WO2008064830A1 - Dérivés bicycliques et hétérobicycliques, leurs procédés de fabrication et leurs utilisations pharmaceutiques - Google Patents

Dérivés bicycliques et hétérobicycliques, leurs procédés de fabrication et leurs utilisations pharmaceutiques Download PDF

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Publication number
WO2008064830A1
WO2008064830A1 PCT/EP2007/010191 EP2007010191W WO2008064830A1 WO 2008064830 A1 WO2008064830 A1 WO 2008064830A1 EP 2007010191 W EP2007010191 W EP 2007010191W WO 2008064830 A1 WO2008064830 A1 WO 2008064830A1
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WIPO (PCT)
Prior art keywords
pyridin
oxospiro
imidazo
phenylalaninate
ethyl
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PCT/EP2007/010191
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English (en)
Inventor
Richard John Davenport
Andrew James Ratcliffe
Benjamin Perry
David Jonathan Phillips
Mark William Jones
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Ucb Pharma, S.A.
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Priority claimed from GB0623615A external-priority patent/GB0623615D0/en
Application filed by Ucb Pharma, S.A. filed Critical Ucb Pharma, S.A.
Publication of WO2008064830A1 publication Critical patent/WO2008064830A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P33/00—Antiparasitic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention concerns bicyclic and heterocyclic derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
  • the integrin ⁇ 4 ⁇ 1 (also termed VLA-4 or Very Late Antigen-4 and designated CD49d/CD29) is predominantly expressed on eosinophils, lymphocytes, monocytes and basophils. It binds primarily to the vascular cell surface adhesion molecule VCAM-1 that is expressed on endothelium in response to inflammatory cytokines (TNF- ⁇ , IL-1 and selectively IL-4 and IL-13) and to the extracellular matrix protein fibronectin.
  • VCAM-1 vascular cell surface adhesion molecule
  • ⁇ 4 ⁇ 1 is not expressed on circulating neutrophils, which are the first defence against infection, it is a target for the pharmacological control of inflammatory diseases.
  • ⁇ 4 ⁇ 1 in cell adhesion mediated inflammatory pathologies and that blocking its function is beneficial.
  • Diseases include asthma, multiple sclerosis (MS), rheumatoid arthritis (RA) or inflammatory bowel diseases.
  • ⁇ 4 ⁇ 1 is also expressed on leukemic cells that show increased survival through binding to fibronectin expressed on bone marrow stormal cells. Blocking this interaction in the presence of chemotherapy is beneficial in preventing relapse of acute myelogenous leukemia.
  • ⁇ 4 ⁇ 1 and VCAM-1 have also been identified in smooth muscle cells from intimal atherosclerotic thickening of adult aorta. Blocking this interaction is beneficial in preventing smooth muscle differentiation and atherosclerosis.
  • ⁇ 4 ⁇ 1 on inflammatory cells with fibronectin has also been shown to increase chronic allograft failure. Blocking this interaction is beneficial in supporting transplant survival.
  • ⁇ 4-has also been related to cancers (including cancers, whether solid or haematopoietic) but not limited to, lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the integrin ⁇ 4 ⁇ 7 (also termed LPAM-1 ) is expressed on certain sub-populations of T and B lymphocytes and on eosinophils. Like ⁇ 4 ⁇ 1 , ⁇ 4 ⁇ 7 binds VCAM-1 and fibronectin. In addition ⁇ 4 ⁇ 7 binds to a cell surface adhesion molecule MAdCAM-1 that is expressed preferentially in the gastrointestinal tract and which is believed to be involved in the homing of leukocytes to gastrointestinal mucosa. The interaction between ⁇ 4 ⁇ 7 and MAdCAM-1 may also be important sites of inflammation outside of mucosal tissue.
  • bicyclic and heterocyclic compounds that are potent and selective inhibitors of ⁇ 4 integrins, such as ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7. These compounds have no or minimal inhibitory action on ⁇ integrins of other subgroups.
  • the invention therefore provides a compound having formula I, its enantiomers, diastereois salt thereof,
  • X 1 is C or N
  • X 2 is CH or N
  • X 3 is C or N
  • X 4 is C- R a , N- Rb or N
  • R a is hydrogen, halogen, 4-7 membered heterocycle or C1.3 alkyl
  • Rb is hydrogen, 4-7 membered heterocycle or C1.3 alkyl;
  • R1 is hydrogen, halogen or C-) _Q alkylamino;
  • R 2 is hydrogen or C- ⁇ alkylamino;
  • R 3 is hydrogen or is 4-7 membered heterocycle (aromatic or non-aromatic) optionally substituted by a group selected from C- ⁇ alkyl, halogen, amino, C-
  • alkyl linear or branched optionally substituted by a group selected from halogen, C3.6 cycloalkyl, nitrile, amino, aryl, C- ⁇ ⁇ dialkylamino or C-
  • R ⁇ is hydrogen or C-
  • R ⁇ is hydrogen, C-
  • R 6 is C-] .3 alkyl
  • R 7 is C-
  • R6 and R 7 can form together a 6 membered ring directly attached to the 4 carbocycle
  • X 5 is CH or N
  • R8 is hydrogen, C-] .5 alkyl, hydroxyl or aryl.
