WO2008064823A1 - Dérivés bicycliques et hétérobicycliques, procédés de préparation de ceux-ci et leurs utilisations - Google Patents

Dérivés bicycliques et hétérobicycliques, procédés de préparation de ceux-ci et leurs utilisations Download PDF

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Publication number
WO2008064823A1
WO2008064823A1 PCT/EP2007/010180 EP2007010180W WO2008064823A1 WO 2008064823 A1 WO2008064823 A1 WO 2008064823A1 EP 2007010180 W EP2007010180 W EP 2007010180W WO 2008064823 A1 WO2008064823 A1 WO 2008064823A1
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WIPO (PCT)
Prior art keywords
pyridin
imidazo
phenylalaninate
dichloroisonicotinoyl
ethyl
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PCT/EP2007/010180
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English (en)
Inventor
Richard John Davenport
Andrew James Ratcliffe
Benjamin Perry
David Jonathan Phillips
Mark William Jones
Thierry Demaude
Laurent Knerr
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Ucb Pharma, S.A.
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Priority claimed from GB0623599A external-priority patent/GB0623599D0/en
Application filed by Ucb Pharma, S.A. filed Critical Ucb Pharma, S.A.
Publication of WO2008064823A1 publication Critical patent/WO2008064823A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention concerns bicyclic and heterobicyclic derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
  • the integrin ⁇ 4 ⁇ 1 (also termed VLA-4 or Very Late Antigen-4 and designated CD49d/CD29) is predominantly expressed on eosinophils, lymphocytes, monocytes and basophils. It binds primarily to the vascular cell surface adhesion molecule VCAM-1 that is expressed on endothelium in response to inflammatory cytokines (TNF- ⁇ , IL-1 and selectively IL-4 and IL-13) and to the extracellular matrix protein fibronectin.
  • VCAM-1 vascular cell surface adhesion molecule
  • ⁇ 4 ⁇ 1 is not expressed on circulating neutrophils, which are the first defense against infection, it is a target for the pharmacological control of inflammatory diseases.
  • ⁇ 4 ⁇ 1 in cell adhesion mediated inflammatory pathologies and that blocking its function is beneficial.
  • Diseases include asthma, multiple sclerosis (MS), rheumatoid arthritis (RA) or inflammatory bowel diseases.
  • ⁇ 4 ⁇ 1 is also expressed on leukaemic 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 leukaemia.
  • ⁇ 4 ⁇ 1 and VCAM-1 have also been identified in smooth muscle cells from intimal atherosclerotic thickening of adult aorta. Blocking this interaction is beneficial in preventing smooth muscle differentiation and atherosclerosis.
  • the integrin ⁇ 4 ⁇ 7 (also termed LPAM-1 ) is expressed on certain sub-populations of T and B lymphocytes and on eosinophils. Like ⁇ 4 ⁇ 1 , ⁇ 4 ⁇ 7 binds VCAM-1 and fibronectin. In addition ⁇ 4 ⁇ 7 binds to a cell surface adhesion molecule MAdCAM-1 that is expressed preferentially in the gastrointestinal tract and which is believed to be involved in the homing of leukocytes to gastrointestinal mucosa. The interaction between ⁇ 4 ⁇ 7 and MAdCAM-1 may also be important sites of inflammation outside of mucosal tissue.
  • EP1323711 discloses novel phenylalanine derivatives of general structure, as shown below, having antagonistic effect on ⁇ 4 intergrins.
  • EP1454898 discloses novel phenylalanine derivatives of general structure, as shown below, having antagonistic activity to ⁇ 4 intergrins.
  • WO99/10312 discloses N-alkanoylphenylalanine derivatives of general structure, as shown below, which have activity asmitibitors of binding between VCAM-1 and cells expressing VLA-4.
  • EP1477482 discloses novel phenylalanine derivatives of general structure, as shown below, having antagonistic activity to ⁇ 4 intergrins and therapeutic agents for various diseases concerning ⁇ 4 intergrin.
  • EP1568697 discloses 1 ,3-benzothiazinone derivatives of general structure, as shown below, as therapeutic agents for cardiovascular diseases , bone or joint diseases, infectious diseases inflammatory diseases, kidney diseases, having excellent effects on death cell inhibition, MIF binding.
