WO2007034282A2 - Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a - Google Patents

Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a Download PDF

Info

Publication number
WO2007034282A2
WO2007034282A2 PCT/IB2006/002568 IB2006002568W WO2007034282A2 WO 2007034282 A2 WO2007034282 A2 WO 2007034282A2 IB 2006002568 W IB2006002568 W IB 2006002568W WO 2007034282 A2 WO2007034282 A2 WO 2007034282A2
Authority
WO
WIPO (PCT)
Prior art keywords
biphenyl
imidazo
dimethyl
tetrahydro
pyridin
Prior art date
Application number
PCT/IB2006/002568
Other languages
English (en)
Other versions
WO2007034282A3 (fr
Inventor
Michelle Marie Claffey
Steven Wayne Goldstein
Stanley Jung
Arthur Nagel
Volker Shulze
Original Assignee
Pfizer Products Inc.
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
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2007034282A2 publication Critical patent/WO2007034282A2/fr
Publication of WO2007034282A3 publication Critical patent/WO2007034282A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention provides novel pharmaceutically active compounds that act as antagonists of the mammalian C3a receptor, and methods of using these compounds to treat chronic inflammatory diseases, including, but not limited to inflammations in the central nervous system, peripheral nervous system, lungs, and bone joints.
  • disease states not classically, categorized as inflammatory diseases, but which in fact have inflammatory components, can also be effectively treated according to the practice of the invention.
  • Alzheimer's 'disease represents a particularly important example of this latter type of disease state, and its discussion usefully demonstrates that disease states not classically categorized as inflammatory share mechanistic linkages with disease states classically characterized as inflammations.
  • the present invention relates to treatment of both such types of disease states via inhibition of binding of the C3a protein to its cellular receptors.
  • AD Alzheimer's disease
  • A-beta protein amyloidogenic peptide termed A-beta protein
  • senile plaques are the focus of a robust and chronic inflammatory response mounted by microglia, the brain's endogenous macrophage cells.
  • Macrophage cells are phagocytic immune system cells of monocytic origin that circulate in the tissues and participate both in first-line initial immunosurveillance , and acquired immunity processes.
  • Complement a phylogenetically old system of enzymes and other proteins that most likely evolved to protect organisms against microbial assault.
  • Complement activation is a prominent feature of the inflammatory response in Alzheimer's disease, and is apparently triggered by the presence of senile plaques.
  • the triggering of the Complement system involves the sequential activation of numerous proteins by a cascade effect.
  • the Complement cascade is best defined as a series of binding and cleavage events wherein active forms of Complement proteins are produced, which in turn act upon each other, often by proteolysis, to produce further active proteins and protein fragments, and complexes thereof, which then 1 interact with immune system components, or with cellular debris, endogenous or foreign macromolecules, or invading cells which are then targeted for destruction.
  • Complement protein C3 is proteolytically cleaved, resulting in a large fragment (C3b) and the smaller 77 residue peptide, C3a.
  • C3b the smaller 77 residue peptide
  • -C3a is known to regulate vasodilation increasing the permeability of small blood vessels, induce contraction of smooth muscles, induce oxidative burst, regulate cytokine release, and stimulate chemotaxis, depending on the involved cells, all inflammation related events.
  • Target cells include macrophages, neutrophils, eosiniphils, basophils, T-lyphocytes and mast cells, all having important immune and inflammation related functions.
  • Receptors for C3a are expressed on a variety of macrophages and macrophage cell lines. Functionally, C3a binding to C3a receptors in macrphages causes a mobilization of intracellular calcium ions, and leads to both chemotaxis and respiratory burst, which are both host defense mechanism that generate high levels of cytotoxic superoxide. , Again, although such mechanisms are useful in protecting against invading bacterial cells, for example, the triggering of such defense mechanism against normal cells (such as brain neurons that happen to be proximal to the site of plaque formation) is devastating to normal brain function. Similar disadvantageous results operate in regard of other inflammatory conditions.
  • the C3a receptor belongs to the rhodopsin family of G protein-coupled receptors (see Embler et al. in The Human Complement System in Health and Disease, Marcel Dekker, New York, pp. 241-284, 1998).
  • C3aR was thought to be present only on myeloid cells, such as macrophages, eosiniphils and mast cells.
  • the demonstration that C3aR receptor messenger RNA is expressed throughout the body (and in particular in the adrenal gland, pituitary.gland, and the central nervous system) is consistent with participation of C3a in a wide variety of cellular process and mediate numerous disease / states.