  • the invention provides a compound having formula Ia its enantiomers, diastereoisomers, stereoisomeric forms, geometrical isomers or pharmaceutically acceptable salts thereof
  • X 1 is C or N
  • X 2 is CH or N
  • X 3 is C, or N
  • X 4 is C- R a , N- R b or N;
  • R a is hydrogen, halogen, 4-7 membered heterocycle or C-1.3 alkyl;
  • R D is hydrogen, 4-7 membered heterocycle or C1.3 alkyl;
  • R1 is hydrogen, halogen or C-
  • R ⁇ is hydrogen or C-] .Q alkylamino;
  • R3 is hydrogen or is 4-7 membered heterocycle (aromatic or non-aromatic) optionally substituted by a group selected from C-j. ⁇ alkyl, halogen, amino, C-
  • alkyl linear or branched optionally substituted by a group selected from halogen, C3.6 cycloalkyl, nitrile, amino, aryl, C- ⁇ dialkylamino or C ⁇
  • R4 is hydrogen or C ⁇ _2 alkyl
  • R 5 is hydrogen, C-
  • R 6 is C-1.3 alkyl
  • R 7 is C-
  • X 5 is CH or N
  • R8 is hydrogen, C-
  • alkyl represents saturated, monovalent hydrocarbon radicals having linear or branched moieties or combinations thereof and containing
  • alkyl 1-6 carbon atoms.
  • One methylene (-CH2-) group, of the alkyl, can be replaced by oxygen or sulfur.
  • Alkyl moieties can be optionally substituted by halogen, C3.6 cycloalkyl, nitrile, amino, C-1.3 alkylamino groups, C-1.3 dialkylamino groups, aryl.
  • alkyl groups are methyl, cyclopropylmethyl, iso-butyl, 1-methylsulfanylethyl, tert-butyl, iso-propyl, trifluoromethyl, methylsulfanyl, iso-propylsulfanyl, acetonitrile
  • Preferred alkyl groups are cyclopropylmethyl, iso-butyl, iso-propylsulfanyl.
  • cycloalkyl refers to a monovalent or divalent group of 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be optionally substituted by halogen or C- j . ⁇ alkyl groups as defined above. Usually cyclolakyl groups, in the present case are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- trifluoromethylcyclopropyl. Preferred cycloalkyl group is cyclopropyl.
  • amino refers to a group of formula -NH2.
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine. Usually halogen is chlorine, bromine or fluorine. Preferred halogens are bromine and fluorine.
  • nitrile refers to a group of formula -CN.
  • hydroxyl refers to a group of formula -OH.
  • aryl refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring or multiple rings, containing 6 to 10 carbon atoms by removal of one hydrogen atom, which can optionally be substituted by 1-3 halogens or by 1-3 C-
  • alkylamino refers to a group of formula -NHR C , wherein R c is a C- ⁇ ⁇ alkyl group as defined above.
  • R c is a C- ⁇ ⁇ alkyl group as defined above.
  • alkylamino groups in the present case, are methylamino, methylcyclopropylamino.
  • dialkylamino refers to a group of formula -NRdR e , wherein R ⁇ is C- ⁇ ⁇ alkyl group as defined above and R e is a C- ⁇ alkyl group as defined above. Usually dialkylamino group, in the present case is dimethylamino.
  • dimethylamino-2-ethanone refers to a group of formula - C(O)-CH 2 N(CH 3 ) 2 .
  • heterocycle refers to a 4 to 7 membered ring, which can be aromatic or non -aromatic, containing at least one heteroatom selected from O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure.
  • the S heteroatom can be oxidized.
  • Heterocycles can be monocyclic or polycyclic. Heterocycles can optionally be substituted by 1 to 3 C- j . ⁇ alkyl, amino, C-
  • heterocycle groups in the present case are, 3-pyridine, 5-dimethylamine-3-pyridine, 5-methylamine-3-pyridine, 5- dimethylamine-2-pyridine, 4-trifluoromethyl-3-pyridine, 4-chloro-3-pyridine, 4-methylamine- 3-pyridine, 4-N-piperidine-3-pyridine, 4-dimethylamine-3-pyridine, 3-piperidine, 4- piperidine, 2-piperidine, N-methyl-2-piperidine, 2-pyrrolidine, N-methyl-2- pyrrolidine, 2- azetidine, 3-pyrrole, 2-bromo-3pyrrole, , 2-morpholine, 2-(N, N dimethylglycine) piperidine.
  • Preferred heterocycles are 3-pyridine, 2-piperidine, 5-dimethylamine-3-pyridine, 5- methylamine-3-pyridine, 5-dimethylamine-2-pyridine, 3-piperidine, 4-trifluoromethyl-3- pyridine, 4-piperidine, 4-chloro-3-pyridine, 4-N-piperidine-3-pyridine, 4-methylamine-3- pyridine, 4-dimethylamine-3-pyridine, N-methyl-2- pyrrolidine, N-methyl-2-piperidine, 2- azetidine, 3-pyrrole, 2-bromo-3pyrrole, 4-perhydro-1 ,3-oxazine.
  • Most preferred heterocycles are 3-pyridine, 2-piperidine.
  • X 1 is C or N.
  • Preferred X 1 is C.
  • X 2 is CH or N.
  • X 3 is C, or N. Preferred X 3 is N.
