkyl
  • R 3 represents -(CH 2 ) P -Cy 1 , Ci -4 alkyl or Ci -4 hydroxyalkyl; m represents 1 or 2;
  • R 4 represents one or more groups selected from hydrogen, halogen, Ci -4 alkyl,
  • Cy 1 represents phenyl, heteroaryl or C 3-7 cycloalkyl, which can all be optionally substituted with one or more R 5 ;
  • R 5 represents Ci -4 alkyl, halogen, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy;
  • R ⁇ represents hydrogen or R 7 ;
  • R 7 represents Ci -6 alkyl optionally substituted with one or more groups selected from halogen, -OR 8 ', -NO 2 , -CN, -COR 8 ', -CO 2 R 8 ', -CONR 9 R 9 ', -NR 9 R 9 ',
  • R 8 represents C 1-4 alkyl, Ci -4 haloalkyl or Ci -4 hydroxyalkyl
  • R 8 ' represents hydrogen or R 8 ;
  • R 9 represents Ci -4 alkyl or Ci -4 hydroxyalkyl
  • R 9 ' represents hydrogen or R 9 ;
  • Cy 2 represents phenyl, heteroaryl, C 3-7 cycloalkyl or heterocyclyl, which can all be optionally substituted with one or more groups selected from Ci -4 alkyl, halogen,
  • Ci -4 alkoxy, Ci -4 haloalkyl and Ci -4 haloalkoxy Ci -4 alkoxy, Ci -4 haloalkyl and Ci -4 haloalkoxy.
  • the present invention also relates to the salts and solvates of the compounds of formula I.
  • Some compounds of formula I can have chiral centres that can give rise to various stereoisomers.
  • the present invention relates to each of these stereoisomers and also mixtures thereof.
  • the compounds of formula I are p38 kinase inhibitors and also inhibit the production of cytokines such as TNF- ⁇ .
  • A represents CRiR 2 or NR 3 ;
  • Ri and R 2 independently represent hydrogen or Ci -4 alkyl
  • R 3 represents -(CH 2 ) P -Cy 1 , Ci -4 alkyl or Ci -4 hydroxyalkyl; m represents 1 or 2;
  • R 4 represents one or more groups selected from hydrogen, halogen, Ci -4 alkyl,
  • R 5 represents Ci -4 alkyl, halogen, Ci -4 alkoxy, Ci -4 haloalkyl or Ci -4 haloalkoxy;
  • R 6 represents hydrogen or R 7 ;
  • R 7 represents Ci -6 alkyl optionally substituted with one or more groups selected from halogen, -OR 8 ', -NO 2 , -CN, -COR 8 ', -CO 2 R 8 ', -CONR 9 R 9 ', -NR 9 R 9 .,
  • R 8 represents Ci -4 alkyl, Ci -4 haloalkyl or Ci -4 hydroxyalkyl
  • R 8 ' represents hydrogen or R 8 ;
  • R 9 represents Ci -4 alkyl or Ci -4 hydroxyalkyl;
  • R 9 ' represents hydrogen or Rg
  • Cy 2 represents phenyl, heteroaryl, C 3-7 cycloalkyl or heterocyclyl, which can all be optionally substituted with one or more groups selected from Ci -4 alkyl, halogen,
  • Ci -4 alkoxy, Ci -4 haloalkyl and Ci -4 haloalkoxy for use in therapy.
  • Another aspect of this invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by p38.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by cytokines.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of diseases mediated by TNF- ⁇ , IL-1 ,
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.
  • a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of diseases mediated by TNF- ⁇ , IL-1 , IL-6 and/or IL-8.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.
  • a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2.
  • Another aspect of the present invention relates to a method of treating or preventing a disease mediated by p38 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention relates to a method of treating or preventing a disease mediated by cytokines in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention relates to a method of treating or preventing a disease mediated by TNF- ⁇ , IL-1 , IL-6 and/or IL-8 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention relates to a method of treating or preventing a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a disease selected from immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with the induction of cyclooxygenase-2 in a subject in need thereof, especially a human being, which comprises administering to said subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
  • A, R 4 and m have the meaning described above and Y represents halogen or trifluoromethanesulfonate, in the presence of a base and a palladium catalyst; or
  • A, R 4 and m have the meaning described above; or (c) converting, in one or a plurality of steps, a compound of formula I into another compound of formula I.