  • C3a receptor-immunoreactivity has been detected in areas of inflammation in multiple sclerosis and bacterial meningitis patients. In the latter disorder, abundant C3a receptor expression on activated microglia and reactive astrocytes was noted.
  • Complement activation has been implicated in the pathogenesis of neurodegenerative disorders in both the central nervous system and the peripheral nervous system such, as Huntington's disease, Pick's disease, and Gullian Barre syndrome.
  • Huntington's disease Pick's disease
  • Gullian Barre syndrome See Campos-Torres et a
  • Complement activation plays a significant role in allergic lung damage caused by repeated inhalation of antigen, which is consistent with the etiology of asthma.
  • controlling the Complement system can impact the treatment or prevention of disease states such as sepsis, adult respiratory distress syndrome, nephrites, graft rejection, myocardial ischemia/reperfusion injury, and intestinal ischemia/reperfusion injury.
  • disease states such as sepsis, adult respiratory distress syndrome, nephrites, graft rejection, myocardial ischemia/reperfusion injury, and intestinal ischemia/reperfusion injury.
  • Such disease states include, but are not limited to: neurological diseases such as Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke; and hemorrhagic stroke; cancer generally and leukemia particularly; allergic and respiratory diseases including allergic dermatitis, anaphylaxis, asthma, eczema, rhinitis, and respiratory distress; cardiovascular or metabolic disease states including shock and hypertension, hyperlipidemia, hypercholesterolemia, edema, and obesity; and inflammatory conditions generally including without limitation, osteoarthritis, ischemia, lung inflammation and rheumatoid arthritis.
  • neurological diseases such as Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke; and hemorrhagic stroke
  • cancer generally and leukemia particularly
  • allergic and respiratory diseases including allergic dermatitis, anaphylaxis, asthma,
  • n is between 3 and 5;
  • the ring containing Z is a 5, 6, or 7-membered heterocyclic or heteroaryl ring containing 1-3 three heteroatoms independently selected from the group consisting of O, N and S;
  • R 1 at each occurrence is independently selected from H, optionally substituted C 1 -Ce alkyl, optionally substituted C 1 -C 6 alkoxy, halo, SQ 2 N(Re) 2 , N(R 6 )SO 2 N(Re) 2 , SO 2 R 6 , CONHSO 2 R 6 , CONHSO 2 (NRe) 2 , optionally substituted 3-10-membered heterocycloalkyl, optionally substituted C 3 -C 10 cycloalkyl, cyano, optionally substituted 5- 10-membered heteroaryl, optionally substituted C 6 -C 10 aryl, COR 6 , CO 2 R 6 , N(R 6 J 2 , NR 6 COR 6 , CON(R 6 ) 2 , and CONCO(R 6 ) 2 ;
  • R 6 at each occurrence is independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 6 -C 10 aryl; optionally substituted C 3 -C 10 cycloalkyl, and optionally substituted 3-10 membered heterocycloalkyl;
  • R 2 , R 3 and R 4 are selected independently from H, optionally substituted C r C 6 alkyl, halo, optionally substituted CrC ⁇ alkenyl, optionally substituted C 3 -C 10 cycloalkyl, trifluoromethyl, CO- optionally substituted C 1 -C 6 alkyl, CO 2- optionally substituted C 1 -C 6 alkyl, optionally substituted and optionally substituted CrCealkylthio, with the proviso that if
  • A, CH IfA 2 -N then at least one of R 2 , R 3 , R 4 and R 5 is not hydrogen; and with the proviso that if
  • R 2 , R 3 , R 4 and R 5 are not hydrogen, wherein if only two of R 2 , R 3 , R 4 and R 5 are not hydrogen, then the two of R 2 , R 3 , R 4 and R 5 that are not hydrogen are not both CF 3 ; and with the proviso that if the compound of formula I is
  • R 1 may not be H, Me, Cl 1 C 1 -C 12 alkenyl, or CONHR or when IS
  • R 3 and R 2 together with the phenyl carbon atoms they are attached to, or R 3 and R 4 together with the phenyl carbon atoms they are attached to, may form a 5, 6, or 7-membered carbocylic, heterocyclic, aromatic or heteroaromatic ring containing 0, d , or 2 heteroatoms selected from the group consisting of O, N, and S; i
  • R 5 is selected from H or F
  • Y 1 , Y 2 , Y 3 , Y 4 are independently selected from CH, CF, or N where no more than two of Y 1 , Y 2 , Y 3 , and Y 4 are N;
  • Y 5 is selected from CH, or N; or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula (I).