  • X 4 is C-R a , N- R b or N.
  • Preferred X 4 is N.
  • R a is hydrogen, halogen, 4-7 membered heterocycle or C-1.3 alkyl.
  • Preferred R a is 3-pyridine.
  • PP is hydrogen, halogen, 4-7 membered heterocycle or C-
  • Preferred Rp is methyl.
  • R ⁇ is hydrogen, halogen or C-
  • Preferred Ri are hydrogen, fluorine, methylcyclopropylamino.
  • Most preferred R1 are fluorine, hydrogen.
  • R 2 is hydrogen or C- ⁇ alkylamine.
  • Preferred R 2 are hydrogen, methylcyclopropylamino. Most preferred R 2 is hydrogen.
  • R 3 is hydrogen or is 4-7 membered heterocycle (aromatic or non-aromatic) optionally substituted by a group selected from C1.5 alkyl, halogen, amino, C-
  • Preferred R 3 groups are 3-pyridine, 5- dimethylamine-3-pyridine, 5-methylamine-3-pyridine, 5-dimethylamine-2-pyridine, 4- trifluoromethyl-3-pyridine, 4-chloro-3-pyridine, 4-methylamine-3-pyridine, 4-N-piperidine-3- pyridine, 4-dimethylamine-3-pyridine, -(N, N dimethylglycine)-2-piperidine , 3-piperidine, 4- piperidine, 2-piperidine, N-methyl-2-piperidine, 2- pyrrolidine, N-methyl-2- pyrrolidine, 2- azetidine, methyl, cyclopropymethyl, iso-butyl, 1-methylsulfanylethyl, tert-butyl, iso-propyl, trifluoromethyl, , acetonitrile, phenyl, 3-pyrrole, 2-bromo-3-pyrrole, , 2-morpholine, cyclopropyl, cyclobutyl and cycl
  • R 3 is cyclopropymethyl, 2-piperidine, 3-pyridine, iso-butyl.
  • R 4 is hydrogen or C-
  • R ⁇ is hydrogen, C1.5 alkyl or halogen.
  • Preferred R ⁇ are bromine, chlorine, hydrogen, iso-propylsulfanyl, methylsulfanyl. Most preferred R ⁇ are bromine, iso- propylsulfanyl.
  • R 6 is C1.3 alkyl.
  • Preferred R 6 is methyl.
  • R 7 is C- ⁇ ⁇ alkyl.
  • Preferred R 7 is methyl.
  • R ⁇ and R 7 can form together a 6 membered ring
  • Preferred 6 membered rings are cyclohexyl, 4-hydroxyl-cyclohexyl, N- methylbenzene-3-piperidine, 3-piperidine, N-methyl-3-piperidine. Most preferred 6 membered ring is cyclohexyl.
  • X 5 is CH or N.
  • Preferred X 5 is CH, N.
  • Most preferred ⁇ 5 is CH.
  • R ⁇ is hydrogen, hydroxyl, C-
  • Preferred R ⁇ are hydrogen, hydroxyl, methyl, methylbenzene.
  • Most preferred R ⁇ is hydrogen.
  • X 1 is C
  • X 2 is CH or N
  • X3 is N
  • X 4 is C- R a , N- Rb or N;
  • R a is 3-pyridine; and R D is methyl;
  • R 1 is hydrogen, fluoro, methylcyclopropylamino
  • R2 is hydrogen, methylcyclopropylamino
  • R3 is 3-pyridine, 5-dimethylamine-3-pyridine, 5-methylamine-3-pyridine, 5- dimethylamine-2-pyridine, 4-trifluoromethyl-3-pyridine, 4-chloro-3-pyridine, 4-methylamine- 3-pyridine, 4-N-piperidine-3-pyridine, 4-dimethylamine-3-pyridine, 3-piperidine, A- piperidine, 2-piperidine, N-methyl-2-piperidine, N-methyl-2- pyrrolidine, 2- pyrrolidine, 2- azetidine, methyl, cyclopropymethyl, iso-butyl, 1-methylsulfanylethyl, tert-butyl, iso-propyl, trifluoromethyl, methylsulfanyl, iso-propylsulfanyl, acetonitrile, phenyl, 3-pyrrole, 2-bromo- 3pyrrole, 2-morpholine, cyclopropyl, N, N dimethylglycine)-2-piperidine
  • R 4 is hydrogen; and R 5 is bromine, chlorine, hydrogen, iso-propylsulfanyl, methylsulfanyl; and
  • R6 is methyl
  • R ⁇ is methyl; or R ⁇ and R ⁇ can form together a 6 membered ring of formula
  • R ⁇ is hydrogen, hydroxyl, methyl, methylbenzene; and " " is a double bond.
  • Preferred compounds of the invention are:
  • Most preferred compounds of the invention are: N-(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)-4-(2-isobutyl-3H-imidazo[4,5-b]pyridin-3- yl)-L-phenylalanine;
  • the asymmetric carbon atom is preferably in the "S" configuration.
  • compositions of formula I include therapeutically active, non-toxic base and acid salt forms which the compounds of formula I are able to form.
  • the acid addition salt form of a compound of formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p- aminosalicylic, pamoic, formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta - Zurich, 2002, 329- 345).
  • the compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine salts, and salts with amino acids such as, for example, arginine, lysine and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta - Zurich, 2002, 329-345).