  • WO03089410 discloses phenylalanine derivatives of general structure, as shown below, as useful ⁇ 4 intergrin inhibitors.
  • WO2005077915 discloses novel compounds of general structure, as shown below, for the treatment of intergrin mediated disorders.
  • the invention therefore provides a compound having formula I, its enantiomers, diastereoisomers, stereoisomeric forms, geometrical isomers or pharmaceutically acceptable salts thereof
  • R a is hydrogen, halogen, 4 to 7 membered heterocycle or C ⁇ .3 alkyl
  • R ⁇ is hydrogen, 4 to 7 membered heterocycle or C- ⁇ 3 alkyl;
  • R1 is hydrogen, halogen or C-
  • R 2 is hydrogen or C- ⁇ alkylamino;
  • R 3 is hydrogen or is 4 to 7 membered heterocycle (aromatic or non-aromatic) optionally substituted by a group selected from C-
  • R 4 is hydrogen or C-
  • R a is hydrogen, halogen, 4 to 7 membered heterocycle or C ⁇
  • Rb is hydrogen, 4 to 7 membered heterocycle or C-1.3 alkyl;
  • R ⁇ is hydrogen, halogen or C-] .Q alkylamino;
  • R 2 is hydrogen or C- ⁇ alkylamino;
  • R 3 is hydrogen or is 4 to 7 membered heterocycle (aromatic or non-aromatic) optionally substituted by a group selected from C-
  • R 4 is hydrogen or
  • X 5 is CH or N; R5 is hydrogen or halogen; R6 is hydrogen or halogen.
  • the invention provides a compound having formula I b, its enantiomers, diastereoisomers, stereoisomeric forms, geometrical isomers or pharmaceutically acceptable salts thereof
  • R a is hydrogen, halogen, 4 to 7 membered heterocycle or C-1.3 alkyl
  • R ⁇ is hydrogen, 4 to 7 membered heterocycle or C-1.3 alkyl;
  • R1 is hydrogen, halogen or C-] _Q alkylamino;
  • R 2 is hydrogen or C-
  • R 3 is hydrogen or is 4 to 7 membered heterocycle (aromatic or non-aromatic) optionally substituted by a group selected from C- ⁇ alkyl, halogen, amino, C-
  • R 4 is hydrogen
  • 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 moieties can be optionally substituted by halogen, C ⁇ .Q cycloalkyl, nitrile, amino, C-
  • alkyl groups are methyl, methoxy, ethyl, cyclopropylmethyl, iso-butyl, methyl- dimethylamine, n-propyl, 2,2 dimethyl-propyl, n-butyl, n-pentyl, 1-methylsulfanylethyl.
  • Preferred alkyl groups are cyclopropylmethyl, methyl- dimethylamine, 2,2 dimethyl-propyl, methyl.
  • Most preferred alkyl group is cyclopropylmethyl.
  • cycloalkyl refers to a monovalent or divalent group of 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be optionally substituted by halogen or C ⁇ _Q alkyl groups as defined above. Usually cyclolakyl groups, in the present case are cyclopropyl and cyclohexyl. Preferred cycloalkyl group is cyclopropyl.
  • amino refers to a group of formula -NH2.
  • halogen refers to an atom of chlorine, bromine, fluorine, iodine. Usually halogen is chlorine or fluorine. Preferred halogen are chlorine and fluorine.
  • nitrile refers to a group of formula -CN.
  • aryl refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring or multiple rings, containing 6 to 10 carbon atoms by removal of one hydrogen atom, which can optionally be substituted by 1-3 halogens, or by 1-3 C- ⁇ g alkyl groups as defined above. Usually aryl groups are, in the present case, 3-methoxy phenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl.
  • alkylamino refers to a group of formula -NHR C , wherein R c is a C- ⁇ .Q alkyl group as defined above. Usually alkylamino group is methylamine.
  • dialkylamino refers to a group of formula -NR ⁇ R e , wherein R ⁇ is a C- ⁇ g alkyl group as defined above and R e is a C-] _ ⁇ alkyl group as defined above. Usually dialkylamino group is dimethylamine.
