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WO2008125210A1 - Quinoline and naphthalene derivatives, processes for their preparation and their use in treatment of inflammatory diseases - Google Patents

Quinoline and naphthalene derivatives, processes for their preparation and their use in treatment of inflammatory diseases Download PDF

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Publication number
WO2008125210A1
WO2008125210A1 PCT/EP2008/002564 EP2008002564W WO2008125210A1 WO 2008125210 A1 WO2008125210 A1 WO 2008125210A1 EP 2008002564 W EP2008002564 W EP 2008002564W WO 2008125210 A1 WO2008125210 A1 WO 2008125210A1
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Prior art keywords
alkyl
cycloalkyl
aryl
heteroaryl
halogen
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PCT/EP2008/002564
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French (fr)
Inventor
Richard John Davenport
Andrew James Ratcliffe
David Jonathan Phillips
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UCB SA
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UCB SA
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Priority claimed from GB0707060A external-priority patent/GB0707060D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring 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
    • A61P11/06—Antiasthmatics
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention concerns bicyclic and heterocyclic derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
  • the integrin oc4 (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 is not expressed on circulating neutrophils, which are the first defence against infection, it is a target for the pharmacological control of inflammatory diseases.
  • Several in vitro and in vivo studies have indicated an important role of ⁇ 4 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 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 and VCAM-1 have also been identified in smooth muscle cells trom intimal atherosclerotic thickening of adult aorta. Blocking this interaction is beneficial in preventing smooth muscle differentiation and atherosclerosis. The interaction of ⁇ 4 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.
  • the integrin ⁇ 4 (also termed LPAM-1 ) is expressed on certain sub-populations of T and B lymphocytes and on eosinophils.
  • the invention therefore provides a compound having formula I, its enantiomers, diastereoisomers or a pharmaceutically acceptable salt thereof,
  • W is CH or N; R is chlorine or methoxy; R1 is chlorine or methoxy; R2 is hydrogen; or is C-
  • g dialkylamino groups Cg_-
  • G-i is a direct bond, -C(O)-, -S(O) 2 - , or -C(O)N(R 6 )-;
  • R5 is C-
  • R6 is hydrogen; or is C 1 -6 alkyl optionally substituted by groups selected from halogen, C 3-10 cycloalkyl, amino, amido, C 1 -6 alkylamino groups, C 1 -6 dialkylamino groups, C 6-10 aryl, cyano, nitro; n is O, 1 , or 2; R ⁇ is a group of formula III .R 8
  • R 4 * N k formula III wherein R ⁇ is hydrogen; or is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C 1 _g alkyl; or is C 1 .5 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C 1 _g alkylamino groups, C 1 _g dialkylamino groups, Cg.-
  • R8 is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C 1 . 6 alkyl; or is C-
  • G 2 is direct bond, -C(O)-, -S(O) 2 - , or -C(O)N(R 1 O)-;
  • R9 is C 1 -6 alkyl optionally substituted by groups selected from halogen, C 3-10 cycloalkyl, amino, amido, C 1 -6 alkylamino groups, C 1 -6 dialkylamino groups, C 6-10 aryl, cyano, nitro; or is C 3-10 cycloalkyl optionally substituted by groups selected from halogen, C-] -6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C 1 -6 alkyl, halogen, C 1 -6 alkylamino, C 1 -6 dialkylamino, C 3-10 cycloalkyl; or is Cg.10 aryl optionally substituted by groups selected from halogen, C 1 _g alkylamino groups, C 1 - g dialkylamino groups, C-
  • R 4 can be hydrogen or halogen; except 6-Quinolinepropanoic acid, 2-(2,6-dichlorophenyl)- ⁇ -[[3,4-dioxo-2- (propylamino)-i -cyclobuten-1 -yl]amino].
  • the invention therefore provides a compound having formula Ia and the configuration at the asymmetric carbon atom is in the "S" configuration, or a pharmaceutically acceptable salt thereof
  • the invention therefore provides a compound, according to formula I, having formula V, or a pharmaceutically acceptable salt thereof,
  • the invention therefore provides a compound, according to formula I, having formula Vl, or a pharmaceutically acceptable salt thereof,
  • Ci_6 alkyl represents saturated, monovalent hydrocarbon radicals having linear or branched moieties or combinations thereof and containing 1-6 carbon atoms.
  • One methylene (-CH2-) group, of the alkyl, can be replaced by oxygen or sulfur.
  • Alkyl groups can be optionally substituted by one or more substituents.
  • Alkyl groups can be optionally substituted by groups selected from halogen, C3-IO cycloalkyl, amino, amido, C-
  • alkyl group in the present case, is ethyl.
  • C3_io cycloalkyl refers to a monovalent or divalent group of 3 to 10 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be mono- or polycyclic. Cycloalkyl groups can be optionally substituted by one or more substituents. Cycloalkyl groups can be optionally substituted by groups selected from halogen or C-
  • carbonyl refers to a group of formula -C(O)-.
  • amino refers to a group of formula -NH2.
  • cyano refers to a group of formula -CN.
  • nitro refers to a group of formula -NO2-
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine. Usually halogen is chlorine, bromine.
  • Cg_io ar y' 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. Aryl groups can be optionally substituted by one or more substituents.
  • Aryl groups can be optionally substituted by groups selected from halogen, C-1.5 alkylamino groups, C-
  • C 6-10 heteroaryl refers to a 6 -10 member ring, containing at least one nitrogen atom interrupting the carbocyclic ring structure.
  • Heteroaryl groups can be optionally substituted by one or more substituents.
  • Heteroaryl groups can be optionally substituted by groups selected from C 2 .
  • 3 to 10 ring member containing one N or O heteroatom interrupting the carbocyclic ring structure
  • the 3-10 ring member non-aromatic heterocycle groups can be optionally substituted by one or more substituents.
  • the 3-10 ring member non-aromatic heterocycle groups can be optionally substituted by groups selected from C 1 ⁇ alkyl, halogen, C 1 . Q alkylamino, C 1 -6 dialkylamino, C3.-10 cycloalkyl.
  • 3 to 10 ring member non- aromatic heterocycle in the present case is pyran.
  • C1.5 alkyloxy refers, to a refers to a group of formula -
  • R ⁇ is a C 1 -6 alkyl group as defined above.
  • C 1 . Q alkylsulfides refers, to a refers to a group of formula -SR9, wherein R9 is a C 1 .5 alkyl group as defined above.
  • C 6 .-] Q arylsulfones refers, to a refers to a group of formula Q aryl group as defined above.
  • C ⁇ -io arylsulfides refers, to a refers to a group of formula -SR', wherein R' is a C5.-10 aryl group as defined above.
  • X is CH or N.
  • Preferred X is CH.
  • W is CH or N.
  • Preferred W is N.
  • R is chlorine or methoxy.
  • Preferred R is chlorine.
  • R ⁇ is chlorine or methoxy.
  • Preferred R 1 is chlorine.
  • R ⁇ is hydrogen; or is C 1 .5 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1.5 alkylamino groups, C- ⁇ .Q dialkylamino groups, C ⁇ .-io ar y!. cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C 1 .
  • Q alkyl or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C 1 ⁇ alkyl, halogen, C-
  • Preferred R ⁇ is carbonyl, or together with R ⁇ a ring or a heterocycle attached to the cyclobutenone as described in formula II.
  • R ⁇ is C ⁇ .Q alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-1.5 alkylamino groups, C-
  • Preferred R ⁇ forms together with R ⁇ a ring or a heterocycle attached to the cyclobutenone as described in formula II.
  • R ⁇ is a group of formula III; or R ⁇ can be a group of formula IV; or is hydrogen or halogen.
  • Preferred R 4 is halogen or a group of formula III.
  • R ⁇ is C-] .5 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-
  • NHCO (C3.10 cycloalkyl) NHCO (Ce-io aryl ), NHCO (Cg ⁇ Q heteroaryl), NHCO (C3.10 non aromatic heterocycle) , N(C-
  • NHCO (C 6 . ⁇ heteroaryl), NHCO (C 3 _-
  • R ⁇ is hydrogen; or is C-
  • R? is hydrogen; or is C 3 _-
  • R 7 is C 1 _ ⁇ alkyl.
  • R ⁇ is C 3-1 Q cycloalkyl optionally substituted by groups selected from halogen, C 1 . g alkyl; or is C-
  • N(Ci_g alkyl)CO Cg.10 heteroaryl
  • N(Ci_g alkyl)CO C3.10 non aromatic heterocycle
  • Cg_io heteroaryl optionally substituted by groups selected from C2-g alkenyl, Cg.10 arylsulfones, Cg.10 arylsulfoxides, Cg.10 arylsulfides, halogen, Ci _g alkylamino groups, Ci_g dialkylamino groups, Ci_g alkyloxy, Ci_g alkylsulfides, Ci_g alkylsulfones, Ci_g alkylsulfoxides, C3.10 cycloalkyl, Ci_g alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino, CONH(Ci.g alkyl), CONH(C3_I Q cycloalkyl ), CON(Ci.g alkyl), CON(Ci.g al
  • R ⁇ is C 1 -6 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C 1 -6 alkylamino groups, C 1 -6 dialkylamino groups, C 6-1 O aryl, cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C 1 -6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C 1 -6 alkyl, halogen, C 1 . g alkylamino, C 1 .
  • . 6 alkyl)CO C 6 .10 heteroaryl
  • N(Ci_ 6 alkyl)CO C 3 . 10 non aromatic heterocycle)
  • C 6 .!o heteroaryl optionally substituted by groups selected from C 2 . 6 alkenyl, C 6 . -
  • N(Ci_ 6 alkyl)CO C 6 _I Q heteroaryl
  • N(Ci_ 6 alkyl)CO C 3 _I Q non aromatic heterocycle
  • R ⁇ is hydrogen; or is Ci_ 6 alkyl optionally substituted by groups selected from halogen, C 3 _I Q cycloalkyl, amino, amido, C 1 ⁇ alkylamino groups, Ci_ 6 dialkylamino groups, C 6 _I Q aryl, cyano, nitro.
  • n O, 1 , or 2.
  • Preferred n is 1.
  • m is O, 1 , or 2.
  • Preferred Y is -O- or - CH 2 -.
  • G 1 is direct bond, -C(O)-, -S(O) 2 - or -C(0)N(R R )-.
  • G 2 is direct bond, -C(O)-, -S(O) 2 - or -C(O)N(R 1 °)-.
  • compounds are according to formula I or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; and W is CH or N; and R is chlorine or methoxy; and R 1 is chlorine or methoxy; and R ⁇ is carbonyl when R ⁇ does not exist; or R ⁇ and R ⁇ can form together a ring or a heterocycle attached to the cyclobutenone such as described in formula II; and Y is O or CH 2 ; and n is O, 1 , or 2; and
  • R ⁇ is a group of formula III; or R 4 can be hydrogen or halogen; and R 7 is hydrogen; or R 7 is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C 1 .5 alkyl; or
  • R 7 is C 1 . ⁇ alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C 1 _g alkylamino groups, C 1 . Q dialkylamino groups, Cg ⁇ o aryl, cyano, nitro; or R 7 is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C 1 . g alkyl, halogen, C 1 . ⁇ alkylamino, C 1 . g dialkylamino, C3.-10 cycloalkyl; and R8 is 03 ⁇ Q cycloalkyl optionally substituted by groups selected from halogen, C 1 .
  • R ⁇ is C 1 .5 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C 1 .5 alkylamino groups, C 1 - S dialkylamino groups, C ⁇ .-io ar y'. cyano, nitro; or R ⁇ is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C 1 .
  • R ⁇ is C ⁇ .-io heteroaryl optionally substituted by groups selected from halogen, C 1 .5 alkyl, cyano, carboxylic acid, hydroxyl, C3.-10 non aromatic heterocyle, amino; except 6-Quinolinepropanoic acid, 2-(2,6-dichlorophenyl)- ⁇ -[[3,4-dioxo-2-(propylamino)-1- cyclobuten-1-yl]amino.
  • Y is O or CH 2 ;
  • X is CH; and W is N; and R is chlorine; and R1 is chlorine; and n is 1 ; and R4 is halogen.
  • X is CH; and W is N; and R is chlorine; and R1 is chlorine; and
  • R ⁇ is C-] .
  • ⁇ alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, Ci_6 alkylamino groups, C- ⁇ dialkylamino groups, C ⁇ -io ar y' > cyano, nitro; and
  • R8 is C-
  • Preferred compounds of the invention are: (2S)-2-[(2-bromo-3-oxo-7-oxaspiro[3.5]non-1 -en-1 -yl)amino]-3-[2-(2,6- dichlorophenyl)quinolin-6-yl]propanoic acid;
  • stereogenic center in their structure.
  • This stereogenic center may be present in a "R” or a ""S configuration, said "R” and “S “ notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
  • the asymmetric carbon atom is preferably in the "S" configuration.
  • the "pharmaceutically acceptable salts" according to the invention 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
  • 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). Some of the compounds of formula I may also exist in tautomeric forms. Such forms although not explicitly indicated in the above formulae are intended to be included within the scope of the present invention.
  • 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.
  • 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 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.
  • ⁇ 4 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, rhe
  • 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 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 applications.
  • 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 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 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 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 s
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer) in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound of formula I or a pharmaceutically acceptable salt thereof to a patient.