  • Ci -n alkyl as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to n carbon atoms.
  • n 4
  • it includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te/f-butyl.
  • n 6 examples include among others the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, pentyl, isopentyl, neopentyl and hexyl.
  • a Ci -4 haloalkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci ⁇ alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different.
  • halogen atoms i.e. fluoro, chloro, bromo or iodo
  • Examples include, among others, trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl and nonafluorobutyl.
  • Ci -4 alkoxy group means an alkoxy group having from 1 to 4 carbon atoms, the alkyl moiety having the same meaning as previously defined. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and ferf-butoxy.
  • Ci -4 haloalkoxy group means a group resulting from the replacement of one or more hydrogen atoms from a Ci -4 alkoxy group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different.
  • halogen atoms i.e. fluoro, chloro, bromo or iodo
  • Examples include, among others, trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy, 1 -fluoroethoxy , 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3- tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4- fluorobutoxy and nonafluorobutoxy.
  • a Ci- 4 hydroxyalkyl group means a group resulting from the replacement of one or more hydrogen atoms from a Ci -4 alkyl group with one or more hydroxy groups. Examples include, among others, hydroxy methyl, 1-hydroxyethyl, 2- hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1- hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxy butyl, 3-hydroxybutyl, 2- hydroxybutyl and 1 -hydroxy butyl.
  • a halogen radical means fluoro, chloro, bromo or iodo.
  • a C 3-7 cycloalkyl group means a saturated monocyclic hydrocarbon ring having 3 to 7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the term heteroaryl means an aromatic 5- or 6-membered monocyclic or 8- to 12-membered bicyclic ring which contains from 1 to 4 heteroatoms selected from N, S and O.
  • the heteroaryl group can be linked to the rest of the molecule through any available carbon or nitrogen atom.
  • N atoms in the ring can be optionally oxidized forming N + O * .
  • heteroaryl group can be optionally substituted as disclosed above in the definitions of Cy 1 and Cy 2 ; if substituted, the substituents can be the same or different and can be placed on any available position in the ring.
  • heteroaryl groups include among others 1,2,4- oxadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, imidazopyrazinyl
  • a heterocyclyl group means a 3- to 7-membered monocyclic carbocyclic ring or an 8- to 12-membered bicyclic carbocyclic ring which can be saturated or partially unsaturated (i.e. non-aromatic) and which contains from 1 to 4 heteratoms selected from N, S and O, and wherein said ring can be linked to the rest of the molecule through any available carbon or nitrogen atom. Additionally, one or more C or S atoms in the ring can be optionally oxidized, forming CO, SO or SO 2 groups.
  • the heterocyclyl group can be optionally substituted as disclosed above in the definition of Cy 2 ; if substituted, the substituents can be the same or different and can be placed on any available position in the ring.
  • the heterocyclyl is a 3- to 7-membered monocyclic ring. More preferably, the heterocyclyl ring has 5 or 6 ring atoms.
  • heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, oxetanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyrrolidinyl, thiazolidinyl, dioxanyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, tetrahydropyranyl, azepinyl, oxazinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolinyl, isothiazolinyl, te
  • heteroaryl when the specified examples refer to a bicycle in general terms, all possible dispositions of the atoms are included.
  • the term pyrazolopyridinyl is to be understood as including groups such as 1 /-/-pyrazolo[3,4-b]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, 1H-pyrazolo[3,4- ⁇ yridinyl, 1H-pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-b]pyridinyl;
  • the term imidazopyrazinyl is to be understood as including groups such as 1/-/-imidazo[4,5- b]pyrazinyl, imidazo[1 ,2-a]pyrazinyl and imidazo[1 ,5-a]pyrazinyl and the term pyrazolopyrimidinyl is to be understood as including groups such as 1 H- pyrazol
  • a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, more preferably with 1 or 2 substituents, provided that said group has enough positions available susceptible of being substituted.
