WO2008125210A1 - Dérivés de quinoline et de naphtalène, procédés de préparation et utilisation de ceux-ci pour traiter des maladies inflammatoires - Google Patents

Dérivés de quinoline et de naphtalène, procédés de préparation et utilisation de ceux-ci pour traiter des maladies inflammatoires Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
aryl
heteroaryl
halogen
Prior art date
Application number
PCT/EP2008/002564
Other languages
English (en)
Inventor
Richard John Davenport
Andrew James Ratcliffe
David Jonathan Phillips
Original Assignee
Ucb Pharma, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0707060A external-priority patent/GB0707060D0/en
Application filed by Ucb Pharma, S.A. filed Critical Ucb Pharma, S.A.
Publication of WO2008125210A1 publication Critical patent/WO2008125210A1/fr

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de quinoline et de naphtalène de formule (I), des procédés de préparation de ceux-ci, des compositions pharmaceutiques contenant ces dérivés, ainsi que leur utilisation comme produits pharmaceutiques. R, R1, R2, R3, R4, X et W sont tels que définis dans la revendication 1.
PCT/EP2008/002564 2007-04-12 2008-04-01 Dérivés de quinoline et de naphtalène, procédés de préparation et utilisation de ceux-ci pour traiter des maladies inflammatoires WO2008125210A1 (fr)

Applications Claiming Priority (4)

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

Publications (1)

Publication Number Publication Date
WO2008125210A1 true WO2008125210A1 (fr) 2008-10-23

Family

ID=39522425

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/002564 WO2008125210A1 (fr) 2007-04-12 2008-04-01 Dérivés de quinoline et de naphtalène, procédés de préparation et utilisation de ceux-ci pour traiter des maladies inflammatoires

Country Status (1)

Country Link
WO (1) WO2008125210A1 (fr)

Cited By (5)

* 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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047867A1 (fr) * 1999-12-23 2001-07-05 Celltech R & D Limited Derives d'acide en tant qu'antagonistes d'integrine
WO2002010136A1 (fr) * 2000-08-02 2002-02-07 Celltech R & D Limited Derives d'isoquinoline-1-yl substitues en 3
WO2003093237A1 (fr) * 2002-04-30 2003-11-13 Ucb, S.A. Derives de 2,6-quinolinyle et de 2,6-naphtyle, leurs procedes de preparation et leur utilisation comme inhibiteurs de vla-4

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047867A1 (fr) * 1999-12-23 2001-07-05 Celltech R & D Limited Derives d'acide en tant qu'antagonistes d'integrine
WO2002010136A1 (fr) * 2000-08-02 2002-02-07 Celltech R & D Limited Derives d'isoquinoline-1-yl substitues en 3
WO2003093237A1 (fr) * 2002-04-30 2003-11-13 Ucb, S.A. Derives de 2,6-quinolinyle et de 2,6-naphtyle, leurs procedes de preparation et leur utilisation comme inhibiteurs de vla-4

Cited By (5)

* 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

Similar Documents

Publication Publication Date Title
US7732614B2 (en) 2,6-quinolinyl derivatives, processes for preparing them and their uses
US11603351B2 (en) Carboxamides as modulators of sodium channels
AU2019271928B2 (en) Prodrugs of pyridone amides useful as modulators of sodium channels
JP4107687B2 (ja) 置換ｎ―［（アミノイミノメチル又はアミノメチル）フェニル］プロピルアミド
EP0385237B1 (fr) Dérivés de 2-(1-pipérazinyl)-4-phénylcycloalkynopyridines, procédés de préparation et compositions pharmaceutiques les contenant
US6323227B1 (en) Substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides
EA007983B1 (ru) Индолизины в качестве ингибиторов киназных белков
BRPI0611250A2 (pt) composto, enanciÈmeros, diastereoisÈmeros do mesmo ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, e, uso de um composto
WO2008125210A1 (fr) Dérivés de quinoline et de naphtalène, procédés de préparation et utilisation de ceux-ci pour traiter des maladies inflammatoires
AU7365198A (en) Protease inhibitors
EA020010B1 (ru) БИЦИКЛИЧЕСКИЕ ТИАЗОЛЫ В КАЧЕСТВЕ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ mGluR5 РЕЦЕПТОРОВ
KR100538152B1 (ko) 디아민 유도체 및 이를 함유하는 의약
US5405848A (en) Substituted thiazolylaminotetrahydropyridopyrimidines derivatives useful as platelet aggregation inhibitors
WO2008064823A1 (fr) Dérivés bicycliques et hétérobicycliques, procédés de préparation de ceux-ci et leurs utilisations
WO2008138591A2 (fr) Dérivés bicycliques et hétérobicycliques, leurs méthodes de préparation et leurs utilisations
WO2008125215A1 (fr) Dérivés bicycliques et hétérobicycliques, procédés de préparation et utilisations de ceux-ci
JP2003508516A (ja) ビトロネクチン受容体アンタゴニスト
JP3786983B2 (ja) ピロリジノン誘導体
WO2008138592A1 (fr) Dérivés bicycliques et hétérobicycliques, leurs méthodes de préparation et leurs utilisations
WO2008138615A1 (fr) Dérivés bicycliques et hétérobicycliques, leurs méthodes de préparation et leurs utilisations
ES2359935T3 (es) Derivados de 2,6-quinolinilo, procedimientos para prepararlos y su uso como medicamento.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08734916

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08734916

Country of ref document: EP

Kind code of ref document: A1