  • the methods of the invention comprise administration to a mammal (preferably human) suffering from above mentioned conditions or disorders, of 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 treatment.
  • substantially refers to a composition of equal or higher than 85% of one isomer, usually 90 % and preferably 95%.
  • curative is meant efficacy in treating a current symptomatic episode of a disorder or condition.
  • prophylactic 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.
  • 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.
  • 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.
  • Suitable diluents and carriers 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.
  • 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.
  • 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.
  • compositions which can release the active substance in a controlled manner 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, 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, citrate
  • 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, D 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.
  • histamine H1 antagonists such as cetirizine
  • histamine H2 antagonists histamine H3 antagonists
  • the present invention concerns also processes for preparing the compounds of formula I.
  • Compounds of formula Ia can be prepared according to scheme 1 , starting with 6- quinolinepropanoic acid 1-(2,6-dichlorophenyl)- ⁇ -[[(1 ,1-dimethylethoxy)carbonyl]amino]-, methylester ( ⁇ S) (RN-623144-30-9) or with 6-quinolinepropanoic acid 1-(2,6- dimethoxyphenyl)- ⁇ -[[(1 ,1-dimethylethoxy)carbonyl]amino]-, methylester ( ⁇ S) (RN-623147- 28-4).
  • the f-butyl group is removed using Trifluoroacetic acid in dichloromethane to yield the free amine.
  • the amino group is coupled with the 7-oxaspiro[3.5]nonane-1 ,3-dione or the diethoxycyclobut-3-ene-1 ,2-dione.
  • the double bond of the enamide is substituted with bromide using N-Bromosuccinamide (NBS). Saponification of the ester to the acid using NBS.
  • the present invention also relates to synthetic intermediates geometrical isomers, enantiomers, diastereoisomers, pharmaceutically acceptable salts and all possible mixtures thereof.
  • the invention concerns also a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention concerns a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above for use as a medicine.
  • the invention concerns a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above in the manufacture of a medicament.
  • the invention concerns a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above in the manufacture of a medicament for the treatment of ⁇ 4 dependent inflammatory or medical conditions.
  • the invention concerns a compound as described above for use as a medicament.
  • the invention concerns a compound as described above for curing 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.
  • 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.
  • DIPEA - ⁇ /, ⁇ /-Diisopropylethylamine; DMF - ⁇ /, ⁇ /-Dimethylformamide; DMSO - Dimethyl sulphoxide; d 6 .DMSO - Dimethyl-d 6 sulphoxide;
  • HP1100 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionisation Column: Luna C 18(2) 100x4.6mm, 5 ⁇ m particle size Analytical column
  • 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
  • the following cellular assay is used to demonstrate the potency of the compounds according to the invention.
  • (2S)-3-[2-(2,6-dichlorophenyl)quinolin-6-yl]-2- ⁇ [2-(diethylamino)-3,4-dioxocyclobut- 1 -en-1 -yl]amino ⁇ propanoic acid has an activity of 1.0 - 1.3 ⁇ M in the above assay.

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Abstract

The present invention concerns naphthalene and quinoline derivatives of formula (I), processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals. R, R1, R2, R3, R4, X and W are defined as in claim I.

Description

QUINOLINE AND NAPHTHALENE DERIVATIVES', PROCESSES FOR THEIR PREPARATION AND THEIR USE IN TREATMENT OF INFLAMMATORY DISEASES
The present invention concerns bicyclic and heterocyclic derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
The integrin oc4 (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-α, IL-1 and selectively IL-4 and IL-13) and to the extracellular matrix protein fibronectin.
Because α4 is not expressed on circulating neutrophils, which are the first defence against infection, it is a target for the pharmacological control of inflammatory diseases. Several in vitro and in vivo studies have indicated an important role of α4 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. α4 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. α4 and VCAM-1 have also been identified in smooth muscle cells trom intimal atherosclerotic thickening of adult aorta. Blocking this interaction is beneficial in preventing smooth muscle differentiation and atherosclerosis. The interaction of α4 on inflammatory cells with fibronectin has also been shown to increase chronic allograft failure. Blocking this interaction is beneficial in supporting transplant survival. α4-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.
The integrin α4 (also termed LPAM-1 ) is expressed on certain sub-populations of T and B lymphocytes and on eosinophils.
Several studies have shown that α4 is involved in inflammatory bowel disease and that blocking its function is beneficial. International patent application WO 03/093237 discloses 2,6-quinolinyl and 2,6- naphthyl derivatives as pharmaceuticals for the treatment of VLA-4 dependent inflammatory diseases.
We have now found some bicyclic and heterobicyclic compounds that are potent and selective inhibitors of α.4 integrins with increased human whole blood alpha4 inhibition. These compounds have no or minimal inhibitory action on α integrins of other subgroups.
In one aspect, the invention therefore provides a compound having formula I, its enantiomers, diastereoisomers or a pharmaceutically acceptable salt thereof,
Figure imgf000003_0001
formula I wherein: " * " represents the point of attachment; nu M-
W is CH or N; R is chlorine or methoxy; R1 is chlorine or methoxy; R2 is hydrogen; or is C-|_6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-j.β alkylamino groups, C<\_Q dialkylamino groups, Cg.10 aryl, cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C-^.g alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-μg alkyl, halogen, C-|_6 alkylamino, C-|.g dialkylamino, C3.10 cycloalkyl; or is carbonyl when R^ does not exist; R3 is C1 _g alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1.5 alkylamino groups, C1. g dialkylamino groups, Cg_-|o aryl. cyano, nitro; or is C3.-10 cycloalkyl, optionally substituted by groups selected from halogen , C1. 6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-] .5 alkyl, halogen, C1 _g alkylamino, C1.5 dialkylamino, C3.10 cycloalkyl; or does not exist when R2 is carbonyl; or R2 and R^ can form together a ring or a heterocycle attached to the cyclobutenone such as described in formula Il
Figure imgf000004_0001
formula Il wherein
Y is N-G1 R5, -S-, -O-, -S=O, -S(O)2-, or -CH2-; G-i is a direct bond, -C(O)-, -S(O)2- , or -C(O)N(R6)-;
R5 is C-|_6 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C-] _g alkylamino groups, C1 _g dialkylamino groups, Cg.-io aryl, cyano, nitro; or is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C1.5 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1. g alkyl, halogen, C1. g alkylamino, C^g dialkylamino, C3.-10 cycloalkyl; or is Cg.-io aryl optionally substituted by groups selected from halogen, C1.5 alkylamino groups, C-|.g dialkylamino groups, C-|_g alkyloxy, C<\_Q alkylsulfides, C-j.ρ alkylsulfones, C-j.g alkylsulfoxides, C3.-10 cycloalkyl, C-μρ alkyl, cyano, carboxylic acid, hydroxyl, 03.-10 non aromatic heterocyle, amino,
CONH(C1.6 alkyl), CONH(C3.10 cycloalkyl ), CON(C1 _6 alkyl)( C1.6 alkyl), CON(C1^ alkyl )( C3.! 0 cycloalkyl), CONH(C6.10 aryl ), CON(C^6 alkyl)(C6.10 aryl ), CONH(Cg-IO heteroaryl ), CON(C1 _g alkyl) (Cg.-io heteroaryl) , CONH (C3.-10 non aromatic heterocycle), CON(C1 _g alkyl) (03^0 non aromatic heterocycle) , CONH2,
CO(C1^ alkyl), CO(C3_-io cycloalkyl) , CO (C3.-10 non aromatic heterocycle ), CO (Cg-1 Q aryl) , CO (C6_<| 0 heteroaryl) , NHSO2(C1 -6 alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO2 (C6-10 aryl), NHSO2 (C6-10 heteroaryl), N(C1 -6 alkyl)SO2 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3--10 cycloalkyl) ,
N(C1 -6 alkyl)SO2 (C6-10 aryl) , N(C1 -6 alkyl)SO2 (C6-10 heteroaryl) , NHCO(C1 -6 alkyl), NHCO (C3-10 cycloalkyl) , NHCO (C6-10 aryl ), NHCO (C6-10 heteroaryl), NHCO (C3-1 Q non aromatic heterocycle) ,
N(C1 -6 8^yI)CO(C1 -6 alkyl), N(C1 -6 alkyl)CO (C3-10 cycloalkyl), N(C1 -6 alkyl)CO (C6-10 aryl) , N(C1 -6 alkyl)CO (C6-10 heteroaryl), N(C1 -6 alkyl)CO (C3-10 non aromatic heterocycle) ; or is C6-10 heteroaryl optionally substituted by groups selected from C2-6 alkenyl,
Cβ-10 arylsulfones, C6-10 arylsulfoxides, C6-10 arylsulfides, halogen, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C1 -6 alkyloxy, C1 -6 alkylsulfides, C1 -6 alkylsulfones, C1 -6 alkylsulfoxides, C3-10 cycloalkyl, C1 -6 alkyl, cyano, carboxylic acid, hydroxyl, C3-10 non aromatic heterocyle, amino, CONH(C1 -6 alkyl), CONH(C3-10 cycloalkyl ), CON(C1 -6 alkyl)( C1 -6 alkyl), CON(C1 -6 alkyl )( C3-10 cycloalkyl), CONH(C6-10 aryl ), CON(C1 -6 alkyl)(C6-10 aryl ), CONH(C6-10 heteroaryl ), CON(C1 -6 alkyl) (C6-i0 heteroaryl) ,
CONH (C3-I0 non aromatic heterocycle), CON(C1 -6 alkyl) (C3-10 non aromatic heterocycle) , CONH2, CO(C1 -6 alkyl), CO(C3-10 cycloalkyl) , CO (C3-10 non aromatic heterocycle ), CO (C6-10 aryl) , CO (C6-10 heteroaryl) , NHSO2(C1 -6 alkyl), NHSO2 (C3- -I Q cycloalkyl) , NHSO2 (C6-10 aryl), NHSO2 (C6-10 heteroaryl), N(C1 -6 alkyl)SO2 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3-10 cycloalkyl) , N(C1 -6 alkyl)SO2 (C6-10 aryl) , N(C1 -6 alkyl)SO2 (C6-10 heteroaryl) , NHCO(C1 -6 alkyl), NHCO (C3-10 cycloalkyl) , NHCO (C6- 10 aryl ), NHCO (C6-10 heteroaryl), NHCO (C3-10 non aromatic heterocycle) , N(C1 -6 alkyl)CO(C-|-6 alkyl), N(C1 -6 alkyl)CO (C3-10 cycloalkyl), N(C1 -6 alkyl)CO (C6-10 aryl) , N(C1 -6 alkyl)CO (C6-1 0 heteroaryl), N(C1 -6 alkyl)CO (C3-10 non aromatic heterocycle) ;
R6 is hydrogen; or is C1 -6 alkyl optionally substituted by groups selected from halogen, C3-10 cycloalkyl, amino, amido, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C6-10 aryl, cyano, nitro; n is O, 1 , or 2; R^ is a group of formula III .R8