  • said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
  • solvates include for example hydrates, alcoholates and the like.
  • the invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).
  • the present invention concerns also processes for preparing the compounds of formula I.
  • resolution of the mixture of stereoisomers can best be effected in one or several steps, involving generally sequential separation of mixtures of diastereomers into their constituting racemates, using preferably chromatographic separations on achiral or chiral phase in reversed or preferably in direct mode, followed by at least one ultimate step of resolution of each racemate into its enantiomers, using most preferably chromatographic separation on chiral phase in reversed or preferably in direct mode.
  • the ultimate step may be a separation of diastereomers using preferably chromatographic separations on achiral or chiral phase in reversed or preferably in direct mode. It has now been found that compounds of formula I and their pharmaceutically acceptable salts are useful in a variety of pharmaceutical indications.
  • the compounds according to the invention are useful for the treatment of asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the present invention in a further aspect, concerns the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders such as mentioned above.
  • the present invention concerns the use of a compound of formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent inflammatory or medical conditions such as for example asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the compounds of the invention are useful for treating conditions mediated by adhesion mechanisms. These conditions include asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • Subjects in need of treatment for a ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent inflammatory or medical condition asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer, can be treated by administering to the patient an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable derivative or salt thereof in a pharmaceutically acceptable carrier or diluent to reduce formation of oxygen radicals.
  • the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, intramuscularly or topically, in liquid, cream, gel or solid form, via a buccal or nasal spray, or aerosol, a patch or suppositories.
  • the invention further concerns the use of the compounds of formula I for the manufacture of a medicament for therapeutic application.
  • the invention concerns the use of the compounds of formula I for the manufacture of a medicament useful for treating conditions in which there is likely to be a ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent component.
  • the invention concerns the use of the compound of formula I for the manufacture of a medicament useful for treating asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the invention further concerns the compounds of formula I for use as medicaments.
  • the invention concerns the compounds of formula I for use as a medicament for treating asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the activity and properties of the active compounds, oral availability and stability in vitro or in vivo can vary significantly among the optical isomers of the disclosed compounds.
  • the active compound is administered in an enantiomerically enriched form, i.e., substantially in the form of one isomer.
  • the present invention also concerns a method for treating ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent inflammatory or medical condition (preferably asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent inflammatory or medical condition preferably asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis,
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer
  • a mammal preferably human
  • administration to a mammal preferably human
  • a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 0.01 to 2000 mg, preferably 0.05 to 500 mg of active ingredient per unit dosage form.
  • treatment includes curative treatment and prophylactic
  • substantially refers to a composition of equal or higher to 95% of the said isomer.
  • curative is meant efficacy in treating a current symptomatic episode of a disorder or condition.
  • prophylactic is meant prevention of the occurrence or recurrence of a disorder or condition.
  • the compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.
  • Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis, vasculitis or polydermatomyositis, multiple sclerosis, transplantation, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
  • inflammatory arthritis such as rheumatoid arthritis, vasculitis or polydermatomyositis, multiple sclerosis, transplantation, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
  • One aspect of the invention includes methods for treating ⁇ 4-related cancers (including cancers, whether solid or haematopoietic).
  • ⁇ 4-related cancers including cancers, whether solid or haematopoietic.
  • cancers include, but are not limited to, lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • compounds of formula I or their pharmaceutically acceptable salts may be employed at an effective daily dosage and administered in the form of a pharmaceutical composition.
  • another embodiment of the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition according to the invention one or more of the compounds of formula I or a pharmaceutically acceptable salt thereof, is intimately admixed with a pharmaceutical diluent or carrier according to conventional pharmaceutical compounding techniques known to the skilled practitioner.
  • a pharmaceutical diluent or carrier may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, or parenteral.
  • compositions comprising compounds according to the invention can, for example, be administered orally or parenterally, i.e., intravenously, intramuscularly, subcutaneously or intrathecally.
  • Pharmaceutical compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatine capsules, solutions, syrups, and the like.
  • the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose.
  • these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatine
  • a disintegrant such as alginic acid
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetener such as sucrose or saccharin
  • colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • the invention also contemplate
  • compositions which can be used for parenteral administration are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.
  • these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • the amount of active ingredient in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient's sex, age, weight and medical condition, as well as on the method of administration.
  • the quantity of compound of formula I in compositions for oral administration is at least 0.5 % by weight and can be up to 80 % by weight with respect to the total weight of the composition.
  • the daily dosage is in the range 0.01 to 2000 milligrams (mg) of compounds of formula I.
  • the quantity of compound of formula I present is at least 0.5 % by weight and can be up to 33 % by weight with respect to the total weight of the composition.
  • the dosage unit is in the range 0.01 mg to 2000 mg of compounds of formula I.
  • the daily dose can fall within a wide range of dosage units of compound of formula I and is generally in the range 0.01 to 2000 mg. However, it should be understood that the specific doses could be adapted to particular cases depending on the individual requirements, at the physician's discretion.
  • the compounds of the invention may be co-administered with another therapeutic agent most likely from a different therapeutic area.
  • Co-administration in this context means the dosing either of components, which are formulated together as a single dosage form; or the administration of separately formulated agents at substantially the same time, or sequential dosing of a compound of the invention followed by a therapeutic agent of a different therapeutic area.