  • Exemplary acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,
  • the present invention also relates to the pharmaceutically acceptable base addition salts of compounds of the formula (I).
  • the bases which are used to prepare the pharmaceutically acceptable base addition salts of the aforementioned base compounds of this invention are those which form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H 1 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon 14, i.e., 14 C 1 isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life.or reduced dosage requirements and, hence, may be preferred in some circumstances
  • lsotopically labelled compounds of Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a no ⁇ -isotopically labelled reagent.
  • the present invention provides for the treatment of a medical condition selected from the group consisting of Alzheimer's disease, multiple sclerosis, Huntington's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke; and hemorrhagic stroke; cancer generally and leukemia particularly; allergic and respiratory diseases including allergic dermatitis, anaphylaxis, asthma, eczema, rhinitis, and adult respiratory distress syndrome; cardiovascular or metabolic disease states including ischemia and reperfusion injury, shock and hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity; nephritis, graft rejection, and inflammatory conditions generally including without limitation, osteoarthritis, ischemia, lung inflammation and rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • Exemplary conditions that may be treated by the compound of the invention are Alzheimer's disease, multiple sclerosis, Huntington's chorea
  • Another aspect of the present invention is a method for preventing excessive Complement activation in a patient comprising administering to said patient, a therapeutically effective amount of a compound(s) of the present invention.
  • Another aspect of the present invention is a method for treating or preventing Complement-mediated tissue damage in a patient comprising administering to said patient, a therapeutically effective amount of a compound(s) of the present invention.
  • Another aspect of the present invention is a method for treating diseases characterized by chronic Complement activation comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • Another aspect of the present invention is a method for antagonizing the C3a receptor in a patient by administering an effective amount of a compound(s) of the present invention.
  • an “effective amount” or “therapeutically effective amount” of a subject compound, with respect to the subject method of treatment refers to an amount of the therapeutic in a preparation which, when applied as part of a desired dosage regimen provides a benefit according to clinically acceptable standards for the treatment or prophylaxis of a particular disorder.
  • a "patient” or “subject” to be treated by the subject method can mean either a human or non-human subject.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
  • alkenyl and alkynyl define hydrocarbon radicals having straight, branched or cyclic moities wherein at least one double bond, or at least one triple bond, respectively, is present.
  • alkyl, alkenyl or alkynyl group is present within another group, such as alkoxy or alkylamine.
  • alkoxy as used herein, includes O-alkyl groups wherein “alkyl” is as defined above.
  • halo as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
  • the C 6 -C 10 aromatic hydrocarbon, or the C 6- C 30 aromatic hydrocarbon may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2.
  • Representative aromatic hydrocarbon compounds are benzene and naphthalene.
  • An aryl group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2.
  • Representative aryl groups are phenyl and naphthyl.
  • arylene group as used herein, unless otherwise indicated, includes an organic diradical derived from a monocyclic or bicylic (C 6- C 10 ) aromatic hydrocarbon compound by removal of two hydrogen radicals from two ring carbons of the aryl compound.
  • An arylene group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 arid 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis.
  • Representative aryl groups are phenyl and naphthyl.
  • a heteroaryl group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis.
  • heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1 ,2,4-triazinyl, 1,2,3-triazinyl, 1 ,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7- dihydro-5H-[1]pyrindin
  • a cycloalkyl group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, ahd perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopr ⁇ penyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,3- cyclobutadienyl, 1 ,3-cyclopentadienyl, 1,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 1 ,3- cycloheptadienyl, 1 ,4-cycloheptadienyl, 1 ,3,5-cycloheptatrienyl, bicyclo[3.2.1]octane, bicyclo [2.2.1] heptane, and the norborn-2-ene unsaturated form thereof.
  • cycloalkyl also includes cycloalkenyl groups having one or two double
  • a heterocycloalkyl group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferably the number of substituents is between 0 and 3, more preferably between 0 and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis.
  • heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1 ,3-oxazolidin-3-yl, isothiazolidinyl, 1 ,3-thiazolidin-3-yl, 1 ,2-pyrazolidin-2-yl, 1 ,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1 ,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydr
  • alkyl In connection with the terms “alkyl”, “aryl”, “heteroaryl”, “cycloalkyl” and “heterocycloalkyl”, as herein defined, the term “optionally substituted” means that at least one chemically and pharmaceutically acceptable functional group may be bonded thereto.