R4 = * N k formula III wherein R^ is hydrogen; or is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C1 _g alkyl; or is C1.5 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C1 _g alkylamino groups, C1 _g dialkylamino groups, Cg.-|o aryl, cyano, nitro; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-] .5 alkyl, halogen, C-|_g alkylamino, C^.g dialkylamino, C3.10 cycloalkyl;
R8 is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C1. 6 alkyl; or is C-| .6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-|_g alkylamino groups, C-j.g dialkylamino groups, Cg.10 aryl, cyano, nitro; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 _g alkyl, halogen, C-|.g alkylamino, C1 _g dialkylamino, C3.10 cycloalkyl; or is Cg_ifj aryl optionally substituted by groups selected from halogen, C1 _g aikyiamino groups, C1 _g diaikyiamino groups, C-|_g aikyioxy, C1 _g aikyisuifides, C1 _g alkylsulfones, C^.g alkylsulfoxides, C3.10 cycloalkyl, C-(.g alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino,
CONH(C1 _g alkyl), CONH(C3.10 cycloalkyl ), CON(C1. g alkyl)( C1. g alkyl), CON(C1^ alkyl )( C3.10 cycloalkyl), CONH(C6.10 aryl ), CON(C1-S alkyl)(C6.10 aryl ), CONH(Cg.-|o heteroaryl ), CON(Ci _g alky0 (c6-10 heteroaryl) , CONH (C3.-10 non aromatic heterocycle), CON(C1 _g alkyl) (03^0 non aromatic heterocycle) , CONH2, CO(C1. g alkyl), CO(C3_-| Q. cycloalkyl) , CO (C3.-10 non aromatic heterocycle ), CO (Cg_io aryl) , CO (Cg.-] 0 heteroaryl) , NHS02(C1.g alkyl), NHSO2 (C3.-10 cycloalkyl) , NHSO2 (C6-10 ary'). NHSO2 (Cg-IO heteroaryl), N(C-|.g alkyl)S02 (Ci.g alkyl), N(C^g alkyl)S02 (C3.-10 cycloalkyl) ,
N(C1. g alkyl)S02 (Cg.-|o aryl) , N(C^g alkyl)S02 (Cg.-] Q heteroaryl) , NHCO(C1. g alkyl), NHCO (C3.10 cycloalkyl) , NHCO (Cg.10 aryl ), NHCO (C6^ 0 heteroaryl), NHCO (^3-10 non aromatic heterocycle) , N(C-|_6 alkyl)CO(C-|_6 alkyl), N(C1-6 alkyi)CO (C3.10 cycloalkyl), N(C1 -6 alkyl)CO (C6-10 aryl) . N(C1 -6 alkyl)CO (C6-10 heteroaryl), N(C1 -6 alkyl)CO (C3-10 non aromatic heterocycle) ; or is Cg.10 heteroaryl optionally substituted by groups selected from C2-6 alkenyl, CQ.10 arylsulfones, Cρ_io arylsulfoxides, C6-10 arylsulfides, halogen, C1.5 alkylamino groups, C1 -6 dialkylamino groups, C1 -6 alkyloxy, C1.5 alkylsulfides, C-|.g alkylsulfones, C1 -6 alkylsulfoxides, C3-10 cycloalkyl, C-|.g alkyl, cyano, carboxylic acid, hydroxyl, C3.-10 non aromatic heterocyle, amino, CONH(C-i_g alkyl), CONH(C3-10 cycloalkyl ), CON(C1-6 alkyl)( C1-6 alkyl), CON(C1 -6 alkyl )( C3-1O cycloalkyl), CONH(C6-1O aryl ), CON(C1 -6 alkyl)(C6-1o aryl), CONH(C6-1O heteroaryl ), CON(C1 -6 alkyl) (C6-1 Q heteroaryl) ,
CONH (C3-1O non aromatic heterocycle), CON(C1 -6 alkyl) (C3-10 non aromatic heterocycle) , CONH2, CO(C1 -6 alkyl), CO(C3-1O cycloalkyl) , CO (C3-1O non aromatic heterocycle ), CO (C6-10 aryl) , CO (C6-1 Q heteroaryl) , NHSO2(C1 -6 alkyl), NHSO2 (C3- !O cycloalkyl) , NHSO2 (C6-1Q aryl), NHSO2 (C6-1O heteroaryl), N(C1 -6 alkyl)SO2 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3-10 cycloalkyl) , N(C1 -6 alkyl)SO2 (C6-10 aryl) , N(C1 -6 alkyl)S02 (C6-1O heteroaryl) , NHCO(C1 -6 alkyl), NHCO (C3-10 cycloalkyl) , NHCO (C6- 10 aryl ), NHCO (C6-10 heteroaryl), NHCO (C3-10 non aromatic heterocycle) , N(C1 -6 alkyl)CO(C1 -6 alkyl), N(C1 -6 alkyl)CO (C3-10 cycloalkyl), N(C1 -6 alkyl)CO (C6-10 aryl) , N(C1 -6 alkyl)CO (C6-10 heteroaryl), N(C1 -6 alkyl)CO (C3-10 non aromatic heterocycle) ; or R4 can be a group of formula IV
Figure imgf000007_0001
formula IV wherein Z is N-G2R9, -S-, -0-, -S=O, -S(O) 2-, or -CH2-;
G2 is direct bond, -C(O)-, -S(O)2- , or -C(O)N(R1O)-;
R9 is C1 -6 alkyl optionally substituted by groups selected from halogen, C3-10 cycloalkyl, amino, amido, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C6-10 aryl, cyano, nitro; or is C3-10 cycloalkyl optionally substituted by groups selected from halogen, C-] -6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 -6 alkyl, halogen, C1 -6 alkylamino, C1 -6 dialkylamino, C3-10 cycloalkyl; or is Cg.10 aryl optionally substituted by groups selected from halogen, C1 _g alkylamino groups, C1 - g dialkylamino groups, C-|.g alkyloxy, C1 _g alkylsulfides, C1 _g alkylsulfones, C^g alkylsulfoxides, 03.10 cycloalkyl, C1.g alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino, CONH(C1 -6 alkyl), CONH(C3.-] 0 cycloalkyl ), CON(C1. g alkyl)( C1 -6 alkyl),
CON(C1 -6 alkyl )( C3-10 cycloalkyl), CONH(Cg.10 aryl ), CON(C1 -6 alkyl)(C6.10 aryl ), CONH(Cg.10 heteroaryl ), CON(C1 -6 alkyl) (Cg.10 heteroaryl) , CONH (C3-1O non aromatic heterocycle), CON(C1 -6 alkyl) (C3.-10 non aromatic heterocycle) , CONH2, CO(C1 -6 alkyl), CO(C3-1O cycloalkyl) , CO (C3-1Q non aromatic heterocycle ), CO (Cg-1O aryl) , CO (Cg-1Q heteroaryl) , NHSO2(C1 -6 alkyl), NHSO2 (C3-10 cycloalkyl) , NHSO2 (Cg-1Q aryl), NHSO2 (Cg-1O heteroaryl), N(C1 -6 alkyl)SO2 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3-10 cycloalkyl) ,
N(C1. g alkyl)SO2 (C6-10 aryl) , N(C1 -6 alkyl)SO2 (Cg-10 heteroaryl) , NHCO(C1 -6 alkyl), NHCO (C3-10 cycloalkyl) , NHCO (C6-10 aryl ), NHCO (C6-10 heteroaryl), NHCO (C3.10 non aromatic heterocycle) ,
N(C1 -6 alkyl)CO(C1 -6 alkyl), N(C1 -6 alkyl)CO (C3-10 cycloalkyl), N(C1 -6 alkyl)CO (C6-10 aryl) , N(C1 _g alkyl)CO (C6-1Q heteroaryl), N(C1 -6 alkyl)CO (C3-1 Q non aromatic heterocycle) ; or is C6-1Q heteroaryl optionally substituted by groups selected from C2-g alkenyl, Cg-1Q arylsulfones, Cg-1Q arylsulfoxides, Cg-1Q arylsulfides, halogen, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C1. g alkyloxy, C1. g alkylsulfides, C1. g alkylsulfones, C1 -6 aikyiSuifύxiuθS, C3.-| Q Cyciϋaikyi, C1 -6 aikyi, cyano, carboxylic acid, hydroxyl, C3-10 non aromatic heterocyle, amino, CONH(C1 -6 alkyl), CONH(C3_io cycloalkyl ), CON(C1 -6 alkyl)( C1 -6 alkyl), CON(C1 -6 alkyl )( C3-10 cycloalkyl), CONH(C6-10 aryl ), CON(C1 -6 alkyl)(C6-10 aryl ), CONH(C6-10 heteroaryl ), CON(C1 -6 alkyl) (Cg-10 heteroaryl) ,
CONH (C3-10 non aromatic heterocycle), CON(C1.g alkyl) (C3-10 non aromatic heterocycle) , CONH2, CO(C1 -6 alkyl), CO(C3-10 cycloalkyl) , CO (C3-10 non aromatic heterocycle ), CO (Cg-10 aryl) , CO (Cg-10 heteroaryl) , NHSO2(C1.g alkyl), NHSO2 (C3- -|o cycloalkyl) , NHSO2 (Cg-1Q aryl), NHSO2 (Cg-1Q heteroaryl), N(C1 -6 alkyl)SO2 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3-10 cycloalkyl) , N(C1 -6 alkyl)SO2 (C6-10 aryl) , N(C1 -6 alkyl)SO2 (C6-10 heteroaryl) , NHCO(C1 -6 alkyl), NHCO (C3-10 cycloalkyl) , NHCO (Cg- 10 aryl ), NHCO (Cg-10 heteroaryl), NHCO (C3-10 non aromatic heterocycle) , N(C1 -6 alkyl)CO(C1 -6 alkyl), N(C1 -6 alkyl)CO (C3-10 cycloalkyl), N(C1 -6 alkyl)CO (C6-10 aryl) , N(C1 _g alkyl)CO (Cg-10 heteroaryl), N(C1 -6 alkyl)CO (C3-10 non aromatic heterocycle) ; R-O is hydrogen; or is C<|_5 alkyl optionally substituted by groups selected from halogen, C3.-1Q cycloalkyl, amino, amido, C-j.β alkylamino groups, C-|.β dialkylamino groups, Cβ.-io aryl. cyano, nitro; m is 0, 1 , or 2; or R4 can be hydrogen or halogen; except 6-Quinolinepropanoic acid, 2-(2,6-dichlorophenyl)-α-[[3,4-dioxo-2- (propylamino)-i -cyclobuten-1 -yl]amino].
In another aspect the invention therefore provides a compound having formula Ia and the configuration at the asymmetric carbon atom is in the "S" configuration, or a pharmaceutically acceptable salt thereof
Figure imgf000009_0001
formula Ia wherein X, R, R1 , W, R2, R3 and R4 are as defined above.
In another aspect, the invention therefore provides a compound, according to formula I, having formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000009_0002
formula V wherein X, R, R1 , W, Y, n and R^ are as defined above.
In another aspect, the invention therefore provides a compound, according to formula I, having formula Vl, or a pharmaceutically acceptable salt thereof,
Figure imgf000010_0001
formula Vl wherein X, R, R^ , W, R7 and R^ are as defined above.
The term "Ci_6 alkyl", as used herein, represents saturated, monovalent hydrocarbon radicals having linear or branched moieties or combinations thereof and containing 1-6 carbon atoms. One methylene (-CH2-) group, of the alkyl, can be replaced by oxygen or sulfur. Alkyl groups can be optionally substituted by one or more substituents. Alkyl groups can be optionally substituted by groups selected from halogen, C3-IO cycloalkyl, amino, amido, C-|_6 alkylamino groups, C-| .Q dialkylamino groups, Cg-io aryl, cyano, nitro. Usually alkyl group, in the present case, is ethyl.
The term "C3_io cycloalkyl", as used herein, refers to a monovalent or divalent group of 3 to 10 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be mono- or polycyclic. Cycloalkyl groups can be optionally substituted by one or more substituents. Cycloalkyl groups can be optionally substituted by groups selected from halogen or C-|.g alkyl groups as defined above. Usually cyclolakyl group, in the present case is cyclohexyl. The term "carbonyl", as used herein, refers to a group of formula -C(O)-.
The term "amino", as used herein, refers to a group of formula -NH2.
The term "amido", as used herein, refers to a group of formula -CONH2.
The term "cyano", as used herein, refers to a group of formula -CN. The term "nitro", as used herein, refers to a group of formula -NO2- The term "halogen", as used herein, refers to an atom of chlorine, bromine, fluorine, iodine. Usually halogen is chlorine, bromine. The term "Cg_io ary' " as used herein, 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. Aryl groups can be optionally substituted by one or more substituents. Aryl groups can be optionally substituted by groups selected from halogen, C-1.5 alkylamino groups, C-|_6 dialkylamino groups, C-|_6 alkyloxy, C1 -6 alkylsulfides, C-1.5 alkylsulfones, C1 -6 alkylsulfoxides, C3.10 cycloalkyl, C-|.β alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocycle, amino, CONH(C1 -6 alkyl), CONH(C3_io cycloalkyl ), CON(C-|.6 alkyl)( C1 -6 alkyl), CON(C1 -6 alkyl )( C3.10 cycloalkyl), CONH(C6.10 aryl ), CON(C1 -6 alkyl)(C6.10 aryl ), CONH(C6.10 heteroaryl ), CON(C1 -6 alky') (C6-10 heteroaryl) , CONH (C3.10 non aromatic heterocycle), CON(C1 -6 alkyl) (C3-10 non aromatic heterocycle) , CONH2, CO(C1 -6 alkyl), CO(C3-1O cycloalkyl) , CO (C3.-10 non aromatic heterocycle ), CO (C6-10 ary') ■ CO (^6-10 heteroaryl) , NHSO2(C1 -6 alkyl), NHSO2 (C3-10 cycloalkyl) , NHSO2 (C6-10 aryl), NHSO2 (C6-10 heteroaryl), N(C1 -6 alkyl)S02 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3-10 cycloalkyl) , N(C1 -6 alkyl)SO2 (C6-10 aryl) , N(C1 -6 alkyl)SO2 (C6-1 0 heteroaryl) , NHCO(C1 -6 alkyl), NHCO (C3-10 cycloalkyl) , NHCO (C6-10 aryl ), NHCO (C6-10 heteroaryl), NHCO (C3-10 non aromatic heterocycle) ,
N(C1 -6 alkyl)CO(C1 -6 alkyl), N(C1 -6 alkyl)CO (C3-10 cycloalkyl), N(C1 -6 alkyl)CO (C6-10 aryl) , N(C1 -6 alkyl)CO (C6-10 heteroaryl), N(C1 -6 alkyl)CO (C3-10 non aromatic heterocycle) .