  • said substituents can be the same or different and can be placed on any available position.
  • R 4 represents one or more, preferably one or two, groups selected from hydrogen, halogen, Ci -4 alkyl, Ci -4 haloalkyl, NH 2 and Ci -4 hydroxyalkyl.
  • the group or groups R 4 can be placed upon any available position of the phenyl ring and when there is more than one R 4 group, they can be the same or different.
  • the invention thus relates to the compounds of formula I as defined here above.
  • the invention relates to compounds of formula I wherein A represents CR1R2.
  • the invention relates to compounds of formula I wherein A represents NR 3 .
  • the invention relates to compounds of formula I wherein m is 1.
  • the invention relates to compounds of formula I wherein m is 2.
  • the invention relates to compounds of formula I wherein A represents CRiR 2 and m is 1. In a further embodiment, the invention relates to compounds of formula I wherein A represents NR 3 and m is 1.
  • the invention relates to compounds of formula I wherein A represents CR1R2 and m is 2.
  • the invention relates to compounds of formula I wherein A represents NR 3 and m is 2.
  • the invention relates to compounds of formula I wherein Ri is identical to R 2 .
  • the invention relates to compounds of formula I wherein p is 0 or 1. In a further embodiment, the invention relates to compounds of formula I wherein R 3 represents -(CH 2 ) P -Cy 1 . In a further embodiment, the invention relates to compounds of formula I wherein R 3 represents -(CH 2 ) P -Cy 1 and Cy 1 represents phenyl or heteroaryl, which can all be optionally substituted with one or more R 5 .
  • the invention relates to compounds of formula I wherein R 4 represents one or two groups selected from hydrogen, halogen, Ci -4 alkyl, C 1-4 haloalkyl, NH 2 and Ci -4 hydroxyalkyl.
  • the invention relates to compounds of formula I wherein R 4 represents one or two groups selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, NH 2 and C 1-4 hydroxyalkyl.
  • the invention relates to compounds of formula I wherein R 4 represents one or two groups selected from halogen, C 1-4 alkyl, NH 2 and C 1-4 hydroxyalkyl.
  • the invention relates to compounds of formula I wherein R 4 represents one or two groups selected from halogen, methyl, NH 2 and Ci -4 hydroxyalkyl.
  • the invention relates to compounds of formula I wherein the phenyl ring bearing R 4 represents a ring selected from (a)-(h):
  • the CH 3 group can be placed on any available position in the phenyl ring.
  • the invention relates to compounds of formula I wherein R 6 represents hydrogen or Ci -6 alkyl optionally substituted with one group selected from -OR 8 ', -NR 9 R 9 ' and Cy 2 .
  • the invention relates to compounds of formula I wherein R 6 represents hydrogen.
  • the present invention covers all possible combinations of particular and preferred groups described hereinabove.
  • the invention relates to compounds according to formula I above which provide more than 50% inhibition of p38 activity at 10 ⁇ M, more preferably at 1 ⁇ M and still more preferably at 0.1 ⁇ M, in a p38 assay such as the ones described in Example 13.
  • the invention relates to a compounds according to formula I selected from:
  • the compounds of the present invention may contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids.
  • salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid
  • organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic
  • Some of the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases.
  • these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, ⁇ /-methylglucamine, procaine and the like.
  • salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I with a sufficient amount of the desired acid or base to give the salt in the conventional manner.
  • the salts of the compounds of formula I can be converted into other salts of the compounds of formula I by ion exchange using ionic exchange resins.
  • the compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates.
  • solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent.
  • solvents include pharmaceutically acceptable solvents such as water, ethanol and the like.
  • a complex with water is known as a hydrate.
  • Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention.
  • Some of the compounds of the present invention may exist as several diastereoisomers and/or several optical isomers.
  • Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on products of general formula I.
  • Optically pure isomers can also be individually obtained using enantiospecific synthesis.
  • the present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.