  • suitable examples of therapeutic agents may include, but are not limited to, histamine H1 antagonists such as cetirizine, histamine H2 antagonists, histamine H3 antagonists, leukotriene antagonists, PDE4 inhibitors such as 3-cyclo- propylmethoxy-4-difluoromethoxy- ⁇ /-[3,5-di-chloropyrid-4-yl]-benzamide, muscarinic M3 antagonists, ⁇ 2 agonists, theophylline, sodium cromoglycate, anti-TNF antibodies such as certolizumab pegol or adalimumab, anti-IL6 antibodies, anti-IL17 antibodies, adhesion molecule inhibitors, inhibitors of cytokine synthesis such as P38 MAP kinase inhibitors and inhibitors of PI3 kinase, methotrexate.
  • the present invention concerns also processes for preparing the compounds of formula I.
  • the compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.
  • the following processes description sets forth certain synthesis routes in an illustrative manner. Other alternative and/or analogous methods will be readily apparent to those skilled in this art.
  • Ring closure to afford the imidazole ring is performed using acetic acid, with heating in a microwave reactor.
  • the t- butyl protecting group is removed using Trifluoroacetic acid in dicloromethane, followed by introduction of the enamide group, by heating the free amine in the presence of the diketone.
  • the double bond is then substituted with either N-Bromosuccinamide (NBS) or N-Chlorosuccinamide (NCS).
  • NBS N-Bromosuccinamide
  • NCS N-Chlorosuccinamide
  • the present invention also relates to synthetic intermediates geometrical isomers, enantiomers, diastereoisomers, pharmaceutically acceptable salts and all possible mixtures thereof.
  • characterization of the compounds is performed according to (LCMS) liquid chromatography mass spectra, preparative liquid chromatography LC, NMR, and silica gel chromatography methods. NMR spectra are recorded on Bruker AV300 and DRX 400 spectrometers at 300 and 400 MHz respectively.
  • Chromatographic separations are performed on Davis 5 ⁇ M silica gel.
  • the Waters mass spectrometers used are of model ZMD or ZQ both Waters. Various reactions took place in an Emrys Optimiser microwave reactor.
  • CDCI 3 Chloroform-d; DCE - Dichloroethane;
  • characterization of the compounds is performed according to the following methods: NMR spectra are recorded on a Bruker AV-300 or DRX-400 Spectrometers operating at 300.13 MHz or 400.13 MHz for protons, and running the Bruker XWINNMR software package. Spectra are acquired at room temperature unless otherwise stated. Chemical shifts are given in ppm referenced either to internal TMS or to the residual solvent signal.
  • Methyl disulfide (190 ⁇ L) is dissolved in THF (5ml_), cooled to -10 0 C, and sulfuryl chloride (86 ⁇ l_) is added slowly over 5 minutes. The reaction is stirred at -10 0 C for 45 minutes, then 1mL of the reaction mixture is added slowly to a stirred solution of Intermediate 20 (232mg) in THF (6ml_) at -10 0 C and the reaction stirred at -10 0 C for 1 hour. The reaction is partitioned between EtOAc (1OmL) and NaHCO 3 solution (1OmL), the layers separated and the aqueous layer extracted with EtOAc (1OmL).
  • Example 36 1 -[4-(Benzyloxy)phenyl]-2-isobutyl-1 H-pyrrolo[2,3-b]pyridine (Intermediate 99) A flask is charged with 2-isobutyl-1 H-pyrrolo[2,3-b]-pyridine (3.14g, RN 58069-42- 4),4-iodobenzyloxybenzene (6.7g, CAS No. 19578-68-8), potassium phosphate (8.02g), and copper iodide (342mg), and a solution of trans-1 ,2-diaminocyclohexane (420 ⁇ l_) in 1 ,4-dioxane (18mL) is added.
  • Example 41 4-(2-lsobutyl-1 H-pyrrolo[2,3-b]pyridin-1-yl)phenylalanine (Intermediate 104)
  • Intermediate 103 (230mg) is dissolved in 1 ,4-dioxane (3mL) and HCI (6.0M, 5mL) and heated to 100 0 C for 2 hours.
  • the reaction mixture is cooled to room temperature and evaporated to dryness to afford the title compound as a brown oil (208mg).
  • the reaction is heated to 11O 0 C for 20 hours, cooled to room temperature and the solvent removed in vacuo.
  • the crude material is taken up in water (5OmL), extracted with EtOAc (2x30mL), the organic layers combined, dried over MgSO 4 , filtered and chromatographed in DCM / MeOH / TEA to yield a crude yellow oil.
  • This oil is dissolved in THF (4OmL), DIPEA (1.5mL) and 10% palladium on carbon (150mg) added, and the resulting mixture subjected to atmospheric hydrogenation for 6 days. The mixture is filtered through celite and evaporated to dryness in vacuo.
  • the reaction mixture is heated to 120 0 C for 90 minutes, the solution poured into cold water, the resulting precipitate is removed by filtration and dried in vacuo for 18 hours.