The term "C6-10 heteroaryl", as used herein refers to a 6 -10 member ring, containing at least one nitrogen atom interrupting the carbocyclic ring structure. Heteroaryl groups can be optionally substituted by one or more substituents. Heteroaryl groups can be optionally substituted by groups selected from C2.6 alkenyl, C6-10 arylsulfones, C6-10 arylsulfoxides, C6-10 arylsulfides, halogen, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C1 -6 alkyloxy, C1 -6 alkylsulfides, C1 -6 alkylsulfones, C1 -6 alkylsulfoxides, C3-10 cycloalkyl, C1 -6 alkyl, cyano, carboxylic acid, hydroxyl, C3-10 non aromatic heterocyle, amino, CONH(C1 -6 alkyl), CONH(C3-10 cycloalkyl ), CON(C1 -6 alkyl)( C1 -6 alkyl), CON(C1 -6 alkyl )( C3-10 cycloalkyl), CONH(C6-10 aryl ), CON(C1 -6 alkyl)(C6-10 aryl ), CONH(C6-10 heteroaryl ), CON(C1 -6 alkyl) (C6-10 heteroaryl) , CONH (C3-10 non aromatic heterocycle), CON(C1 -6 alkyl) (C3-10 non aromatic heterocycle), CONH2, CO(C1 -6 alkyl), CO(C3-10 cycloalkyl) , CO (C3-10 non aromatic heterocycle ), CO (C6-10 aryl), CO (C6-10 heteroaryl), NHSO2(C1 -6 alkyl), NHSO2 (C3-10 cycloalkyl) , NHSO2 (C6-10 aryl), NHSO2 (C6-10 heteroaryl), N(C1 -6 alkyl)SO2 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3-10 cycloalkyl) , N(C1 -6 alkyl)SO2 (C6-10 aryl) , N(C1 -6 alkyl)SO2 (C6-10 heteroaryl) , NHCO(C-|_6 alkyl), NHCO (C3.10 cycloalkyl) , NHCO (C6.10 aryl ), NHCO (C6.10 heteroaryl), NHCO (C3.10 non aromatic heterocycle) , N(C-) .5 alkyl)C0(C<|_6 alkyl), N(C-] . 6 alkyl)CO (C3.10 cycloalkyl), N(C1.6 alkyl)CO (C6.1 0 aryl) , N(C1.6 alkyl)CO (C6.-] 0 heteroaryl), N(C1^ alkyl)CO (03.10 non aromatic heterocycle). The term "3-10 ring member non-aromatic heterocycle", as used herein refers to a
3 to 10 ring member, containing one N or O heteroatom interrupting the carbocyclic ring structure The 3-10 ring member non-aromatic heterocycle groups can be optionally substituted by one or more substituents. The 3-10 ring member non-aromatic heterocycle groups can be optionally substituted by groups selected from C1^ alkyl, halogen, C1. Q alkylamino, C1 -6 dialkylamino, C3.-10 cycloalkyl. Usually 3 to 10 ring member non- aromatic heterocycle, in the present case is pyran.
The term " C1.5 alkyloxy", as used herein refers, to a refers to a group of formula -
ORf, wherein R^ is a C1 -6 alkyl group as defined above.
The term " C1. Q alkylsulfides", as used herein refers, to a refers to a group of formula -SR9, wherein R9 is a C1.5 alkyl group as defined above.
The term " C1^ alkylsulfones", as used herein refers, to a refers to a group of formula -S(=O)2Rn, wherein Rn is a C-\ .Q alkyl group as defined above.
The term " C1.6 alkylsulfoxides", as used herein refers, to a refers to a group of formula -S(=O)R', wherein R' is a C1^ alkyl group as defined above. The term " C6.-] Q arylsulfones", as used herein refers, to a refers to a group of formula
Figure imgf000012_0001
Q aryl group as defined above.
The term " C5.-10 arylsultoxides", as used herein refers, to a refers to a group of formula -Sf=O)R^, wherein R^ is a CQ.<\ Q aryl group as defined above.
The term " Cβ-io arylsulfides", as used herein refers, to a refers to a group of formula -SR', wherein R' is a C5.-10 aryl group as defined above.
Usually X is CH or N. Preferred X is CH.
Usually W is CH or N. Preferred W is N.
Usually R is chlorine or methoxy. Preferred R is chlorine.
Usually R^ is chlorine or methoxy. Preferred R1 is chlorine. Usually R^ is hydrogen; or is C1.5 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1.5 alkylamino groups, C-\ .Q dialkylamino groups, Cβ.-io ary!. cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C1. Q alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1^ alkyl, halogen, C-|_6 alkylamino, C-\ .Q dialkylamino, C3.-10 cycloalkyl; or is carbonyl when R^ does not exist. Preferred R^ is carbonyl, or together with R^ a ring or a heterocycle attached to the cyclobutenone as described in formula II.
Usually R^ is C^ .Q alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-1.5 alkylamino groups, C-| _Q dialkylamino groups, Cβ-io aryl, cyano, nitro; or is Cβ.-jQ cycloalkyl, optionally substituted by groups selected from halogen , C-\ .Q alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-|.ø alkyl, halogen, C^ .5 alkylamino, C-\ .Q dialkylamino, C3.10 cycloalkyl; or does not exist when R^ is carbonyl. Preferred R^ forms together with R^ a ring or a heterocycle attached to the cyclobutenone as described in formula II.
Usually R^ is a group of formula III; or R^ can be a group of formula IV; or is hydrogen or halogen. Preferred R4 is halogen or a group of formula III.
Usually R^ is C-] .5 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-|_6 alkylamino groups, C-μρ dialkylamino groups, Cβ-io aryl, cyano, nitro; or is C3..10 cycloalkyl optionally substituted by groups selected from halogen , C<|_6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-j.g alkyl, halogen, C-μβ alkylamino, C-μβ dialkylamino, C3.-10 cycloalkyl; or is Cβ-10 aryl optionally substituted by groups selected from halogen, C-|_g alkylamino groups, C-|.β dialkylamino groups, C-μβ alkyloxy, C-| _Q alkylsulfides, C-) .5 alkylsulfones, C<\ _Q alkylsulfoxides, C3.10 cycloalkyl, C-j.5 alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino, CONH(C-|.g alkyl), CONH(C3.10 cycloalkyl ), CON(Ci_6 alkyl)( C-|.6 alkyl), CON(C1^ alkyl )( C3.10 cycloalkyl), CONH(CQ-IO aryl ). CON(C-|_6 alkyl)(Cg_-|o aryl ), CONH(Cg-IO heteroaryl ), CON(C-| .g alkyl) {CQ.-\ Q heteroaryl) , CONH (C3.10 non aromatic heterocycle), CON(Ci_6 alkyl) (C3.10 non aromatic heterocycle) , CONH2, CO(C-|_6 alkyl), CO(C3_-|o cycloalkyl) , CO (C3.10 non aromatic heterocycle ), CO (Cβ-10 ary0 - CO (Cβ-io neteroary0 - NHSθ2(Ci_e alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO2 (Cg-io aryl), NHSO2 (C6-10 heteroaryl), N(C^6 alkyl)S02 (C1.6 alkyl), N(C <|_β alkyl)SO2 (C3.10 cycloalkyl) , N(C^e alkyl)S02 (Cg-io aryl) , N(C-|_6 alkyl)SO2 (Cg-io heteroaryl) , NHCO(Ci .5 alkyl). NHCO (C3.10 cycloalkyl) , NHCO (Ce-io aryl ), NHCO (Cg^ Q heteroaryl), NHCO (C3.10 non aromatic heterocycle) , N(C-|_6 alkyl)C0(C-i_6 alkyl), N(C^g alkyl)CO (C3.10 cycloalkyl), N(Ci_6 alkyl)CO (Cg-io aryl) , N(C^e alkyl)CO (Cβ-io heteroaryl), N(Ci_6 alkyl)CO (C3. 10 non aromatic heterocycle) ; or is C5.10 heteroaryl optionally substituted by groups selected from C2-6 alkenyl, CQ_<\ Q arylsulfones, Cβ-10 arylsulfoxides, Cβ-io arylsulfides, halogen, C-i.β alkylamino groups, C<\_Q dialkylamino groups, Ci_g alkyloxy, C-\.Q alkylsulfides, C-|.g alkylsulfones, C1 _g alkylsulfoxides, C3-1Q cycloalkyl, C1.g alkyl, cyano, carboxylic acid, hydroxyl, C3-1 Q non aromatic heterocyle, amino, CONH(C1 _g alkyl), CONH(C3.-! 0 cycloalkyl ), CON(C1.6 alkyl)( C1 _6 alkyl), CON(C1 -6 alkyl )( C3.10 cycloalkyl), CONH(C6--|o ary' ), CON(C1. g alkyl)(CQ_-jo ary' ). CONH(Cg.-^ heteroaryl ), CON(C1. e alkyl) (Cg. -| Q heteroaryl) , CONH (C3.-^ non aromatic heterocycle), CON(C1.6 alkyl) (C3.-|o non aromatic heterocycle) , CONH2, CO(C1.5 alkyl), CO(C3.-|o cycloalkyl) , CO (C3.-10 non aromatic heterocycle ), CO (Cg.-jo aryl) , CO (Cg-1Q heteroaryl) , NHSO2(C-^6 alkyl), NHSO2 (C3^o cycloalkyl) , NHSO2 (C6.10 aryl), NHSO2 (C6.-] 0 heteroaryl), N(C^g alkyl)SO2 (C1. g alkyl), N(C1. g alkyl)SO2 (C3.-] Q cycloalkyl) , N(C1. g alkyl)SO2 (C6.-) 0 aryl) , N(C1.6 alkyl)SO2 (C6.10 heteroaryl) , NHCO(C1.6 alkyl), NHCO (C3--|0 cycloalkyl) , NHCO (Cg.-! 0 aryl ). NHCO (C6.^ heteroaryl), NHCO (C3_-| Q non aromatic heterocycle) , N(C1^ alkyl)CO(C-|.g alkyl), N(C1 -6 alkyl)CO (C3_-|o cycloalkyl), N(C1 _β alkyOCO (C6.-] 0 aryl) , N(C1.6 alkyl)CO (C6-10 heteroaryl), N(C1 -6 alkyl)CO (C3. -|0 non aromatic heterocycle) . Usually R^ is hydrogen; or is C-|_6 alkyl optionally substituted by groups selected from halogen, C3-1 Q cycloalkyl, amino, amido, C-1.5 alkylamino groups, C-|.g dialkylamino groups, Cg-1Q ary!. cyano, nitro.
Usually R? is hydrogen; or is C3_-|o cycloalkyl optionally substituted by groups selected from halogen, C1. g alkyl; or is C1. Q alkyl optionally substituted by groups selected from halogen, C3.-|o cycloalkyl, amino, amido, C-μg alkylamino groups, C-|_g dialkylamino groups, Cg.-jQ aryl, cyano, nitro; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 _g alkyl, halogen, C1.5 alkylamino, C1 - Q dialkylamino, C3-1Q cycloalkyl.
Preferred R7 is C1 _β alkyl. Usually R^ is C3-1Q cycloalkyl optionally substituted by groups selected from halogen, C1. g alkyl; or is C-|_6 alkyl optionally substituted by groups selected from halogen, C3^ Q cycloalkyl, amino, amido, C1.5 alkylamino groups, C1. Q dialkylamino groups, Cg-1Q aryl, cyano, nitro; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 _g alkyl, halogen, C1 _g alkylamino, C1. g dialkylamino, C3-1 Q cycloalkyl; or is Cg^o aryl optionally substituted by groups selected from halogen, C1. g alkylamino groups, C1. g dialkylamino groups, C1. g alkyloxy, C1. g alkylsulfides, C1 ^g alkylsulfones, C1 -6 alkylsulfoxides, C3-1O cycloalkyl, C1 -6 alkyl, cyano, carboxylic acid, hydroxyl, C3-1O non aromatic heterocyle, amino, CONH(C1. g alkyl), CONH(C3^ Q cycloalkyl ), CON(C1 _g alkyl)( C1. g alkyl), CON(C1. g alkyl )( C3.-|Q cycloalkyl), CONH(Cg- 10 aryl ), CON(C1 -6 alkyl)(Cg.10 aryl ), CONH(Cg-IO heteroaryl ), CON(Ci-6 alkyl) (Cg. 10 heteroaryl) , CONH (C3.10 non aromatic heterocycle), CON(Ci _g alkyl) (C3-IO non aromatic heterocycle) , CONH2, CO(Ci_g alkyl), CO(C3_I Q cycloalkyl) , CO (C3.10 non aromatic heterocycle ), CO (Cg_io aryl) , CO (Cg_io heteroaryl) , NHSO2(Ci_g alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO2 (Cg.10 aryl), NHSO2 (Cg-io heteroaryl), N(Ci.g alkyl)S02 (Ci.g alkyl), N(Ci.g alkyl)S02 (C3.10 cycloalkyl) , N(Ci.g alkyl)SO2 (Cg_io aryl) , N(Ci.g alkyl)SO2 (Cg_i0 heteroaryl) , NHCO(Ci.g alkyl), NHCO (C3_10 cycloalkyl) , NHCO (Cg.10 ary! )- NHCO (Cg_io heteroaryl), NHCO (C3.10 non aromatic heterocycle) , N(C1 _6 alkyl)CO(Ci_6 alkyl), N(C1 -6 alkyl)CO (C3.10 cycloalkyl), N(C1 -6 alkyl)CO (C6. 10 aryl) , N(Ci_g alkyl)CO (Cg.10 heteroaryl), N(Ci_g alkyl)CO (C3.10 non aromatic heterocycle) ; or is Cg_io heteroaryl optionally substituted by groups selected from C2-g alkenyl, Cg.10 arylsulfones, Cg.10 arylsulfoxides, Cg.10 arylsulfides, halogen, Ci _g alkylamino groups, Ci_g dialkylamino groups, Ci_g alkyloxy, Ci_g alkylsulfides, Ci_g alkylsulfones, Ci_g alkylsulfoxides, C3.10 cycloalkyl, Ci_g alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino, CONH(Ci.g alkyl), CONH(C3_I Q cycloalkyl ), CON(Ci.g alkyl)( Ci.g alkyl), CON(Ci. g alkyl )( C3-10 cycloalkyl), CONH(Cg. 10 aryl ), CON(Ci _g alkyl)(Cg.io aryl ), CONH(Cg_io heteroaryl ), CON(Ci.6 alkyl) (C6- 10 heteroaryl) , CONH (C3.10 non aromatic heterocycle), CON(Ci _g alkyl) (C3.10 non aromatic heterocycle) , CONH2, CO(Ci.g alkyl), CO(C3_I Q cycloalkyl) , CO (C3.10 non aromatic heterocycle ), CO (C6^ Q aryl) , CO (Cg.-|o heteroaryl) , NHSO2(Ci_g alkyl), NHSO2 (C3-1Q cycloalkyl) , NHSO2 (Cg_i0 aryl), NHSO2 (Cg.io heteroaryl), N(C1. g alkyl)SU2 (Ci.g alkyl), N(Ci.g aiκyi)Sϋ2 (C3.10 cycioaikyi) , N(C-|.g aikyi)SO2 (Cg.-|o aryl) , N(C1. g alkyl)SO2 (Cg.10 heteroaryl) , NHCO(C1. g alkyl), NHCO (C3.-10 cycloalkyl) , NHCO (Cg.10 aryl )- NHCO (Cg_io heteroaryl), NHCO (C3.10 non aromatic heterocycle) , N(C1 -6 alkyl)CO(Ci_g alkyl), N(C1 -6 alkyl)CO (C3-1O cycloalkyl), N(C1 -6 alkyl)CO (C6. -10 aryl) , N(C1 -6 alkyl)CO (Cg-1Q heteroaryl), N(C1. g alkyl)CO (C3.-10 non aromatic heterocycle). Preferred R^ is C1 -6 alkyl.