  • the compounds of formula I can be obtained by following the processes described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups by conventional protective groups. Both the nature of these protective groups and the procedures for their introduction or removal are well known in the art (see for example Greene T.W. and Wuts P. G. M, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd edition, 1999). As an example, as protective groups of an amino function tert- butoxycarbonyl (Boc) or benzyl (Bn) groups can be used.
  • Boc tert- butoxycarbonyl
  • Bn benzyl
  • the carboxyl groups can be protected for example in the form of Ci -4 alkyl esters or arylalkyl esters, such as benzyl, while the hydroxyl groups can be protected for example with tetrahydropyranyl (THP) or benzyl (Bn) groups.
  • THP tetrahydropyranyl
  • Bn benzyl
  • A, R 4 and m have the meaning described above and Y represents halogen, preferably bromo, or trifluoromethanesulfonate.
  • This reaction can be carried out in the presence of a base, such as CS 2 CO 3 or sodium te/f-butoxide, in the presence of a palladium catalyst, such as palladium acetate (II) or tris(dibenzylideneacetone)dipalladium(0), and a phosphine such as 2,2'- bis(diphenylphosphino)-1 ,1'-binaphthyl, in a solvent such as toluene or dioxane.
  • a base such as CS 2 CO 3 or sodium te/f-butoxide
  • a palladium catalyst such as palladium acetate (II) or tris(dibenzylideneacetone)dipalladium(0)
  • a phosphine such as 2,2'- bis(dip
  • R 1 and/or R 2 represent Ci -4 alkyl
  • m has the meaning described above
  • Y represents halogen, preferably bromo
  • Rj represents Ci -4 alkyl
  • W represents halogen or alkylsulfonate, preferably iodo.
  • This reaction can be carried out in the presence of a base such as sodium hydride, in a suitable solvent such as toluene, tetrahydrofuran or dimethylformamide, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent.
  • R 1 and R 2 represent Ci -4 alkyl and Ri ⁇ R2
  • this reaction is carried out in a two step sequence that involves alkylating a compound of formula Ha with an alkylating agent RiW to give a mono-alkylated intermediate and then reacting this intermediate with a second alkylating agent R2W to yield the compound of formula lib.
  • R represents C 1 - 4 alkyl
  • Y represents halogen, preferably bromo
  • R 3 has the meaning described above.
  • This reaction can be carried out in a suitable solvent such as methanol, ethanol or dimethylformamide, optionally in the presence of a base such as a tertiary amine (like triethylamine or N, N- diisopropylethylamine), sodium carbonate or potassium carbonate, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent.
  • a suitable solvent such as methanol, ethanol or dimethylformamide
  • a base such as a tertiary amine (like triethylamine or N, N- diisopropylethylamine), sodium carbonate or potassium carbonate
  • this reaction can be carried out in a two step sequence that involves bromo displacement from a compound of formula Va by the amine Vl, in a suitable solvent such as methanol, ethanol or dimethylformamide, to yield an intermediate aminoester, and final cyclization to the compound of formula Hc by heating in acetic acid or polyphosphoric acid.
  • a suitable solvent such as methanol, ethanol or dimethylformamide
  • a and m have the meaning described above and Y represents trifluoromethanesulfonate.
  • This reaction can be carried out in the presence of a suitable sulfonylating agent, such as trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride, in a suitable solvent such as pyridine or dichloromethane, in the presence of a base such as pyridine or triethylamine, and at a suitable temperature comprised between 0 0 C and room temperature.
  • a suitable sulfonylating agent such as trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride
  • a suitable solvent such as pyridine or dichloromethane
  • a base such as pyridine or triethylamine
  • a and m have the meaning described above.
  • This reaction can be carried out in the presence of a strong acid, such as 48% HBr, and at a suitable temperature comprised between room temperature and the temperature of the boiling point of the solvent, or in the presence of a Lewis acid such as boron tribromide, in a suitable solvent such as dichloromethane, and at a temperature comprised preferably between -78 0 C and room temperature.
  • a strong acid such as 48% HBr
  • a Lewis acid such as boron tribromide
  • Ci-4 alkyl (VIIIb) can be obtained by reaction of compounds of formula Villa under the same conditions previously described for the conversion of a compound of formula Ua into a compound of formula lib, as shown in the following scheme:
  • Ri and/or R 2 represent C 1-4 alkyl, and m and Rj have the meaning described above.