  • the crude solid is dissolved in DMF (20 mL), sodium hydride (1.4g, 60% dispersion in mineral oil) is added, the solution is stirred for 30 minutes at room temperature, then methyl iodide (141 mg) is added. After 30 minutes the reaction is quenched with water (50 mL), extracted with EtOAc (2 x 50 mL), the organic layers combined, washed with brine, dried over MgSO 4 , filtered, and subjected to column chromatography in DCM/MeOH.
  • the resulting crude material is dissolved in THF (24mL), DIPEA (0.5mL), methanol (15mL) and 10% palladium on carbon (50mg) are added, and the mixture subjected to atmospheric hydrogenation for 18 hours. The suspension is filtered and the filtrate evaporated to dryness. This crude material is dissolved in DCM (1OmL), pyridine (150 ⁇ L) is added, followed by trifluoromethylsulfonic anhydride (276 ⁇ L).
  • reaction mixture is concentrated in vacuo, dissolved in DCM (8mL) and TFA (2mL) and stirred at room temperature for 18 hours.
  • the reaction mixture is concentrated in vacuo, partitioned between EtOAc (1OmL) and NaHCO 3 solution (1OmL), the organic layer is separated, washed with brine (1OmL), dried over MgSO 4 , filtered and evaporated to dryness in vacuo.
  • Compound 58 is prepared in a similar manner to the method described in Example 59.
  • the crude material is dissolved in AcOH (5mL) and heated to 130 0 C by microwave irradiation for 10 minutes.
  • the solvent is removed in vacuo, dissolved in DCM (8mL) and the solution treated with TFA (7mL) at room temperature.
  • the reaction is stirred at room temperature for 18 hours.
  • the solvent is removed in vacuo and the residue partitioned between EtOAc and saturated NaHCO 3 solution.
  • the organic layer is washed with brine, dried over MgSO 4 , filtered and evaporated to dryness in vacuo.
  • the resulting crude material is dissolved in AcOH (4.3mL) and heated in a microwave at 125°C for 5 minutes.
  • the reaction mixture is concentrated in vacuo, partitioned between DCM (1OmL) and NaHCO 3 solution (1OmL), the layers separated, the aqueous layer extracted with DCM (1OmL), the organic layers combined, washed with brine (2OmL), dried over MgSO 4 , filtered and evaporated to dryness in vacuo.
  • Compound 62 is prepared in a similar manner to the method described in Example 62.
  • Compound 64 is prepared in a similar manner to the method described in Example 63.
  • the obtained material (274mg) in THF is cooled to 0 0 C and treated dropwise with a third of a preformed solution of propane-2-sulfenyl chloride (formed from diisopropylsulfide (137 ⁇ l) in THF (3mL) cooled to 0 0 C and treated with sulfuryl chloride (60 ⁇ l) over 5 minutes and then stirred at 0 0 C for 30 minutes).
  • the reaction is stirred at 0 0 C for 1 hour.
  • the reaction is partitioned between EtOAc (2OmL) and saturated NaHCO 3 solution (2OmL). The organic layer is dried over Na 2 SO 4 , filtered and then evaporated to dryness.
  • Example 66 N-(2-Bromo-3-oxospiro[3.5]non-1-yl)-4-(2-morpholin-3-yl-3H-imidazo[4,5-b]pyridin-3- yl)-L-phenylalanine (Compound 67)
  • Intermediate 17 (7.72g) in MeOH (20OmL) is treated with 10% Pd/C (700mg) and hydrogenated at room temperature for 18 hours. The reaction is filtered and evaporated to dryness in vacuo.
  • the reaction is poured into saturated NaHCO 3 solution (5OmL) and extracted into EtOAc (5OmL). The organic layer is washed with brine (5OmL), dried over MgSO 4 , filtered and the solvent removed in vacuo.
  • the obtained material (930mg) in MeOH (3OmL) is treated with 10% Pd/C (93mg) and hydrogenated at atmospheric pressure for 18 hours.
  • the reaction is filtered and evaporated to dryness in vacuo and the residue purified by chromatography on silica eluting with DCM/10% MeOH in DCM.
  • the obtained material (545mg) in EtOAc/MeCN (5ml_/5mL) is treated with N-Bromosuccinimide (225mg) at room temperature.
  • the mixture is flushed with H 2 (g) and stirred at atmospheric pressure for 4 days.
  • the mixture is filtered through a pad of celite and the filtrate concentrated in vacuo.
  • the residue is dissolved in DCM (5mL) and treated with N, N-Dimethylglycine (16mg) (CAS No. 1118-68-9), EDC (31 mg), HOBt (2mg) and DIPEA (55 ⁇ L) and stirred at room temperature for 30 hours.
  • the reaction is partitioned between DCM (5OmL) and saturated NaHCO 3 (5OmL), the organic layer dried over Na 2 SO 4 , filtered and evaporated to dryness in vacuo.
  • the purified material (109mg) is dissolved in AcOH (2mL) and heated to 125°C by microwave irradiation for 600 seconds. The solvent is removed in vacuo and the residue is purified by chromatography on silica eluting with 30 to 90% EtOAc/heptane.
  • MeCN MeCN
  • N-Bromosuccinimide 20mg
  • the reaction is diluted with EtOAc and washed with 1% sodium thiosulfate solution.
  • the organic layer is dried over Na 2 SO 4 , filtered and evaporated to dryness in vacuo.