Usually R^ is C1 -6 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C6-1O aryl, cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C1 -6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 -6 alkyl, halogen, C1. g alkylamino, C1. g dialkylamino, C3.-10 cycloalkyl; or is C6_-| Q aryl optionally substituted by groups selected from halogen, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C1 -6 alkyloxy, C1 -6 alkylsulfides, C1 -6 alkylsulfones, C1 -6 alkylsulfoxides, C3-1O cycloalkyl, C1 -6 alkyl, cyano, carboxylic acid, hydroxyl, C3_I Q. non aromatic heterocyle, amino, CONH(C-] .5 alkyl), CONH(C3.10 cycloalkyl ), CON(C-i.6 alkyl)( C-|.6 alkyl), CON(C^6 alkyl )( C3.-| 0 cycloalkyl), CONH(C6_io aryl ). CON(C-|_6 alkyl)(C6-io aryl ), CONH(C6_io heteroaryl ), CON(C-] _e alkyl) (C6_io heteroaryl) , CONH (C3.-] Q non aromatic heterocycle), CON(Ci _6 alkyl) (C3.-] Q non aromatic heterocycle) , CONH2, CO(Ci _6 a'W). CO(C3^ Q cycloalkyl) , CO (C3.-] 0 non aromatic heterocycle ), CO (C6_io aryl) . CO (C6.10 heteroaryl) , NHSO2(C-|_6 alkyl), NHSO2 (C3.-] 0 cycloalkyl) , NHSO2 (C6.10 aryl), NHSO2 (C6.10 heteroaryl), N(Ci.6 alkyl)SO2 (C-] _6 alkyl), N(Ci_6 alkyl)SO2 (C3.-] Q cycloalkyl) , N(C-J _6 alkyl)SO2 (C6.10 aryl) , N(C1 _6 alkyl)SO2 (C6.-] 0 heteroaryl) , NHCO(Ci _6 alkyl), NHCO (C3-10 cycloalkyl) , NHCO (C6. -| Q aryl ), NHCO (C6^ Q heteroaryl), NHCO (C3. -j Q non aromatic heterocycle) , N(C-J _6 alkyl)CO(Ci_6 alkyl), N(C-] _6 alkyl)CO (C3.10 cycloalkyl), N(C-^6 alkyl)CO (C6. -| Q aryl) , N(C-|.6 alkyl)CO (C6.10 heteroaryl), N(Ci_6 alkyl)CO (C3. 10 non aromatic heterocycle) ; or is C6.!o heteroaryl optionally substituted by groups selected from C2.6 alkenyl, C6. -|o arylsulfones, C6.-|o arylsulfoxides, C6.10 arylsulfides; halogen, C-] _6 alkylamino groups, C-i.6 dialkylamino groups, Ci_6 alkyloxy, C-|.6 alkylsulfides, C-|_6 alkylsulfones, Ci_6 alkylsulfoxides, C3_io cycloalkyl, C-|.6 alkyl, cyano, carboxylic acid, hydroxyl, C3. -| Q non aromatic heterocyle, amino, CONH(Ci _6 alkyl), CONH(C3_I Q cycloalkyl ), CON(Ci -6 alkyl)( Ci.6 alkyl), CON(Ci.6 alkyl )( C3_I Q cycloalkyl), CONH(C6_io aryl ), CON(Ci _6 alkyl)(C6_io aryl ), CONH(C6_I Q heteroaryl ), C0N(Ci.6 alkyl) (C6_I Q heteroaryl) ,
CONH (C3_io non aromatic heterocycle), CON(Ci _6 alkyl) (^3-10 non aromatic ncitii υuyuie; , OVJIN Π2,
Figure imgf000016_0001
, υυ V^3-I O l lυM ai ui i icaiiu heterocycle ), CO (C6_I Q aryl) , CO (C6_I Q heteroaryl) , NHSO2(Ci.6 alkyl), NHSO2 (C3.
10 cycloalkyl) , NHSO2 (C6_I Q aryl), NHSO2 (C6_io heteroaryl), N(Ci_6 alkyl)SO2 (C-j.6 alkyl), N(Ci_6 alkyl)SO2 (C3_I Q cycloalkyl) , N(Ci_6 alkyl)SO2 (C6_io aryl) , N(Ci_6 alkyl)SO2 (C6^ 0 heteroaryl) , NHCO(Ci.6 alkyl), NHCO (C3_i0 cycloalkyl) , NHCO (C6.
10 aryl ), NHCO (C6_I Q heteroaryl), NHCO (C3_I Q non aromatic heterocycle) , N(Ci_6 alkyl)CO(Ci_6 alkyl), N(C1 _6 alkyl)CO (C3.i0 cycloalkyl), N(Ci.6 alkyl)CO (C6.io aryl) ,
N(Ci_6 alkyl)CO (C6_I Q heteroaryl), N(Ci_6 alkyl)CO (C3_I Q non aromatic heterocycle). Usually R^ is hydrogen; or is Ci_6 alkyl optionally substituted by groups selected from halogen, C3_I Q cycloalkyl, amino, amido, C1^ alkylamino groups, Ci_6 dialkylamino groups, C6_I Q aryl, cyano, nitro.
Usually n is O, 1 , or 2. Preferred n is 1. Usually m is O, 1 , or 2. Usually Y is N- G1 R5, -S-, -O-, -S=O, -S(O)2- or -CH2.. Preferred Y is -O- or - CH2-.
Usually Z is N- G2R9, -S-, -O-, -S=O, S(O)2- or -CH2-. Usually G1 is direct bond, -C(O)-, -S(O)2- or -C(0)N(RR)-. Usually G2 is direct bond, -C(O)-, -S(O)2- or -C(O)N(R1 °)-.
In a preferred embodiment of the invention compounds are according to formula I or a pharmaceutically acceptable salt thereof, wherein: X is CH or N; and W is CH or N; and R is chlorine or methoxy; and R1 is chlorine or methoxy; and R^ is carbonyl when R^ does not exist; or R^ and R^ can form together a ring or a heterocycle attached to the cyclobutenone such as described in formula II; and Y is O or CH2; and n is O, 1 , or 2; and
R^ is a group of formula III; or R4 can be hydrogen or halogen; and R7 is hydrogen; or R7 is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C1.5 alkyl; or
R7 is C1. β alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1 _g alkylamino groups, C1. Q dialkylamino groups, Cg^o aryl, cyano, nitro; or R7 is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1. g alkyl, halogen, C1. β alkylamino, C1. g dialkylamino, C3.-10 cycloalkyl; and R8 is 03^ Q cycloalkyl optionally substituted by groups selected from halogen, C1. g alkyl; or R^ is C1.5 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1.5 alkylamino groups, C1 -S dialkylamino groups, Cβ.-io ary'. cyano, nitro; or R^ is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1. R alkyl, halogen, C-I .R alkylamino, C-|_R dialkylamino, C3.-K) cycloalkyl; or R^ is Cg.-j Q aryl optionally substituted by groups selected from halogen, C1. 6 alkyl, cyano, carboxylic acid, hydroxyl, C3.-10 non aromatic heterocyle, amino; or R^ is Cβ.-io heteroaryl optionally substituted by groups selected from halogen, C1.5 alkyl, cyano, carboxylic acid, hydroxyl, C3.-10 non aromatic heterocyle, amino; except 6-Quinolinepropanoic acid, 2-(2,6-dichlorophenyl)-α-[[3,4-dioxo-2-(propylamino)-1- cyclobuten-1-yl]amino.
In another preferred embodiment of the invention compounds are according to formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000018_0001
formula V wherein:
Y is O or CH2; and
X is CH; and W is N; and R is chlorine; and R1 is chlorine; and n is 1 ; and R4 is halogen.
In another preferred embodiment of the invention compounds are according to formula Vl, or a pharmaceutically acceptable salt thereof,
Figure imgf000018_0002
wherein: X is CH; and W is N; and R is chlorine; and R1 is chlorine; and
R^ is C-] . β alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, Ci_6 alkylamino groups, C-μβ dialkylamino groups, Cβ-io ary'> cyano, nitro; and
R8 is C-|_6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-] .5 alkylamino groups, C-1.5 dialkylamino groups, 05.10 ary'- cyano, nitro.
Preferred compounds of the invention are: (2S)-2-[(2-bromo-3-oxo-7-oxaspiro[3.5]non-1 -en-1 -yl)amino]-3-[2-(2,6- dichlorophenyl)quinolin-6-yl]propanoic acid;
(2S)-3-[2-(2,6-dichlorophenyl)quinolin-6-yl]-2-{[2-(diethylamino)-3,4-dioxocyclobut- 1-en-1-yl]amino}propanoic acid;
(2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-[2-(3,5-dichloropyridin-4- yl)quinolin-6-yl]propanoic acid.
Compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a "R" or a ""S configuration, said "R" and "S " notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. In all the above-mentioned scopes, the asymmetric carbon atom, is preferably in the "S" configuration.
The "pharmaceutically acceptable salts" according to the invention 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). Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
Compounds of formula I and their salts, can be in the form of a solvate, which is included within the scope of the present invention. Such 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). Some of the compounds of formula I may also exist in tautomeric forms. Such forms although not explicitly indicated in the above formulae are intended to be included within the scope of the present invention.
With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically.
Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.
The present invention concerns also processes for preparing the compounds of formula I.
When compounds of formula I present one stereogenic center, and non- stereoselective methods of synthesis are used, 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. Alternatively, when partly stereoselective methods of synthesis are used, 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. For example, 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, α4-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.
Thus, 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.
In particular, 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 α4 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, α4-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, α4-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 α4 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, α4-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 applications. In particular, 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 α4 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, α4-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, α4-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.
In a preferred embodiment, 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 α4 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, α4-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) in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound of formula I or a pharmaceutically acceptable salt thereof to a patient.
The methods of the invention comprise administration to a mammal (preferably human) suffering from above mentioned conditions or disorders, of 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.
The term "treatment" as used herein includes curative treatment and prophylactic treatment. The term "substantially" as used herein refers to a composition of equal or higher than 85% of one isomer, usually 90 % and preferably 95%.
By "curative" is meant efficacy in treating a current symptomatic episode of a disorder or condition.
By "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.
One aspect of the invention includes methods for treating α4-related cancers (including cancers, whether solid or haematopoietic). Examples of such 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.
Results obtained with compounds of formula I are indicative of a strong pharmacological effect.
For treating diseases, 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.
Therefore, another embodiment of the present invention concerns 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.
To prepare 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.
Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, or parenteral.
Pharmaceutical 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. To this end the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, 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.
The invention also contemplates compositions which can release the active substance in a controlled manner. Pharmaceutical 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.
In addition to the active ingredient, 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.
These pharmaceutical forms are prepared using methods which are routinely used by pharmacists.
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. Thus 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.
For the preferred oral compositions, the daily dosage is in the range 0.01 to 2000 milligrams (mg) of compounds of formula I.
In compositions for parenteral administration, 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. For the preferred parenteral compositions, 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.
In this context 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-Λ/-[3,5-di-chloropyrid-4-yl]-benzamide, muscarinic M3 antagonists, D2 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.