  • R has the meaning described above and Y' represents halogen, preferably bromo, or methoxy.
  • This reaction can be carried out in the presence of a suitable halogenating agent, such as ⁇ /-bromosuccinimide, optionally in the presence of a radical initiator such as 2,2'-azobis(2-methylbutyronitrile) or benzoyl peroxide, in a suitable solvent such as CCI 4 , CHCI3, acetonitrile or chlorobenzene, and at a suitable temperature comprised between room temperature and the temperature of the boiling point of the solvent, optionally irradiating the mixture.
  • a suitable halogenating agent such as ⁇ /-bromosuccinimide
  • a radical initiator such as 2,2'-azobis(2-methylbutyronitrile) or benzoyl peroxide
  • a suitable solvent such as CCI 4 , CHCI3, acetonitrile or chlorobenzene
  • R and Y' have the meaning described above.
  • This reaction can be carried out in the presence of an inorganic acid such as concentrated sulfuric acid, using the alcohol of formula Xl as the solvent, and at a suitable temperature comprised between room temperature and the temperature of the boiling point of the solvent.
  • an inorganic acid such as concentrated sulfuric acid
  • a compound of formula X can be converted into the corresponding acyl chloride by using standard conditions and then the latter can be converted into the corresponding ester of formula IX by reaction with an alcohol of formula Xl, in the presence of a base such as triethylamine, in a suitable solvent such as or example dichloromethane, and at a suitable temperature comprised between 0 0 C and room temperature.
  • R 3 and m have the meaning described above.
  • this reaction can be carried out by treatment with an alkylating agent such as a halide or alkylsulfonate of formula XIII, preferably an alkyl iodide, in the presence of a base such as sodium hydride, in a suitable solvent such as toluene, tetrahydrofuran or dimethylformamide, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent.
  • an alkylating agent such as a halide or alkylsulfonate of formula XIII, preferably an alkyl iodide
  • R 3 is a phenyl or heteroaryl group
  • this reaction can be carried out by reaction with an halide of formula XIII, preferably a bromide, in the presence of a base, such as K 2 CO 3 , Na 2 CO 3 or K 3 PO 4 , and a copper catalyst, such as copper(l) iodide, in a solvent such as ⁇ /-methylpyrrolidone and heating, preferably at reflux.
  • a base such as K 2 CO 3 , Na 2 CO 3 or K 3 PO 4
  • a copper catalyst such as copper(l) iodide
  • This reaction can be carried out in the presence of a suitable reducing agent such as tin (II) chloride or iron, in a suitable solvent such as ethanol or acetic acid, or alternatively in the presence of hydrogen gas and a palladium catalyst, such as palladium on carbon, in a suitable solvent such as methyl alcohol, ethyl alcohol or ethyl acetate.
  • a suitable reducing agent such as tin (II) chloride or iron
  • a suitable solvent such as ethanol or acetic acid
  • a palladium catalyst such as palladium on carbon
  • A, R 4 and m have the meaning described above and Y represents halogen, preferably bromo, or trifluoromethanesulfonate. This reaction is carried out under the same reaction conditions described above for the preparation of compounds Ia from Il and III.
  • compounds of formula XV can be obtained starting from an amine of formula XVII and a fluoro compound of formula XVIII 1 as shown in the following scheme:
  • reaction can be carried out optionally in the presence of a base, such as potassium terf-butoxide, in a suitable solvent, such as dimethyl sulfoxide, and at a temperature comprised between room temperature and the temperature of the boiling point of the solvent.
  • a base such as potassium terf-butoxide
  • suitable solvent such as dimethyl sulfoxide
  • some compounds of the present invention can also be obtained from other compounds of formula I by appropriate conversion reactions of functional groups in one or several steps, using well-known reactions in organic chemistry under the reported standard experimental conditions.
  • a group R 3 can be converted into another group R 3 , giving rise to new compounds of formula I.