  • heterocycle refers to a 4 to 7 membered ring, which can be aromatic or non -aromatic, containing at least one heteroatom selected from O or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure.
  • the S heteroatom can be oxidized.
  • Heterocycles can be monocyclic or polycyclic. Heterocycles can optionally be substituted by 1 to 3 C-
  • heterocycle groups in the present case are, 4-chloro-3-pyridine, 4- methylamine-3-pyridine, 3-pyridine, 2-piperidine, 3-furan, 2-furan, 1 methyl-1 H imidazol, 2- thiophene, 4-chloro-1 methyl-1 H pyrazole.
  • Preferred heterocycle groups are 3-pyridine, 2- piperidine, 4-chloro-3-pyridine, 4-methylamine-3-pyridine.
  • Most preferred heterocycles are 3-pyridine, 2-piperidine.
  • X 1 is C or N.
  • Preferred X 1 is C.
  • X 2 is CH or N. Most preferred X 2 is N.
  • X 3 is C or N.
  • Preferred X 3 is N.
  • X 4 is C-R a , N- R b or N.
  • Preferred X 4 are C- R a , N.
  • Most preferred X 4 is N.
  • R a is hydrogen, halogen, 4 to 7 membered heterocycle or C1.3 alkyl.
  • Preferred R a is methyl
  • R b is hydrogen, 4 to 7 membered heterocycle or C-1.3 alkyl.
  • Preferred R b is hydrogen.
  • R ⁇ is hydrogen, halogen or C ⁇ .Q alkylamine.
  • Preferred R ⁇ is hydrogen.
  • R 2 is hydrogen or C- ⁇ ⁇ alkylamine.
  • Preferred R 2 is hydrogen.
  • R 3 is hydrogen or is 4 to 7 membered heterocycle (aromatic or non- aromatic) optionally substituted by a group selected from C1.5 alkyl, halogen, amino, C- j . ⁇ alkylamino, C- ⁇ dialkylamino; or is C-) .5 alkyl (linear or branched) optionally substituted by a group selected from halogen, C3.6 cycloalkyl, nitrile or C-
  • R 3 is hydrogen, 4-chloro-3-pyridine, 4-methylamine-3-pyridine, 3-pyridine, 2- piperidine, 3-furan, 2-furan, 1 methyl-I H imidazol, 2-thiophene, 4-chloro-1 methyl-1 H pyrazole, carbonyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, N-methyl-2- piperidine, methyl, ethyl, cyclopropylmethyl, iso-butyl, methyl- dimethylamine, n-propyl, 2,2 dimethyl-propyl, n-butyl, n-pentyl, 1-methylsulfanylethyl.
  • R 3 is N-methyl-2- piperidine, 4-chloro-3-pyridine, 4-methylamine-3-pyridine, 3-pyridine, 2-piperidine, carbonyl, methyl-dimethylamine, cyclopropylmethyl, hydrogen, iso-butyl. Most preferred R 3 is cyclopropylmethyl, 2-piperidine, 3-pyridine. Usually R 4 is hydrogen or C-] .2 alkyl. Preferred R 4 is hydrogen.
  • X 5 is CH or N.
  • R ⁇ is hydrogen or halogen.
  • Preferred R ⁇ is hydrogen, chlorine.
  • R ⁇ is hydrogen or halogen.
  • Preferred R ⁇ is hydrogen, fluoride.
  • X 1 is C;
  • X 2 is CH, N; and X 3 is C, N; and X 4 is C- R a , N, N- R b ; and R a is methyl; and R ⁇ is hydrogen; and
  • R ⁇ is hydrogen; and R 2 is hydrogen;
  • R 3 is 4-chloro-3-pyridine, 4-methylamine-3-pyridine, 3-pyridine, 2-piperidine, carbonyl, methyl-dimethylamine, cyclopropylmethyl, hydrogen, N-methyl-2-piperidine, iso-butyl; and R 4 is hydrogen; and
  • X 5 is CH, N; and R5 is hydrogen, chlorine; and R6 is hydrogen, fluorine.