Most compounds of formula I may be prepared according to the following scheme:
Scheme 1
Figure imgf000027_0001
Compounds of formula Ia can be prepared according to scheme 1 , starting with 6- quinolinepropanoic acid 1-(2,6-dichlorophenyl)-α-[[(1 ,1-dimethylethoxy)carbonyl]amino]-, methylester (αS) (RN-623144-30-9) or with 6-quinolinepropanoic acid 1-(2,6- dimethoxyphenyl)-α-[[(1 ,1-dimethylethoxy)carbonyl]amino]-, methylester (αS) (RN-623147- 28-4).
The f-butyl group is removed using Trifluoroacetic acid in dichloromethane to yield the free amine. The amino group is coupled with the 7-oxaspiro[3.5]nonane-1 ,3-dione or the diethoxycyclobut-3-ene-1 ,2-dione. The double bond of the enamide is substituted with bromide using N-Bromosuccinamide (NBS). Saponification of the ester to the acid using
2N NaOH yields the desired products in both cases.
Most compounds of formula I may be prepared according to scheme 1 , starting with
6-quinolinepropanoic acid 1-(2,6-dichlorophenyl)-α-[[(1 ,1- dimethylethoxy)carbonyl]amino]-, methylester (RN-23144-13-8) or with 6- quinolinepropanoic acid 1-(2,6-dimethoxyphenyl)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-, methylester (RN-623146-89-4).
The present invention also relates to synthetic intermediates geometrical isomers, enantiomers, diastereoisomers, pharmaceutically acceptable salts and all possible mixtures thereof.
Specific synthetic intermediates are selected from the group consisting of: Methyl (2S)-3-[2-(2,6-dichlorophenyl)quinolin-6-yl]-2-[(3-oxo-7-oxaspiro[3.5]non-1-en-1- yl)amino]propanoate;
Methyl (2S)-2-[(2-bromo-3-oxo-7-oxaspiro[3.5]non-1 -en-1 -yl)amino]-3-[2-(2,6- dichlorophenyl)quinolin-6-yl]propanoate;
Ethyl (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1 -en-1 -yl)amino]-3-[2-(3,5- dichloropyridin-4-yl)quinolin-6-yl]propanoate.
The invention concerns also a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above and a pharmaceutically acceptable adjuvant, diluent or carrier. The invention concerns a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above for use as a medicine. The invention concerns a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above in the manufacture of a medicament. The invention concerns a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound as described above in the manufacture of a medicament for the treatment of α4 dependent inflammatory or medical conditions. The invention concerns a compound as described above for use as a medicament. The invention concerns a compound as described above for curing 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, α4-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 following examples are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Unless specified otherwise in the examples, 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 μM 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.
The following abbreviations are used in the examples: AcOH - acetic acid CDCI3- Chloroform-d; DCM - Dichloromethane;
DIPEA - Λ/,Λ/-Diisopropylethylamine; DMF - Λ/,Λ/-Dimethylformamide; DMSO - Dimethyl sulphoxide; d6.DMSO - Dimethyl-d6 sulphoxide;
Et2O - Diethyl ether; EtOH - Ethanol;
EtOAc - Ethyl acetate; EDC - 1 -(3-Dimethylaminopropyl)-3- ethylcarbodiimide
HCI - hydrochloric acidHOBT - 1-Hydroxybenzotriazole hydrate; MeCN - Acetonitrile d4-MeOH - Methanol-d4; MeOH - Methanol;
MgSO4 - Magnesium Sulfate NaHCO3 - Sodium Hydrogen Carbonate
NaOH - sodium hydroxide Na2SO4 - sodium sulfate NMP - 1-Methyl-2-pyrrolidinone; MeCN - acetonitrile
TBS - Tris buffered saline
RT - Retention time; TEA - Triethylamine;
TFA - Trifluoroacetic acid; THF - Tetrahydrofuran
FACS - Fluorescent Activated Cell Sorting LCMS_Prep LC conditions and abbreviations
The following LCMS conditions are used to obtain the retention times (RT) as described herein:
LCMS conditions (Method A):
HP1100 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionisation Column: Luna C 18(2) 100x4.6mm, 5μm particle size Analytical column
Column Temp: 35°C
Mobile Phase: A: Water + 0.08% formic acid
B: Acetonitrile + 0.08% formic acid Flow rate: 3ml/min
Gradient: Time (mins): % Composition B:
0 5
4.4 95 5.30 95 5.32 5
6.5 5 Run time: 6.5 mins
Typical Injection VoI: 10μl
Detector Wavelength: DAD 200-400nm Preparative LC conditions (Method B):
Gilson 215 liquid handler setup.
Column: Luna C18(2) 250x21.2mm, 5μM particle size prep column
Column Temp: Ambient
Gradient: Variable - depends on retention time of sample in LC-MS analysis. Run Time: 20 mins
Flow rate: 25ml/min
Typical Injection VoI: 0.5 - 4.0ml at 25mg/ml
Detector Wavelength:210 and 254nm
Mobile Phase: A: Water + 0.08% formic acid B: Acetonitrile + 0.08% formic acid
The IUPAC names of the compounds mentioned in the examples are generated with ACD version 6.00.
Unless specified otherwise in the examples, 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.
Synthetic examples: Example 1 : Synthesis of Methyl (2S)-3-r2-(2,6-dichlorophenyl)quinolin-6-yll-2-r(3- oxo-7-oxaspiror3.51non-1-en-1-yl)amino1propanoate (Intermediate 1)
To a stirred solution of Methyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6- dichlorophenyl)-6-quinolinyl]propanoate (RN 623144-30-9) (10g) in DCM (70ml) at 00C is added TFA (1.2ml) in portions over 5-10 mins. The ice-bath is removed and the reaction stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. EtOAc (100ml) is added and the mixture treated with saturated aqueous NaHCO3 (100ml), followed by solid NaHCO3 in small portions until the effervescence ceased. A further 100ml EtOAc is added and the layers separated. The aqueous phase is extracted with EtOAc (2 x 50ml) and the combined organic extracts washed with brine (100ml), dried (MgSO4) and concentrated in vacuo to afford a yellow oil, which is dissolved in EtOAc (100ml) and 7- oxaspiro[3.5]nonane-1 ,3-dione (3.71 g, RN 455264-53-6) is added and the reaction is heated to reflux for 3 hours, before being cooled to room temperature over night. The reaction mixture is reduced in vacuo and the solid precipitate collected and washed with EtOAc (2 x 10ml), and dried under vacuum to yield the title compound as a yellow solid (7.77g, 100%). LCMS (Method A) 511 [M+H]+ RT 3.25 mins. 1H NMR 300 MHz (DMSO) δ 1.17 (d, 1H), 1.48 (d, 1H), 1.78 (dt, 1H), 1.91 (dt, 1H), 3.23 (dd, 1H), 3.37 (s, 3H), 3.44 (dd, 1H), 3.50-3.78 (m, 4H), 4.39-4.51 (m, 2H), 7.52 (d, 1 H), 7.54 (d, 1 H), 7.65(d, 2H), 7.73 (dd, 1 H)1 7.88 (s, 1 H), 7.95 (d, 1 H), 8.42 (d, 1 H), 8.62 (d, 1H). Example 2: Synthesis of methyl (2S)-2-r(2-bromo-3-oxo-7-oxaspiror3.51non-1-en-1- yl)aminol-3-r2-(2.6-dichlorophenyl)quinolin-6-vHpropanoate (Intermediate 2)
To Intermediate 1 (500mg) in EtOAc (10ml) is added N-Bromosuccinimide (980mg) and the reaction stirred at room temperature for 16 hours. The reaction is diluted with EtOAc (10ml) and washed with water (10ml) and brine (10ml), before being dried over MgSO4 and the solvent is removed in vacuo. Purification using flash chromatography (eluent Heptane to EtOAc) affords the title compound as a white solid (642mg). LCMS (Method A) 591 [M+H]+, RT 3.74 mins. 1H NMR 300 MHz (DMSO) δ 1.13 (d, 1H), 1.48 (d, 1H), 1.82 (dd, 1 H), 1.95 (dt, 1 H), 3.28 (dd, 1 H), 3.44 (dd, 1H), 3.50-3.75 (m, 4H), 3.80 (s, 3H), 5.00 (sx, 1H), 7.52 (dd, 2H), 7.65(d, 2H), 7.73 (dd, 1 H), 7.88 (s, 1 H), 7.95 (d, 1 H), 8.44 (d, 1 H)1 9.14 (d, 1 H).
Example 3: Ethyl (2S)-2-r(2-bromo-3-oxospirof3.51non-1-en-1-yl)amino1-3-r2-(3.5- dichloropyridin-4-yl)quinolin-6-vnpropanoate (Intermediate 3)
(S)-3-(4-Amino-phenyl)-2-(3-oxo-spiro[3.5]non-1 -en-1 -ylamino)-propionic acid ethyl ester (RN644995-09-05) (4.89g) is dissolved in MeCN (50ml) with 3,5-Dichloropyridine-4- carboxaldehyde (RN 136590-83-5) (2.5g) and heated at reflux for 18 hrs. On cooling the solvent is removed and DCM (50ml), n-butylvinyl ether (RN 111-34-2) (3.8ml) and Ytterbium Triflate (1g) are added and the reaction heated at reflux for 2 days. On cooling the mixture is washed with brine (50ml) and dried over MgSO4 and the solvent is removed in vacuo. The resultant oil is taken up in Dioxane (150ml), manganese oxide (4.21 g) and heated at refluxed for 18 hrs. On cooling the reaction is adsorbed onto silica and purified using flash chromatography (eluent Heptane to 100% EtOAc) to yield a clear oil (1.38g). To a 250 mg portion in EtOAc (5ml) is added N-Bromosuccinimide (86mg) and the reaction stirred at room temperature for 16 hours. The reaction is diluted with EtOAc (10ml) and washed with water (10ml) and brine (10ml), before being dried over MgSO4 and the solvent is removed in vacuo. Purification using flash chromatography (eluent
Heptane to EtOAc) affords the title compound as a white solid (141mg). LCMS (Method A) 602, 604, 606 [M+H]+, RT 4.10 mins. 1H NMR 300 MHz (CDCI3) δ 1.20- 1.38 (m, 7H), 1.40- 1.92 (m, 6H), 3.55 (d, 2H),4.33 (2H, q), 5.16 (dt, 1 H), 5.82 (d, 1 H), 7.45 (d, 1 H), 7.55 (dd, 1 H), 7.66 (s, 1 H), 8.11 (d, 1 H), 8.25 (d, 1 H), 8.65 (s, 1H). Example 4: Synthesis of (2S)-2-f(2-bromo-3-oxo-7-oxaspirof3.51non-1-en-1- yl)amino1-3-f2-(2.6-dichlorophenyl)quinolin-6-vnpropanoic acid (Compound 1) To a stirred solution of 2M NaOH (3ml) is added a solution of Intermediate 2 (598mg) in THF (4ml) and water (0.5ml_) at 1.98 cc/hr dropwise via a syringe pump. After addition the reaction is stirred over night at room temperature before being diluted with water (1ml) and the pH adjusted to pH 2-3 using 2M HCI. The reaction mixture is concentrated in vacuo, and the resultant precipitate collected by filtration and dried under vacuum, affording the title compound as an off -white solid (550mg). LCMS (Method A) 577 [M+H]+, RT 3.35 mins. 1H NMR 300 MHz (DMSO) δ 1.13 (d, 1 H), 1.48 (d, 1 H), 1.89 (dt, 1H), 2.00 (dt, 1 H), 3.28 (dd, 1 H), 3.42-3.75 (m, 5H), 4.85 (sx, 1 H), 7.52 (d, 2H), 7.65 (d, 2H), 7.73 (dd, 1 H), 7.88 (s, 1 H), 8.00 (d, 1 H), 8.44 (d, 1 H), 9.10 (d, 1 H).
Example 5: (2S)-2-r(2-bromo-3-oxospiror3.5lnon-1 -en-1 -yl)amino1-3-r2-(3.5- dichloropyridin-4-yl)quinolin-6-yllpropanoic acid (Compound 2)
Prepared in a similar manner to Example 4 using Ethyl (2S)-2-[(2-bromo-3- oxospiro[3.5]non-1-en-1-yl)amino]-3-[2-(3,5-dichloropyridin-4-yl)quinolin-6-yl]propanoate (Intermediate 3) (141 mg) to yield the title compound as white solid (57mg) LCMS (Method A) 574, 576, 578 [M+H]\ RT 3.43 mins. 1H NMR 300 MHz (DMSO) δ 1.03-1.28 (m, 4H), 1.42-1.75 (m, 6H), 3.28 (dd, 1H), 3.51 (dd, 1H), 4.92 (sx, 1H), 7.65 (d, 1H), 7.75 (dd, 1H), 7.92 (d, 1 H), 8.04 (d, 1 H), 8.50 (d, 1 H), 8.85 (s, 1 H), 8.95 (d, 1 H). Example 6: Synthesis of (2S)-3-r2-(2.6-dichlorophenyl)quinolin-6-vH-2-{r2- (diethylamino)-3.4-dioxocvclobut-1-en-1-yllamino>propanoic acid (Compound 3) Methyl-(2S)-2-[(tert-butoxycarbonyl)amino]-3-[2-(2,6-dichlorophenyl)-6- quinolinyl]propanoate (RN 623144-30-9) (500mg) is dissolved in dichloromethane (4.5ml) and a solution of trifluoroacetic acid (0.33ml) in dichloromethane (1ml) is added dropwise over 10 minutes. After the addition is complete the reaction is stirred at RT over night, before the reaction is diluted with EtOAc and washed with a saturated NaHCO3 solution and the solvent is removed in vacuo. The resultant slurry is taken up in EtOH with 3,4- Diethoxycyclobut-3-ene-1 ,2-dione (0.093ml) and the reaction is heated at reflux for 3 hours, followed by the addition of diethylamine (0.33ml) and further heating at reflux overnight. On cooling the EtOH is removed in vacuo and the reation diluted with EtOAc and washed with a saturated NaHCO3 solution. The solvent is removed and the slurry taken up in THF (3ml) and added dropwise to a 2N NaOH solution (2ml). On completion of addition the reaction is purified by mass triggered prep HPLC (Method B) to yield the title compound (49mg) as a white solid. LCMS (Method A) M+1 (512, 514), Retention Time 3.20min, 1H NMR, 300Mz, CD3OD: .81.18 (t, 6H), 3.39 (dd, 1H), 3.46-3.62 (m, 4H), 3.70 (1H, dd), 5.50 (dd, 1 H), 7.50-7.62 (m, 4H), 7.81 (1H, dd), 7.95 (1H, s), 8.05 (1H, d), 8.46 (1 H, d).