  • a palladium catalyst such as palladium on carbon
  • a suitable alkylating agent such as a halide, preferably a iodide, or an alkyl- or arylsulfonate
  • a base such as
  • the compounds of the present invention act as p38 kinase inhibitors, inducing the reduction of proinflammatory cytokines. Therefore, the compounds of the invention are expected to be useful to treat or prevent diseases in which p38 plays a role in mammals, including human beings. This includes diseases caused by overproduction of cytokines such as TNF- ⁇ , IL- 1 , IL-6 or IL-8. These diseases include, but are not limited to, immune, autoimmune and inflammatory diseases, cardiovascular diseases, infectious diseases, bone resorption disorders, neurodegenerative diseases, proliferative diseases and processes associated with cyclooxygenase-2 induction. Preferred diseases to be treated or prevented with the compounds of the invention are immune, autoimmune and inflammatory diseases.
  • immune, autoimmune and inflammatory diseases that can be treated or prevented with the compounds of the present invention include rheumatic diseases (e.g. rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis), glomerulonephritis (with or without nephrotic syndrome), autoimmune hematologic disorders (e.g. hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia and neutropenia), autoimmune gastritis and autoimmune inflammatory bowel diseases (e.g.
  • rheumatic diseases e.g. rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovit
  • ulcerative colitis and Crohn's disease host versus graft disease, allograft rejection, chronic thyroiditis, Graves' disease, schleroderma, diabetes (type I and type II), active hepatitis (acute and chronic), primary biliary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, chronic renal insufficiency, Stevens-Johnson syndrome, idiopathic sprue, sarcoidosis, Guillain- Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome
  • Cardiovascular diseases that can be treated or prevented include, among others, myocardial infarction, cardiac hypertrophy, cardiac insufficiency, ischaemia-reperfusion disorders, thrombosis, thrombin-induced platelet aggregation, acute coronary syndromes, atherosclerosis and cerebrovascular accidents.
  • Infectious diseases that can be treated or prevented include, among others, sepsis, septic shock, endotoxic shock, sepsis by Gram-negative bacteria, shigellosis, meningitis, cerebral malaria, pneumonia, tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and hepatitis C), HIV infection, retinitis caused by cytomegalovirus, influenza, herpes, treatment of infections associated with severe bums, myalgias caused by infections, cachexia secondary to infections, and veterinary viral infections such as lentivirus, caprine arthritic virus, visna-maedi virus, feline immunodeficiency virus, bovine immunodeficiency virus or canine immunodeficiency virus.
  • Bone resorption disorders that can be treated or prevented include osteoporosis, osteoarthritis, traumatic arthritis and gouty arthritis, as well as bone disorders related with multiple myeloma, bone fracture and bone grafting and, in general, all these processes wherein it is necessary to induce osteoblastic activity and increase bone mass.
  • Neurodegenerative diseases that can be treated or prevented include Alzheimer's disease, Parkinson's disease, cerebral ischaemia and traumatic neurodegenerative disease, among others.
  • Proliferative diseases that can be treated or prevented include endometriosis, solid tumors, acute and chronic myeloid leukemia, Kaposi sarcoma, multiple myeloma, metastatic melanoma and angiogenic disorders such as ocular neovascularisation and infantile haemangioma.
  • p38 kinase inhibitors also inhibit the expression of proinflammatory proteins such as cyclooxygenase-2 (COX-2), the enzyme responsible for prostaglandin production.
  • COX-2 cyclooxygenase-2
  • the compounds of the present invention can also be used to treat or prevent diseases mediated by COX-2 and especially to treat processes with edema, fever and neuromuscular pain such as cephalea, pain caused by cancer, tooth pain, arthritic pain, hyperalgesia and allodynia.
  • a compound to be tested can be contacted with the purified p38 enzyme to determine whether inhibition of p38 activity occurs.
  • cell-based assays can be used to measure the ability of a compound to inhibit the production of cytokines such as TNFalpha, e.g. in stimulated peripheral blood mononuclear cells (PBMCs) or other cell types.