  • the crude material is dissolved in MeOH (8mL), thionyl chloride (1mL) is added and the solution stirred at room temperature for 36 hours. The reaction is quenched with NaHCO 3 solution (3OmL), extracted with DCM (2x20mL), the organic layers combined, dried over MgSO 4 , filtered and evaporated to dryness in vacuo.
  • the crude material above is dissolved in EtOAc (5mL), Spiro[3.5]nonane-1 ,3- dione(152mg) is added, and the solution heated to 80 0 C for 1 hour. The reaction is cooled to 0 0 C and N-bromosuccinimide (178mg) is added.
  • the crude material is dissolved in AcOH (15mL) and heated in a microwave for 20 minutes at 120 0 C.
  • the reaction mixture is concentrated in vacuo and partitioned between EtOAc (5OmL) and NaHCO 3 solution (5OmL).
  • the organic layer is separated, washed with brine (5OmL), dried over MgSO 4 , filtered, concentrated in vacuo and chromatographed with EtOAc / heptane.
  • the isolated crude material is dissolved in EtOH (4OmL), 10% Palladium on Carbon (200mg, Johnson Matthey type 367) is added and the reaction mixture subjected to atmospheric hydrogenation for 60 hours. The reaction mixture is filtered through celite and evaporated to dryness in vacuo.
  • the purified residue containing the desired coupling product is dissolved in THF (5mL), DIPEA (0.38mL) and 10% Palladium on carbon (50mg) are added, and the suspension subjected to atmospheric hydrogenation conditions for 16 hours.
  • the reaction mixture is filtered through celite, evaporated to dryness, dissolved in 1 ,4 dioxan (5mL) and HCI (6M, 8mL), and heated to 100 0 C for 6 hours.
  • the reaction is evaporated to dryness in vacuo, and dissolved in MeOH (6mL). Thionyl chloride (1mL) is added and the reaction stirred at room temperature for 18 hours.
  • the compounds of the invention are tested in this assays and show IC50 values of 1 ⁇ M and below.
  • MAdCAM-Ig (150ng/ml) is used in place of 2d VCAM-Ig and a sub-line of the ⁇ - lymphoblastoid cell-line JY is used in place of Jurkat cells.
  • the IC50 value for each test compound is determined as described in the ⁇ 4 ⁇ 1 integrin assay.
  • the compounds of the invention are tested in this assays and show IC50 values of 1 ⁇ M and below.
  • Compound N-(2-chloro-3-oxospiro[3.5]non-1 -en-1 -yl)-4-(2-isobutyl-3H-imidazo[4,5- b]pyridin-3-yl)-L-phenylalanine has an activity of ⁇ 20nM in the ⁇ 4 ⁇ 7 Integrin-dependent JY cell adhesion to MAdCAM-Ig. c).
  • Compound N-(2-chloro-3-oxospiro[3.5]non-1 -en-1 -yl)-4-(2-isobutyl-3H-imidazo[4,5- b]pyridin-3-yl)-L-phenylalanine has an activity of ⁇ 50nM in the Whole blood VCAM-binding assay for ⁇ 4 integrins.
  • ⁇ 5 ⁇ 1 Integrin-dependent K562 cell adhesion to fibronectin 96 well tissue culture plates are coated with human plasma fibronectin (Sigma F0895) at 5 ⁇ g/ml in PBS for 2 hr at 37oC.
  • the plates are washed (3x in PBS) and then blocked for 1h in 100 ⁇ l PBS/1% BSA at RT on a rocking platform.
  • the blocked plates are washed (3x in PBS) and the assay then performed at 37 0 C in a total volume of 200 ⁇ l containing 2.5x 105 K562 cells, phorbol-12-myristate-13-acetate at 10ng/ml, and in the presence or absence of titrated test compounds. Incubation time is 30 minutes.
  • Each plate is fixed and stained as described in the ⁇ 4 ⁇ 1 assay above. e).
  • ⁇ m ⁇ 2-dependent human polymorphonuclear neutrophils adhesion to plastic 96 well tissue culture plates are coated with RPMI 1640/10% FCS for 2h at 37oC. 2 x 105 freshly isolated human venous polymorphonuclear neutrophils (PMN) are added to the wells in a total volume of 200 ⁇ l in the presence of 10ng/ml phorbol-12-myristate-13- acetate, and in the presence or absence of test compounds, and incubated for 20min at 37 0 C followed by 30min at room temperature RT.
  • PMN human venous polymorphonuclear neutrophils
  • the plates are washed in medium and 100 ⁇ l 0.1% (w/v) hexadecyl trimethyl ammonium bromide(Sigma H5882) in 0.05M potassium phosphate buffer, pH 6.0 added to each well. The plates are then left on a rocker at room temperature RT for 60 min. Endogenous peroxidase activity is then assessed using TMB as follows: PMN lysate samples mixed with 0.22% H2O2 (Sigma) and 50 ⁇ g/ml TMB (Boehringer Mannheim) in 0.1 M sodium acetate/citrate buffer, pH 6.0 and absorbance measured at 630nm.
  • Human platelet aggregation is assessed using impedance aggregation on the Chronolog Whole Blood Lumiaggregometer.
  • Human platelet-rich plasma PRP
  • Human platelet-rich plasma is obtained by spinning fresh human venous blood anticoagulated with 0.38% (v/v) tri-sodium citrate at 220xg for 10 min and diluted to a cell density of 6 x 108/ml in autologous plasma.