Biological examples: Example 7
The following cellular assay is used to demonstrate the potency of the compounds according to the invention. In each of these assays an IC50 value is determined for each test compound and represents the concentration of compound necessary to achieve 50% inhibition of cell adhesion where 100% = adhesion assessed in the absence of the test compound and 0% = absorbance in wells that did not receive cells.
Whole blood VCAM-bindinq assay for α4 inteqrins: The following reagents are added to FACS tubes: 3μl 10OmM MnCl2 (100X required cone), 1 μl 1mg/ml streptavidin-FITC (supplier Pierce 100X required cone), 2μl 500 μg/ml biotinylated hVCAM-1-mFc (5OX required cone), and 2μl serially-diluted test compound at 5OX desired final concentrations. 100μl heparinised blood from healthy human donors is then added to each FACS tube which are then sealed and rocked for 30 minutes at RT. 2ml "FACS Lysing Solution" (BD Biosciences) solution is added to tubes for 5 minutes at room temperature RT, and tubes are spun at 1200 rpm and washed 2X in 3ml TBS, before final suspension in 100μl TBS. Flow cytometry is then performed on a Becton Dickinson FACScan to assess the % of cells in the lymphocyte gate capable of binding VCAM. The compounds of the invention are tested in this assays and show IC50 values of
1.5 μM and below.
(2S)-3-[2-(2,6-dichlorophenyl)quinolin-6-yl]-2-{[2-(diethylamino)-3,4-dioxocyclobut- 1 -en-1 -yl]amino}propanoic acid has an activity of 1.0 - 1.3 μM in the above assay.

Claims

1. A compound having formula I or pharmaceutically acceptable salts thereof or stereoisomeric forms thereof, and the geometrical isomers, enantiomers, diastereoisomers, and pharmaceutically acceptable salts thereof
Figure imgf000035_0001
formula I wherein:
" * " represents the point of attachment;
X is CH or N;
W is CH or N;
R is chiorine or methoxy; R^ is chlorine or methoxy;
R2 is hydrogen; or is C-| .6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C^ .5 alkylamino groups, C-| .Q dialkylamino groups, Cβ-10 aryl- cyano, nitro; or is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C-μg alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-] .5 alkyl, halogen, C-j.ø alkylamino, C^ .5 dialkylamino, C3.10 cycloalkyl; or is carbonyl when R^ does not exist; R3 is C-|_6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C^ .5 alkylamino groups, C-) _Q dialkylamino groups, Cg.-|o aryl, cyano, nitro; or is C3.10 cycloalkyl, optionally substituted by groups selected from halogen , C1. 6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 _g alkyl, halogen, C1 _g alkylamino, C1 _g dialkylamino, C3.10 cycloalkyl; or does not exist when R^ is carbonyl; or R2 and R^ can form together a ring or a heterocycle attached to the cyclobutenone such as described in formula Il
Figure imgf000036_0001
formula Il wherein
Y is N-G1 R5, -S-, -O-, -S=O, -S(O)2-, Or -CH2-; G1 is a direct bond, -C(O)-, -S(O)2- , or -C(O)N(R6)-;
R5 is C1. g alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1.5 alkylamino groups, C1. g dialkylamino groups, Cg^rj aryl, cyano, nitro; or is C3.-10 cycloalkyl optionally substituted by groups selected from halogen, C1. g alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1. ρ alkyl, halogen, C1. g alkylamino, C^g dialkylamino, C3.-10 cycloalkyl; or is Cg. -|o aryl optionally substituted by groups selected from halogen, C1. g alkylamino groups, C-j.g dialkylamino groups, C-|.g alkyloxy, C-|.g alkylsulfides, C-|.g alkylsulfones,
Figure imgf000036_0002
non aromatic heterocyle, amino,
CONH(C1. g alkyl), CONH(C3_-|o cycloalkyl ), CON(C^g alkyl)( C^g alkyl), CON(C1. e alkyl )( C3.-] 0 cycloalkyl), CONH(Cg.10 aryl ), CON(C1. g alkyl)(C6.10 aryl ), CONH(Cg-1O heteroaryl ), CON(C-|.g alkyl) (Cg.^ heteroaryl) , CONH (C3.-10 non aromatic heterocycle), CON(C1. g alkyl)
Figure imgf000036_0003
non aromatic heterocycle) , CONH2, CO(C1. g alkyl), CO(C3_I Q cycloalkyl) , CO (C3.-10 non aromatic heterocycle ), CO (Cg_-|o aryl) , CO (C6.10 heteroaryl) , NHSO2(C1. g alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO2 (Cg_-|o aryl), NHSO2 (Cg_-|o heteroaryl), N(C1. g alkyl)SO2 (C1. g alkyl), N(C1. g alkyl)SO2 (C3--10 cycloalkyl) , N(C-] .5 alkyl)SO2 (C6_io ary') - N(Ci-6 alkyl)SC>2 (C6_I Q heteroaryl) , NHCO(C-J _6 alkyl), NHCO (C3.10 cycloalkyl) , NHCO (C6.-! 0 aryl ), NHCO (C6.10 heteroaryl), NHCO (C3.10 non aromatic heterocycle) ,
N(C-i_6 alkyl)CO(C-i.6 alkyl), N(C1^ alkyl)CO (C3.10 cycloalkyl), N(C-i.6 alkyl)CO (C6.io aryl) , N(C-|.6 alkyl)CO (C6. I Q heteroaryl), N(C-|.6 alkyl)CO (C3. IQ non aromatic heterocycle) ; or is C6. io heteroaryl optionally substituted by groups selected from C2-6 alkenyl,
C6. -jo arylsulfones, C6. -| Q arylsulfoxides, C6_I Q arylsulfides, halogen, C-) _6 alkylamino groups, C-μ6 dialkylamino groups, Ci_6 alkyloxy, Ci_6 alkylsulfides, Ci_6 alkylsulfones, C-|_6 alkylsulfoxides, C3_I Q cycloalkyl, C-|_6 alkyl, cyano, carboxylic acid, hydroxyl, C3_I Q non aromatic heterocyle, amino, CONH(C-|_6 alkyl), CONH(C3.10 cycloalkyl ), CON(C-i.6 alkyl)( C-|.6 alkyl), CON(C-|_6 alkyl )( C3.10 cycloalkyl), CONH(C6.10 aryl ), CON(C^6 alkyl)(C6.10 aryl ), CONH(C6.-] 0 heteroaryl ), CON(C-] _6 alkyl) (C6.-] Q heteroaryl) , CONH (C3.-|o non aromatic heterocycle), CON(Ci _6 alkyl) (C3.-] Q non aromatic heterocycle) , CONH2, CO(Ci _6 alky0. CO(C3_I Q cycloalkyl) , CO (C3_I Q non aromatic heterocycle ), CO (C6_i0 aryl) , CO (C6. -] 0 heteroaryl) , NHSO2(Ci _6 alkyl), NHSO2 (C3. 10 cycloalkyl) , NHSO2 (C6_I Q aryl), NHSO2 (C6.I Q heteroaryl), N(Ci_6 alkyl)SO2 (Ci.6 alkyl), N(Ci.6 alkyl)SO2 (C3_i0 cycloalkyl) , N(Ci.6 alkyl)SO2 (C6_i0 aryl) , N(Ci.6 alkyl)SO2 (C6_i0 heteroaryl) , NHCO(C1 _6 alkyl), NHCO (C3_i0 cycloalkyl) , NHCO (C6. 10 aryl ), NHCO (C6_I Q heteroaryl), NHCO (C3.I Q non aromatic heterocycle) , N(Ci_6 aikyi)Cϋ(Ci_6 aikyi), N(Ci_6 aikyijCO (C3_I Q cycioaikyi), N(Ci.6 aikyijCO (C6_I Q aryi) , N(Ci_6 alkyl)CO (C6_I Q heteroaryl), N(Ci_6 alkyl)CO (C3_I Q non aromatic heterocycle) ;
R^ is hydrogen; or is C-|_6 alkyl optionally substituted by groups selected from halogen, C3_I Q cycloalkyl, amino, amido, Ci_6 alkylamino groups, Ci.6 dialkylamino groups, C6_I Q aryl, cyano, nitro; n is 0, 1 , or 2; R4 is a group of formula III
Figure imgf000037_0001
formula III wherein
R7 is hydrogen; or is C3_io cycloalkyl optionally substituted by groups selected from halogen, Ci_6 alkyl; or is C-|_5 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C5.10 aryl, cyano, nitro; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 -6 alkyl, halogen, C-] .5 alkylamino, C1 -6 dialkylamino, C3-1O cycloalkyl; Rδ is C3-1Q cycloalkyl optionally substituted by groups selected from halogen, C1 -
6 alkyl; or is C1-6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C6-1O aryl, cyano, nitro; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C1 _6 alkyl, halogen, C1 -6 alkylamino, C1.5 dialkylamino, C3.10 cycloalkyl; or is Cg.10 aryl optionally substituted by groups selected from halogen, C1 -6 alkylamino groups, C1 -6 dialkylamino groups, C-|_6 alkyloxy, C1 -6 alkylsulfides, C1 -6 alkylsulfones, C-] .5 alkylsulfoxides, C3.10 cycloalkyl, C1 -6 alkyl, cyano, carboxylic acid, hydroxyl, C3.-10 non aromatic heterocyle, amino,
CONH(C-|_6 alkyl), CONH(C3.10 cycloalkyl ), CON(C1-6 alkyl)( C-|.6 alkyl), CON(C-|. e alkyl )( C3-1Q cycloalkyl), CONH(Cg-IO aryl ). CON(C1 -6 alkyl)(Cg.-|o aryl ), CONH(C6.-] 0 heteroaryl ), CON(C1 _g alkyl) (Cg.10 heteroaryl) , CONH (C3_10 non aromatic heterocycle), CON(C-|.g alkyl) (C3.10 non aromatic heterocycle) , CONH2, CO(C1 _g alkyl), CO(Cs-1O cycloalkyl) , CO (C3_-]o non aromatic heterocycle ), CO (Cg. -| Q aryl) , CO (Cg.-|o heteroaryl) , NHSθ2(C1.g alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO2 (c6-10 ary'). NHSO2 (Cg.10 heteroaryl), N(C-|.g alkyl)SO2 (C1 -6 alkyl), N(C1 -6 alkyl)SO2 (C3--10 cycloalkyl) ,
N(C-|.g alkyl)SO2 (Cg. -|o aryl) , N(C1 -6 alkyl)SO2 (C6-1O heteroaryl) , NHCO(C-].g alkyl), NHCO (C3-10 cycloalkyl) , NHCO (C6.-] 0 aryl ), NHCO (Cg-10 heteroaryl), NHCO (C3-10 non aromatic heterocycle) ,
N(C1 -6 alkyl)CO(C1 -6 alkyl), N(C1 -6 alkyl)CO (C3.10 cycloalkyl), N(C1 -6 alkyl)CO (Cg-1O aryl) , N(C-|.g alkyl)CO (Cg.-|o heteroaryl), N(C-|.g alkyl)CO (C3-1O non aromatic heterocycle) ; or is Cg-1Q heteroaryl optionally substituted by groups selected from C2-6 alkenyl,
C6.-] 0 arylsulfones, C6-1Q arylsulfoxides, C6-1 Q arylsulfides, halogen, C-|.6 alkylamino groups, C1 -6 dialkylamino groups, C1 -6 alkyloxy, C1 -6 alkylsulfides, C1 -6 alkylsulfones, C1 -6 alkylsulfoxides, C3-1O cycloalkyl, C1 -6 alkyl, cyano, carboxylic acid, hydroxyl, C3_-|o non aromatic heterocyle, amino, CONH(C1 -6 alkyl), CONH(C3-10 cycloalkyl ), CON(C1 -6 alkyl)( C1 -6 alkyl), CON(C1 -6 alkyl )( C3-10 cycloalkyl), CONH(C6.10 aryl ), CON(C^6 alkyl)(C6.10 aryl), CONH(C6.10 heteroaryl ), CON(C-|.6 alkyl) (Cø-io heteroaryl) ,
CONH (C3.10 non aromatic heterocycle), CON(C^ .5 alkyl) (C3.10 non aromatic heterocycle) , CONH2, CO(C-^6 alkyl), CO(C3_-|o cycloalkyl) , CO (C3.10 non aromatic heterocycle ), CO (C6_I Q aryl) • co (c6-10 heteroaryl) , NHSO2(Ci _6 alkyl), NHSO2 (C3. 10 cycloalkyl) , NHSO2 (c6-10 ary'). NHSO2 (C6_io heteroaryl), N(C^6 alkyl)S02 (C-] _6 alkyl), N(C-] .5 alkyl)SO2 (C3.10 cycloalkyl) , N(C-].6 alkyl)SO2 (C6_I Q aryl) , N(C^ .6 alkyl)S02 (C6_io heteroaryl) , NHCO(C-|.6 alkyl), NHCO (C3_I Q cycloalkyl) , NHCO (C6. 10 aryl ). NHCO (C5.10 heteroaryl), NHCO (C3.-10 non aromatic heterocycle) , N(C^ _6 alkyl)CO(Ci_6 alkyl), N(Ci.6 alkyl)CO (C3.10 cycloalkyl), N(Ci_6 alkyl)CO (C6_I Q aryl) , N(C-] .6 alkyl)CO {CQ_*\ Q heteroaryl), N(C-] .5 alkyl)CO (C3.10 non aromatic heterocycle) ; or R4 can be a group of formula IV