  • PBMCs peripheral blood mononuclear cells
  • testing at 10 ⁇ M must result in an activity of more than 50% inhibition in at least one of the tests provided in Example 13. More preferably, compounds should exhibit more than 50% inhibition at 1 ⁇ M, and still more preferably, they should exhibit more than 50% inhibition at 0.1 ⁇ M.
  • the present invention also relates to a pharmaceutical composition which comprises a compound of the present invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients.
  • the excipients must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral, nasal, ocular, rectal and topical administration.
  • Solid compositions for oral administration include tablets, granulates and capsules.
  • the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients.
  • excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc.
  • Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability.
  • the active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents.
  • Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.
  • Powders and granulates for the preparation of oral suspensions by the additon of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives.
  • Other excipients can also be added, for example sweetening, flavouring and colouring agents.
  • Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly-used inert diluents, such as purified water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol.
  • Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, flavouring agents, preservatives and buffers.
  • Injectable preparations for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils.
  • aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils.
  • These compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process.
  • the active compound can be preferably formulated as a suppository on an oily base, such as for example vegetable oils or solid semisynthetic glycerides, or on a hydrophilic base such as polyethylene glycols (macrogol).
  • an oily base such as for example vegetable oils or solid semisynthetic glycerides
  • a hydrophilic base such as polyethylene glycols (macrogol).
  • the compounds of the invention can also be formulated for their topical application for the treatment of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract.
  • Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.
  • the compound for the nasal administration or for inhalation, can be formulated as an aerosol and it can be conveniently released using suitable propellants.
  • the dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors.
  • a representative example of a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.
  • MS spectra have been obtained with positive electrospray ionization mode over a scan range from 100 to 800 amu.
  • the reaction mixture was allowed to cool to room temperature and some drops of MeOH were added to destroy the excess of hydride. It was diluted with EtOAc and water and the phases were separated. The aqueous phase was thoroughly reextracted with EtOAc and the combined organic phases were washed with 2N NaOH and 1N HCI. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated.
  • the crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 1.60 g of the title compound (yield: 46%).
  • a total of 5 ⁇ l_ of the test product (final concentration, 0.001-10 ⁇ M), 5-10 mil of p38 ⁇ with 0.33 mg/mL of myelin basic protein, Mg 2+ acetate (10 mM) and [ ⁇ 33 P-ATP] (100 ⁇ M, specific activity 500 cpm/pmol) in buffer Tris 25 mM pH7.5, EGTA 0.02 mM is incubated.
  • the reaction is started by adding Mg 2+ [ ⁇ 33 P-ATP]. After incubation for 40 min at room temperature, the reaction is quenched by adding 5 ⁇ L of 3% phosphoric acid solution.
  • the reaction mixture (10 ⁇ l_) is passed through a filter (P30) and washed three times for 5 min with a 75 mM phosphoric acid solution and once with methanol before drying it and counting it, by liquid scintillation.
  • Compound stocks in 100% DMSO are first diluted in DMSO to a concentration of 1x10 "3 up to 3.2x10 "8 M and then further diluted in kinase assay buffer (10 mM Tris-HCI, pH 7.2, 10 mM MgCI 2 , 0.01% tween 20, 0.05% NaN 3 , 1 mM DTT) to a concentration range of 4x10 "5 up to 1.3x10 "9 M.
  • kinase assay buffer (10 mM Tris-HCI, pH 7.2, 10 mM MgCI 2 , 0.01% tween 20, 0.05% NaN 3 , 1 mM DTT
  • the reaction is stopped by the addition of 60 ⁇ l_ of IMAP binding reagent, which has been diluted 400-fold in IMAP binding buffer (stock concentration 5 times diluted in MiIIi Q). After incubation for 30 min at RT, FP is measured on an AnalystTM multimode fluorescence plate reader (Molecular Devices) at excitation wavelength of 485 nm and emission wavelength of 530 nm (1 sec/well).
  • PBMCs peripheral blood mononuclear cells
  • PBMCs Heparinized venous blood, obtained from healthy volunteers, is diluted with an equal volume of saline phosphate buffer without calcium or magnesium. Aliquots of 30 ml_ of the mixture are transferred to 50 ml_ centrifuge tubes containing 15 ml_ of Ficoll-Hypaque (1.077 g/mL). The tubes are centrifuged at 1200 x g for 20 min at room temperature without braking. Approximately two-thirds of the band of platelets lying above the mononuclear cells is removed with a pipette.