  • Preferred compounds of the invention are: N-(3,5-dichloroisonicotinoyl)-4-(2-pyridin-3-yl-3H-imidazo[4,5-b]pyridin-3-yl)-L- phenylalanine;
  • Compounds of formula I and some of their intermediates have at least one stereogenic centre in their structure.
  • This stereogenic centre may be present in an R or an 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 & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta - Zurich, 2002, 329- 345).
  • the compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine salts, and salts with amino acids such as, for example, arginine, lysine and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta - Zurich, 2002, 329-345).
  • said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
  • solvates include for example hydrates, alcoholates and the like.
  • the invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).
  • prodrug includes compound forms, which are rapidly transformed in vivo to the parent compound according to the invention, for example, by hydrolysis in blood.
  • Prodrugs are compounds bearing groups that are removed by biotransformation prior to exhibiting their pharmacological action.
  • Prodrugs form a class of groups well known to practitioners of the art. In the present case they include, alkoxycarbonyl groups (such as methoxycarbonyl or ethoxycarbonyl). The compounds bearing this functional group are also used as synthetic intermediates.
  • Prodrug compounds have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption (T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery System", Vol. 14 of the A.C.S. Symposium Series; “Bioreversible Carriers in Drug Design”, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987).
  • Potential prodrugs of the invention are:
  • 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 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent inflammatory or medical conditions such as for example asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the compounds of the invention are useful for treating conditions mediated by adhesion mechanisms. These conditions include asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • Subjects in need of treatment for a ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent inflammatory or medical condition 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.
  • 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, syrup, a patch or suppositories.
  • the invention further concerns the use of the compounds of formula I for the manufacture of a medicament for therapeutic application.
  • the invention concerns the use of the compounds of formula I for the manufacture of a medicament useful for treating conditions in which there is likely to be a ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent component.
  • the invention concerns the use of the compound of formula I for the manufacture of a medicament useful for treating asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, cc4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the invention further concerns the compounds of formula I for use as medicaments.
  • the invention concerns the compounds of formula I for use as a medicament for treating asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders including dermatitis, psoriasis, urticaria, pruritus and eczema, rheumatoid arthritis, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, multiple sclerosis and other autoimmune disorders, acute myelogenous leukaemia, transplantation and atherosclerosis, transplant rejection, ⁇ 4-related cancers such as lung e.g.
  • non-small cell lung pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • the activity and properties of the active compounds, oral availability and stability in vitro or in vivo can vary significantly among the optical isomers of the disclosed compounds.
  • the active compound is administered in an enantiomerically enriched form, i.e., substantially in the form of one isomer.
  • the present invention also concerns a method for treating ⁇ 4 ⁇ 1 and/or ⁇ 4 ⁇ 7 dependent inflammatory or medical condition (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
  • a mammal preferably human
  • administration to a mammal preferably human
  • a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 0.01 to 2000 mg, preferably 0.05 to 500 mg of active ingredient per unit dosage form.
  • treatment includes curative treatment and prophylactic treatment.
  • substantially refers to a composition of equal or higher to 95% of the said isomer.
  • curative is meant efficacy in treating a current symptomatic episode of a disorder or condition.
  • prophylactic is meant prevention of the occurrence or recurrence of a disorder or condition.
  • the compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.
  • Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis, vasculitis or polydermatomyositis, multiple sclerosis, transplantation, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
  • inflammatory arthritis such as rheumatoid arthritis, vasculitis or polydermatomyositis, multiple sclerosis, transplantation, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
  • One aspect of the invention includes methods for treating ⁇ 4-related cancers (including cancers, whether solid or haematopoietic).
  • ⁇ 4-related cancers including cancers, whether solid or haematopoietic.
  • cancers include, but are not limited to, lung e.g. non-small cell lung, pancreatic, prostate, renal, cervical, ovarian, colorectal, mammary carcinoma, endometrial, bladder, malignant melanoma, seminomas, thyroid, acute myelogenous leukaemia and gastric cancer.
  • results obtained with compounds of formula I are indicative of a strong pharmacological effect.
  • 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 intrathecal Iy.