Figure imgf000039_0001
formula IV wherein
Z is N-G2R9, -S-, -O-, -S=O, -S(O) 2-, or -CH2-; G2 is direct bond, -C(O)-, -S(O)2- , or -C(O)N(R10)-;
R9 is Ci_6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C1.5 alkylamino groups, Ci_6 dialkylamino groups, C6_io aryl, cyano, nitro; or is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C-|_6 alkyl; or is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from Ci_6 alkyl, halogen, Ci_6 alkylamino, C-|_6 dialkylamino, C3.10 cycloalkyl; or is C6_io aryl optionally substituted by groups selected from halogen, Ci_6 alkylamino groups, Ci_6 dialkylamino groups, C<|_6 alkyloxy, C-j_6 alkylsulfides, Ci_6 alkylsulfones, Ci_6 alkylsulfoxides, C3.10 cycloalkyl, Ci_6 alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino, CONH(C-|.6 alkyl), CONH(C3.10 cycloalkyl ), CON(C1 _6 alkyl)( C^6 alkyl),
CON(Ci_6 alkyl )( C3.10 cycloalkyl), CONH(C6.io aryl ), CON(C^6 alkyl)(C6.-|o aryl ), CONH(C6.io heteroaryl ), CON(Ci.6 alkyl) (C6_I Q heteroaryl) , CONH (C3.10 non aromatic heterocycle), CON(C-] _6 alkyl) (C3.10 non aromatic heterocycle) , CONH2, CO(C-i_ 6 alkyl), CO(C3_I Q cycloalkyl) , CO (C3.10 non aromatic heterocycle ), CO (C6_-|o aryl) , CO (C6. -| Q heteroaryl) , NHSO2(C^6 alkyl), NHSO2 (C3.10 cycloalkyl) , NHSO2 (C6-10 aryl)- NHSO2 (C6_10 heteroaryl), N(C1 _6 alkyl)SO2 (C1 _6 alkyl), N(C1 _6 alkyl)SO2 (C3-10 cycloalkyl) , N(C-|_6 alkyl)SO2 (C6^n aryl) , N(C-|_6 alkyl)SO2 (C6. -|n heteroaryl) , NHCO(C-|_6 alkyl), NHCO (C3.-] 0 cycloalkyl) , NHCO (C6-IO aryl ), NHCO (C6_10 heteroaryl), NHCO (C3--10 non aromatic heterocycle) ,
N(C1.6 alkyl)CO(C-i_6 alkyl), N(C1.6 alkyl)CO (C3.-] 0 cycloalkyl), N(C1.6 alkyl)CO (c6-10 ary') - N(c1-6 alkyl)CO (CQ.I O heteroaryl), N(C-^6 alkyl)CO (C3.-10 non aromatic heterocycle) ; or is Cβ.-io heteroaryl optionally substituted by groups selected from C2_6 alkenyl,
C5.-10 arylsulfones, Cg-io arylsulfoxides, C6^ Q arylsulfides, halogen, C1.5 alkylamino groups, C1.6 dialkylamino groups, C1.5 alkyloxy, C1.5 alkylsulfides, C1.5 alkylsulfones, C1. β alkylsulfoxides, C3.-10 cycloalkyl, C1 -6 alkyl, cyano, carboxylic acid, hydroxyl, 03^o non aromatic heterocyle, amino,
CONH(C1 _6 alkyl), CONH(C3.10 cycloalkyl ), CON(C1 _6 alkyl)( C1.6 alkyl), CON(C^6 alkyl )( C3.10 cycloalkyl), CONH(C6.10 aryl ), C0N(C-|_6 alkyl)(C6.10 aryl ), CONH(C6.10 heteroaryl ), CON(C1.6 alkyl) (C6.-) Q heteroaryl) ,
CONH (C3.-10 non aromatic heterocycle), CON(C1^ alkyl) (C3.-10 non aromatic heterocycle) , CONH2, CO(C1.6 alkyl), CO(C3_-|o cycloalkyl) , CO (C3.-10 non aromatic heterocycle ), CO (C6^n aryl) , CO (C6. -| Q. heteroaryl) , NHSO2(C-|.6 alkyl), NHSO2 (C3. •10 cycloalkyl) , NHSO2 (C6.-] Q aryl), NHSO2 (CQ.-\ Q heteroaryl), N(C1.6 alkyl)SO2 (C1.6 alkyl), N(C1.6 alkyl)SO2 (C3_<ιo cycloalkyl) , N(C1.6 alkyl)SO2 (C6^n aryl) , N(C1.6 alkyl)SO2 (C6.-] Q heteroaryl) , NHCO(C1 _6 alkyl), NHCO (C3^ 0 cycloalkyl) , NHCO (C6. ■I O aryl ), NHCO (C6_-|n heteroaryl), NHCO (C3.-10 non aromatic heterocycle) , N(C1 -6 alkyl)CO(C-i_6 alkyl), N(C-|.6 alkyl)CO (03^0 cycloalkyl), N(C-|.6 alkyl)CO (C6. -J Q aryl) , N(C^6 alkyl)CO (C6^n heteroaryl), N(C1 -6 alkyl)CO (03.^ non aromatic heterocycle) ;
R10 js hydrogen; or is C-|_5 alkyl optionally substituted by groups selected from halogen, C3.-10 cycloalkyl, amino, amido, C1.6 alkylamino groups, C1.6 dialkylamino groups, C6-1 Q aryl, cyano, nitro; m is O, 1 , or 2; or R4 can be hydrogen or halogen; except 6-Quinolinepropanoic acid, 2-(2,6-dichlorophenyl)-α-[[3,4-dioxo-2-(propylamino)-1- cyclobuten-1 -yljamino].
2. A compound according to claim 1 , wherein the compound has formula Ia, and the configuration at the asymmetric carbon atom is in the "S" configuration
Figure imgf000041_0001
formula Ia.
3. A compound according to claim 1 or 2 wherein: X is CH or N; and W is CH or N; and R is chlorine or methoxy; and RI is chlorine or methoxy; and
R2 is carbonyl when R^ does not exist; or R2 and R3 can form together a ring or heterocycle attached to the cyclobutenone such as described in formula II; and Y is O or CH2; and n is 0, 1 , or 2; and
R4 is a group of formula III; or R4 can be hydrogen or halogen; and R7 is hydrogen; or R7 is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C-|_6 alkyl; or R7 is C-μβ alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-\.Q alkylamino groups, C-|.β dialkylamino groups, Cβ_io aryl, cyano, nitro; or R7 is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-1.5 alkyl, halogen, C^ .Q alkylamino, C-|_6 dialkylamino, C3.10 cycloalkyl; and
R8 is C3.10 cycloalkyl optionally substituted by groups selected from halogen, C-μ 5 alkyl; or R^ is C-] .5 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C<\ _Q alkylamino groups, C-|.β dialkylamino groups, Cβ-io ary'- cyano, nitro; or R^ is 3-10 ring member non-aromatic heterocycle optionally substituted by groups selected from C-) .5 alkyl, halogen, C^ .5 alkylamino, C-|.5 dialkylamino, C3.10 cycloalkyl; or R^ is CQ_I O aryl optionally substituted by groups selected from halogen, C-|. 5 alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino; or R^ is C5-10 heteroaryl optionally substituted by groups selected from halogen, C1.5 alkyl, cyano, carboxylic acid, hydroxyl, C3.10 non aromatic heterocyle, amino; except 6-Quinolinepropanoic acid, 2-(2,6-dichlorophenyl)-α-[[3,4-dioxo-2-(propylamino)-1- cyclobuten-1 -yl]amino.
4. A compound according to claim 1 or 2 having formula V, or a pharmaceutically acceptable salt thereof,
Figure imgf000042_0001
wherein:
Y is O or CH2; and
X is CH; and W is N; and
R is chlorine; and R1 is chlorine; and n is 1 ; and R4 is halogen.
5. A compound according to claim 1 or 2 having formula Vl, or a pharmaceutically acceptable salt thereof,
Figure imgf000043_0001
formula Vl wherein: X is CH; and W is N; and R is chlorine; and R1 is chlorine; and
R^ is C-j .6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C-μg alkylamino groups, C-|.β dialkylamino groups, Cβ.-ig ary'. cyano, nitro; and
R8 is C-|_6 alkyl optionally substituted by groups selected from halogen, C3.10 cycloalkyl, amino, amido, C^ _g alkylamino groups, C-μg dialkylamino groups, Cg-io ary'- cyano, nitro.
6. A compound according to claim 1 selected from the group consisting of
(2S)-2-[(2-bromo-3-oxo-7-oxaspiro[3.5]non-1-en-1-yl)amino]-3-[2-(2,6- dichlorophenyl)quinolin-6-yl]propanoic acid;
(2S)-3-[2-(2,6-dichlorophenyl)quinolin-6-yl]-2-{[2-(diethylamino)-3,4-dioxocyclobut-
1-en-1-yl]amino}propanoic acid; (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-[2-(3,5-dichloropyridin-4- yl)quinolin-6-yl]propanoic acid.
7. Synthesis intermediates selected from a group consisting of Methyl (2S)-3-[2-(2,6-dichlorophenyl)quinolin-6-yl]-2-[(3-oxo-7-oxaspiro[3.5]non-1-en-1- yl)amino]propanoate; Methyl (2S)-2-[(2-bromo-3-oxo-7-oxaspiro[3.5]non-1 -en-1 -yl)amino]-3-[2-(2,6- dichlorophenyl)quinolin-6-yl]propanoate;
Ethyl (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1 -en-1 -yl)amino]-3-[2-(3,5- dichloropyridin-4-yl)quinolin-6-yl]propanoate.
8. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 6 for use as a medicine.
10. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 6 in the manufacture of a medicament.
11. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of <x4 dependent inflammatory or medical conditions.
12. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament 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, α4-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.
13. Compound according to any one of claims 1 to 6 for use as a medicament.
14. Compound according to any one of claims 1 to 6 for curing 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, α4-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.
PCT/EP2008/002564 2007-04-12 2008-04-01 Quinoline and naphthalene derivatives, processes for their preparation and their use in treatment of inflammatory diseases Ceased WO2008125210A1 (en)

Applications Claiming Priority (4)

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GB0707060.0 2007-04-12
GB0707060A GB0707060D0 (en) 2007-04-12 2007-04-12 Bicyclic and heterobicyclic derivatives, processes for preparing them and their uses
EP07010007.8 2007-05-19
EP07010007 2007-05-19

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US12247071B2 (en) 2016-12-21 2025-03-11 Amgen Inc. Anti-TNF alpha antibody formulations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047867A1 (en) * 1999-12-23 2001-07-05 Celltech R & D Limited Squaric acid derivatives as integrin antagonists
WO2002010136A1 (en) * 2000-08-02 2002-02-07 Celltech R & D Limited 3-substituted isoquinolin-1-yl derivatives
WO2003093237A1 (en) * 2002-04-30 2003-11-13 Ucb, S.A. 2,6-quinolinyl and 2,6-naphthyl derivatives, processes for preparing them and their uses as vla-4 inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047867A1 (en) * 1999-12-23 2001-07-05 Celltech R & D Limited Squaric acid derivatives as integrin antagonists
WO2002010136A1 (en) * 2000-08-02 2002-02-07 Celltech R & D Limited 3-substituted isoquinolin-1-yl derivatives
WO2003093237A1 (en) * 2002-04-30 2003-11-13 Ucb, S.A. 2,6-quinolinyl and 2,6-naphthyl derivatives, processes for preparing them and their uses as vla-4 inhibitors

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12247071B2 (en) 2016-12-21 2025-03-11 Amgen Inc. Anti-TNF alpha antibody formulations
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
US12053462B2 (en) 2018-10-30 2024-08-06 Gilead Sciences, Inc. Quinoline derivatives
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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