  • the mononuclear cells are carefully transferred to a 50 mL tube, washed twice with saline phosphate buffer, centrifuged at 300 x g for 10 min at room temperature and resuspended in RPMI supplemented with 1% inactivated fetal bovine serum at a cell density of 2x10 6 cells/mL Assay: 100 ⁇ l_ of mononuclear cells (2x10 6 cells/mL) are incubated in 96-well plates with 50 ⁇ L of the test product (final concentration, 0.001-10 ⁇ M) and 50 ⁇ l_ LPS (E.

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Abstract

L'invention se rapporte à de nouveaux dérivés bicycliques de formule (I), dans laquelle les significations des différents substituants sont précisées dans la description. Ces composés sont utiles en tant qu'inhibiteurs de p38 kinase.
PCT/EP2006/006253 2005-06-29 2006-06-28 Derives bicycliques utilises en tant qu'inhibiteurs de p38 kinase WO2007000337A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
DE102007024283A1 (de) 2007-05-23 2008-11-27 Lothar Ernst Wilhelm Weber Mittel zum Abbau von Schadstoffen, insbesondere aus der Raumluft
CN110498759A (zh) * 2019-09-12 2019-11-26 天津瑞岭化工有限公司 异吲哚啉酮类化合物的合成方法
US10513515B2 (en) 2017-08-25 2019-12-24 Biotheryx, Inc. Ether compounds and uses thereof
WO2021146543A1 (fr) * 2020-01-15 2021-07-22 The Trustees Of Princeton University Inhibiteurs de glucose-6-phosphate déshydrogénase et leurs utilisations
US11236103B2 (en) 2018-07-27 2022-02-01 Biotheryx, Inc. Bifunctional compounds
US11897930B2 (en) 2020-04-28 2024-02-13 Anwita Biosciences, Inc. Interleukin-2 polypeptides and fusion proteins thereof, and their pharmaceutical compositions and therapeutic applications

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WO2004108672A1 (fr) * 2003-06-02 2004-12-16 Abbott Laboratories Composes d'isoindoline-1-one utilises en tant qu'inhibiteurs de kinase
WO2005035503A1 (fr) * 2003-10-15 2005-04-21 Ube Industries, Ltd. Nouveau derive isoquinoline
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WO2004108672A1 (fr) * 2003-06-02 2004-12-16 Abbott Laboratories Composes d'isoindoline-1-one utilises en tant qu'inhibiteurs de kinase
WO2005039564A1 (fr) * 2003-10-02 2005-05-06 Vertex Pharmaceuticals Incorporated Composes phtalimide utiles en tant qu'inhibiteurs de proteine kinase
WO2005035503A1 (fr) * 2003-10-15 2005-04-21 Ube Industries, Ltd. Nouveau derive isoquinoline

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
DE102007024283A1 (de) 2007-05-23 2008-11-27 Lothar Ernst Wilhelm Weber Mittel zum Abbau von Schadstoffen, insbesondere aus der Raumluft
US10513515B2 (en) 2017-08-25 2019-12-24 Biotheryx, Inc. Ether compounds and uses thereof
US10927104B2 (en) 2017-08-25 2021-02-23 Biotheryx, Inc. Ether compounds and uses thereof
US11236103B2 (en) 2018-07-27 2022-02-01 Biotheryx, Inc. Bifunctional compounds
CN110498759A (zh) * 2019-09-12 2019-11-26 天津瑞岭化工有限公司 异吲哚啉酮类化合物的合成方法
WO2021146543A1 (fr) * 2020-01-15 2021-07-22 The Trustees Of Princeton University Inhibiteurs de glucose-6-phosphate déshydrogénase et leurs utilisations
US11897930B2 (en) 2020-04-28 2024-02-13 Anwita Biosciences, Inc. Interleukin-2 polypeptides and fusion proteins thereof, and their pharmaceutical compositions and therapeutic applications

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