  • 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, suppositories 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 cetihzine, histamine H2 antagonists, histamine H3 antagonists, leukotriene antagonists, PDE4 inhibitors such as 3-cyclo- propylmethoxy-4-difluoromethoxy- ⁇ /-[3,5-di-chloropyrid-4-yl]-benzamide, muscarinic M3 antagonists, ⁇ 2 agonists, theophylline, sodium cromoglycate, anti-TNF antibodies such as certolizumab pegol or adalimumab, anti-IL6 antibodies, anti-IL17 antibodies, adhesion molecule inhibitors , inhibitors of cytokine synthesis such as P38 MAP kinase inhibitors and inhibitors of PI3 kinase, methotrexate.
  • the present invention concerns also processes for preparing the compounds of formula I.
  • Ring closure to afford the imidazole ring is performed using acetic acid, with heating in a microwave reactor.
  • the t-butyl protecting group is removed using trifluoracetic acid in dicloromethane, followed by amide coupling with the free amine and a suitable aryl acid chloride.
  • the ester is then saponified to the acid using 2N NaOH.
  • N- ⁇ .S-DichloroisonicotinoyO- ⁇ S-methyl-I H-pyrrolo ⁇ .S-bjpyridin-i- yl)phenylalanine is synthesized from 4-iodobenzyloxybenzene (CAS No. 19578-68-8), 7- azaindole (CAS No. 271-63-6), copper (I) iodide frans-1 ,2-diaminocyclohexane through several chemical transformations.
  • N-(3,5-Dichloroisonicotinoyl)-4-(1 H-indol-3-yl)-L-phenylalanine is synthesized from 4-Bromo-N-[(1 ,1 -dimethylethoxy)carbonyl]-ethylester-L-phenylalanine (RN-591249-54-6), 2,6-dichloroisonicotinoyl chloride and 1-(phenylsulfonyl)-3-indoleboronic acid through several chemical transformations.
  • the present invention also relates to synthetic intermediates geometrical isomers, enantiomers, diastereoisomers, pharmaceutically acceptable salts and all possible mixtures thereof.
  • characterization of the compounds is performed according to (LCMS) liquid chromatography mass spectra, preparative liquid chromatography LC, NMR, and silica gel chromatography methods. NMR spectra are recorded on Bruker AV300 and DRX 400 spectrometers at 300 and 400 MHz respectively.
  • Chromatographic separations are performed on Davis 5 ⁇ M silica gel.
  • the Waters mass spectrometers used are of model ZMD or ZQ both Waters.
  • CDCI 3 Chloroform-d; DCE - Dichloroethane; DCM - Dichloromethane; DIBAL-H-Diisobutylaluminium hydride;
  • DIPEA - ⁇ /, ⁇ /-Diisopropylethylamine
  • DME ethyleneglycol dimethylether
  • DMF - ⁇ /, ⁇ /-Dimethylformamide
  • EtOAc Ethyl acetate
  • Et 3 SiH Triethylsilane
  • FCS Foetal Calf Serum
  • HBTU 2-[7H-Benzotriazole-1-yl]-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate
  • HCI hydrochloric acid
  • HOBT 1-Hydroxybenzotriazole hydrate
  • LHMDS Lithium bis(trimethylsilyl)amide
  • MeCN Acetonitrile
  • d 4 -MeOH Methanol-d 4 ;
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • TBS Tris buffered saline
  • the crude material is dissolved in DMF (7ml), ⁇ /s-triphenylphosphine palladium dichloride (46mg), methylacetamidoacrylate (300mg) (CAS No. 35356-70-8), TEA (0.29ml), lithium iodide (173mg) and tributylammonium chloride (390mg) are added, and the solution heated to 9O 0 C for 6 hours.
  • reaction mixture is cooled to room temperature, concentrated in vacuo partitioned between DCM (100ml) and NaHCO 3 solution (100ml), the layers separated, the aqueous layer extracted with DCM (100ml), the organic layers combined, dried over MgSO 4 , filtered, concentrated in vacuo and purified using flash chromatography (eluent EtOAc / heptane) to afford the title compound as a pale yellow solid, (6.19g, 50%) LCMS (Method A) 628.2 [M+H] ⁇ RT 4.42 mins.
  • Compound 5 is prepared in a similar manner to the method as described in Example 16. The reagents used and the results obtained are tabulated below.