  • Cuvettes contained equal volumes of PRP and filtered Tyrode's buffer (g/liter: NaCI 8.0; MgCl2-H2 ⁇ 0.427; CaCI 2 0.2; KCI 0.2; D-glucose 1.0; NaHCO 3 1.0; NaH 2 PO 4 .2H 2 O 0.065).
  • 96 well NUNC plates are coated with human vitronectin (Promega) at 2.5 ⁇ g/ml in PBS for 2 hours at 37oC.
  • the plates are washed (2X in PBS) and then blocked for 1 h in 100 ⁇ l PBS/1 %BSA at RT on a rocking platform.
  • the blocked plates are then washed (2X in PBS) and the assay is then performed at 37oC in a total volume of 200 ⁇ l containing 2X105 JY cells, phorbol-12-myristate-13-aceteate at 10ng/ml, and in the absence or presence of titrated test compound.
  • the JY cells are preincubated for 15 minutes with 5 ⁇ g/ml monoclonal antibody against ⁇ 2 integrins, called 6.5E, to prevent ⁇ 2-dependent nonspecific binding.
  • ⁇ 2 integrins 5 ⁇ g/ml monoclonal antibody against ⁇ 2 integrins, called 6.5E, to prevent ⁇ 2-dependent nonspecific binding.
  • Each plate is fixed and stained as described above in the ⁇ 4 ⁇ 1 assay above.
  • the compounds of the invention have IC50 values of > 50 ⁇ M and above thus demonstrating the potency and selectivity of their action against ⁇ 4 integrins.

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Abstract

La présente invention concerne des dérivés bicycliques et hétérobicycliques de formule I, leurs procédés de fabrication, des compositions pharmaceutiques les contenant et leur utilisation comme produits pharmaceutiques.
PCT/EP2007/010191 2006-11-27 2007-11-23 Dérivés bicycliques et hétérobicycliques, leurs procédés de fabrication et leurs utilisations pharmaceutiques WO2008064830A1 (fr)

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GB0623615A GB0623615D0 (en) 2006-11-27 2006-11-27 Bicyclic and heterobicyclic derivatives,processes for preparing them and their uses
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WO2011042474A1 (fr) * 2009-10-07 2011-04-14 Karo Bio Ab Nouveaux ligands récepteurs d'oestrogènes
WO2011074658A1 (fr) * 2009-12-18 2011-06-23 田辺三菱製薬株式会社 Nouvel agent antiplaquettaire
WO2011027249A3 (fr) * 2009-09-01 2011-09-01 Pfizer Inc. Dérivés de benzimidazole
JP2013018771A (ja) * 2011-06-17 2013-01-31 Mitsubishi Tanabe Pharma Corp 新規抗血小板薬
US8431597B2 (en) 2007-06-29 2013-04-30 Pfizer Inc. Benzimidazole derivatives
US9586891B2 (en) 2011-08-04 2017-03-07 Karo Pharma Ab Estrogen receptor ligands
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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EP1323711A1 (fr) * 2000-09-29 2003-07-02 Ajinomoto Co., Inc. Nouveaux derives de phenylalanine
WO2006127584A1 (fr) * 2005-05-20 2006-11-30 Elan Pharmaceuticals, Inc. Derives d'imidazolone phenylalanine utilises comme antagonistes de vla-4

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Publication number Priority date Publication date Assignee Title
EP1323711A1 (fr) * 2000-09-29 2003-07-02 Ajinomoto Co., Inc. Nouveaux derives de phenylalanine
WO2006127584A1 (fr) * 2005-05-20 2006-11-30 Elan Pharmaceuticals, Inc. Derives d'imidazolone phenylalanine utilises comme antagonistes de vla-4

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8431597B2 (en) 2007-06-29 2013-04-30 Pfizer Inc. Benzimidazole derivatives
WO2011027249A3 (fr) * 2009-09-01 2011-09-01 Pfizer Inc. Dérivés de benzimidazole
WO2011042474A1 (fr) * 2009-10-07 2011-04-14 Karo Bio Ab Nouveaux ligands récepteurs d'oestrogènes
AU2010331175B2 (en) * 2009-12-18 2014-08-28 Mitsubishi Tanabe Pharma Corporation Novel antiplatelet agent
JPWO2011074658A1 (ja) * 2009-12-18 2013-05-02 田辺三菱製薬株式会社 新規抗血小板薬
US8703760B2 (en) 2009-12-18 2014-04-22 Mitsubishi Tanabe Pharma Corporation Antiplatelet agent
JP5543980B2 (ja) * 2009-12-18 2014-07-09 田辺三菱製薬株式会社 新規抗血小板薬
WO2011074658A1 (fr) * 2009-12-18 2011-06-23 田辺三菱製薬株式会社 Nouvel agent antiplaquettaire
US9533983B2 (en) 2009-12-18 2017-01-03 Mitsubishi Tanabe Pharma Corporation Antiplatelet agent
JP2013018771A (ja) * 2011-06-17 2013-01-31 Mitsubishi Tanabe Pharma Corp 新規抗血小板薬
US9586891B2 (en) 2011-08-04 2017-03-07 Karo Pharma Ab Estrogen receptor ligands
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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