  • Example 26 N- ⁇ S-DichloroisonicotinoylM- ⁇ -oxo-i ⁇ -dihydro-SH-imidazo ⁇ .S-blpyridin-S-ylJ-L- phenylalanine (Compound 10) To Intermediate 5 (750mg) in DCM (5ml) is added DIPEA (0.6ml) followed by dimethylcarbamyl chloride (204mg) at room temperature. The reaction is stirred for 24 hours. The solvent is removed in vacuo and the residue is dissolved in AcOH (1 ml) and heated in a microwave at 125 0 C for 10 minutes.
  • the reaction is evaporated to dryness in vacuo and the residue dissolved in DCM then washed with saturated NaHCO 3 solution. The organic layer is washed with brine, dried over MgSO 4 and evaporated to dryness in vacuo.
  • the crude material is dissolved in DCM (40ml) and treated with TFA (855 ⁇ l) at room temperature. The reaction is stirred at room temperature for 20 hours. The reaction is diluted with DCM (110ml) and washed with saturated NaHCO 3 solution. The organic layer is dried over MgSO 4 and evaporated to dryness in vacuo. The residue (100mg) is taken up in Dioxane (4ml).
  • APCI spectra are performed using a FINNIGAN (San Jose, CA, USA) LCQ ion trap mass spectrometer.
  • the APCI source is operated at 450 0 C and the capillary heater at 160 °C.
  • a WATERS Prep 4000 HPLC system is connected to a Waters 996 PDA, and the chromatography is carried out at room temperature with a flow of 35 ml/min.
  • ⁇ 4 ⁇ 1 Integrin-dependent Jurkat cell adhesion to VCAM-Ig 96 well NUNC plates are coated with F(ab)2 fragment goat anti-human IgG Fcy- specific antibody [Jackson lmmuno Research 109-006-098: 100 ⁇ l at 2 ⁇ g/ml in 0.1 M NaHCO3, pH 8.4], overnight at 4°C.
  • the plates are washed (3x) in PBS and then blocked for 1 h in PBS/1% BSA at RT on a rocking platform. After washing (3x in PBS) 9 ng/ml of purified 2d VCAM-Ig diluted in PBS/1% BSA is added and the plates left for 60 minutes at RT on a rocking platform. The plates are washed (3x in PBS) and the assay then performed at 37 0 C for 30 min in a total volume of 200 ⁇ l containing 2.5 x 105 Jurkat cells in the presence or absence of titrated test compounds.
  • Compound 1 4-[2-(6-Chloropyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-N-(3,5- dichloroisonicotinoyl)-L-phenylalanine shows a IC50 value of ⁇ 200nM.
  • ⁇ 4 ⁇ 7 Integrin-dependent JY cell adhesion to MAdCAM-Ig This assay is performed in the same manner as the ⁇ 4 ⁇ 1 assay except that MAdCAM-Ig (150ng/ml) is used in place of 2d VCAM-Ig and a sub-line of the ⁇ - lymphoblastoid cell-line JY is used in place of Jurkat cells.
  • the IC50 value for each test compound is determined as described in the ⁇ 4 ⁇ 1 integrin assay.
  • the compounds of the invention are tested in this assay (a and b and c ) and show IC50 values of 1 ⁇ M and below.
  • the following reagents are added to FACS tubes: 3 ⁇ l 10OmM MnCl2 (100X required cone), 1 ⁇ l 1 mg/ml streptavidin-FITC (supplier Pierce 100X required cone), 2 ⁇ l 500 ⁇ g/ml biotinylated hVCAM-1-mFc (5OX required cone), and 2 ⁇ l serially-diluted test compound at 5OX desired final concentrations.
  • 100 ⁇ l heparinised blood from healthy human donors is then added to each FACS tube which are then sealed and rocked for 30 minutes at RT.
  • FACS Lysing Solution 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 100 ⁇ l 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 ⁇ M and below.
  • Compound 1 4-[2-(6-Chloropyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]-N-(3,5- dichloroisonicotinoyl)-L-phenylalanine shows a IC50 value of ⁇ 200 nM. d).
  • ⁇ 5 ⁇ 1 Integrin-dependent K562 cell adhesion to fibronectin 96 well tissue culture plates are coated with human plasma fibronectin (Sigma F0895) at 5 ⁇ g/ml in PBS for 2 hr at 37oC. The plates are washed (3x in PBS) and then blocked for 1 h in 100 ⁇ l PBS/1% BSA at RT on a rocking platform.
  • the blocked plates are washed (3x in PBS) and the assay then performed at 37 0 C in a total volume of 200 ⁇ l containing 2.5x 105 K562 cells, phorbol-12-myristate-13-acetate at 10ng/ml, and in the presence or absence of titrated test compounds. Incubation time is 30 minutes. Each plate is fixed and stained as described in the ⁇ 4 ⁇ 1 assay above. e). ⁇ m ⁇ 2-dependent human polymorphonuclear neutrophils adhesion to plastic: 96 well tissue culture plates are coated with RPMI 1640/10% FCS for 2h at 37oC.
  • Human platelet aggregation is assessed using impedance aggregation on the Chronolog Whole Blood Lumiaggregometer.
  • Human platelet-rich plasma (PRP) is obtained by spinning fresh human venous blood anticoagulated with 0.38% (v/v) tri-sodium citrate at
  • Cuvettes contained equal volumes of PRP and filtered Tyrode's buffer (g/liter: NaCI 8.0; MgCl2-H2 ⁇
  • the compounds of the invention have IC50 values of > 50 ⁇ M and above thus demonstrating the potency and selectivity of their action against ⁇ 4 integrins.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des dérivés bicycliques et hétérobicycliques, des procédés de préparation de ceux-ci, des compositions pharmaceutiques les contenant ainsi que leur utilisation comme médicaments.
PCT/EP2007/010180 2006-11-27 2007-11-23 Dérivés bicycliques et hétérobicycliques, procédés de préparation de ceux-ci et leurs utilisations WO2008064823A1 (fr)

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GB0623599A GB0623599D0 (en) 2006-11-27 2006-11-27 Bicyclic and heterobicyclic derivatives,processes for preparing them and their uses
GB0623599.8 2006-11-27
EP07002036.7 2007-01-31
EP07002036 2007-01-31

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
EP2842945A4 (fr) * 2012-04-24 2015-09-16 Ajinomoto Kk Dérivé de sulfonamide et utilisation médicale associée
JP2016528180A (ja) * 2013-06-11 2016-09-15 レセプトス， インコーポレイテッド 新規なｇｌｐ−１レセプターモジュレーター
WO2022156351A1 (fr) * 2021-01-20 2022-07-28 杭州普洛药物研究院有限公司 Composé de n-(benzoyl)-phénylalanine, composition pharmaceutique le contenant et utilisation associée
WO2023236199A1 (fr) * 2022-06-10 2023-12-14 杭州普洛药物研究院有限公司 Cristal de composé de n-(benzoyl)-phénylalanine, composition pharmaceutique de celui-ci, procédé de préparation correspondant et utilisation associée

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2842945A4 (fr) * 2012-04-24 2015-09-16 Ajinomoto Kk Dérivé de sulfonamide et utilisation médicale associée
US9533985B2 (en) 2012-04-24 2017-01-03 Ea Pharma Co., Ltd. Sulfonamide derivative and medicinal use thereof
JP2016528180A (ja) * 2013-06-11 2016-09-15 レセプトス， インコーポレイテッド 新規なｇｌｐ−１レセプターモジュレーター
WO2022156351A1 (fr) * 2021-01-20 2022-07-28 杭州普洛药物研究院有限公司 Composé de n-(benzoyl)-phénylalanine, composition pharmaceutique le contenant et utilisation associée
AU2021422269B2 (en) * 2021-01-20 2024-02-08 Apeloa Pharmaceutical Co., Ltd. N-(benzoyl)-phenylalanine compound, pharmaceutical composition containing same, and use thereof
WO2023236199A1 (fr) * 2022-06-10 2023-12-14 杭州普洛药物研究院有限公司 Cristal de composé de n-(benzoyl)-phénylalanine, composition pharmaceutique de celui-ci, procédé de préparation correspondant et utilisation associée

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