  • Such a functional group is selected from the group consisting of hydroxy, halo, amino, trifluoromethyl, carboxy, (C r C 6 )alkoxy-, (C 1 -C 6 JaCyIoXy-, (C r C 6 )alkylamino-, ((CrCeJalkyOaamino-, ⁇ C r C 6 )acylamino-, cyano, nitro, (CrCeJalkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyl-, cyano(C r C 6 )alkyl-, trifluoromethyKC-i-CeJalkyl-, nitro(C 1 -C 6 )alkyl-, (C 1 -C 3 )alkyl(monofluoroalkylene)(C 1 -C 3 )alkyl-, (C 1 -C 3 )alkyl(
  • Y 5 is CH. In another embodiment of the invention, Y 5 is N.
  • Y 1 , Y 2 , Y 3 , Y 4 are independently selected from CH, and CF. In another embodiment of the invention, one of Y 1 , Y 2 , Y 3 , and Y 4 is CF and the remaining three of Y 1 , Y 2 , Y 3 , and Y 4 are each CH.
  • one R 1 is a C 3 -Ci 0 heterocycloalkyl, which is preferably selected from the group consisting of morpholinyl and aziridinyl.
  • one R 1 is a 5- to 9-membered heteroaryl, which is preferably selected from the group consisting of oxadiazolyl and tetrazolyl.
  • R 1 at each occurrence is independently, selected from H, optionally substituted C 1 -C 8 alkyl, optionally substituted C r C 6 alkoxy, halo, SO 2 NH 2 , SO 2 NHC 1 -C 6 alkyl, SO 2 N(C 1 -C 6 alkyl) 2 , CONHSO 2 C 1 -C 6 aikyl, CONHSO 2 NH 2 , CONHSO 2 NHC 1 -C 6 alkyl, CONHSO 2 N(C 1 -C 6 alkyl) 2 , cyano, substituted 5- 10-membered heteroaryl, CONH 2 , R 6 NHCO, COR 6 , CO 2 R 6 , N(R 6 ) 2> NHCOR 6 , NR 6 COR 6 , CON(R 6 ) 2 , and CONCO(R 6 J 2 .
  • at least one R 1 is not H.
  • no more than two of R 2 , R 3 , R 4 and R 5 are H.
  • Y 6 is CO, N, NR 1 , CHR 1 or CR 1 ; Y 7 and Y 8 are each independently N, NR 1 , CHR 1 or CR 1 ; and Y 9 is CR 1 , CHR 1 , or (CHR 1 J 2 ; and • (B)
  • Y 10 and Y 11 are each independently CR 1 , CHR 1 , N or NR 1 ; and Y 12 is N, NR 1 , S or O.
  • the dotted bonds indicate that the bond between Y 6 and Y 7, Y 7 and Y 8 , and Y 8 and Y 9 , respectively, may be independently single or double.
  • the dotted bonds indicate that the bond between Y 10 and Y 11 , and Y 11 and Y 12 , respectively, may be independently single or double.
  • the choice of groups Y 6 , Y 7, Y 81 Y 9 , Y 10 Y 11 and Y 12 , and whether the bonds between Y 6 and Y 7 , Y 7 and Y 8, Y 8 and Y 9 , Y 10 and Y 11, and Y 11 and Y 12 are independently single bonds or double bonds may be determined in accordance with the valence, independently, of each of the groups Y 6 , Y 7 , Y 8 , Yg, Yio Yn and Y 12 .
  • Y 6 is a divalent group such as CHR 1
  • the bond to Y 7 is a single bond
  • it is a trivalent group such CR 1 the bond to Y 7 is a double bond.
  • At least one of Y 7 and Y 8 of group ⁇ A) is CH.
  • group (A) is
  • Exemplary compounds according to the invention include
  • Furan-2-carboxylic acid [2-(3',4'-dimethyl-biphenyl-4-yl)-5,6,7,8-tetrahydro- imidazo[1 ,2-a]pyridin-6-ylmethyl]-amide; N-[2-(3',4 I -Dimethyl-biphenyl-4-yl)-5 > 6,7,8-tetrahydro-imidazo[1 I 2-a]pyridin-6- ylmethylj-nicotinamide;
  • Cyclopropanecarboxylic acid [2-(3',4'-dimethyl-biphe ⁇ yl-4-yl)-5,6,7;8-tetrahydro- imidazoti ,2-a]pyridin-6-ylmethyl]-amide; N-[2-(3',4 I -Dimethyl-biphenyl-4-yl)-5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyridin-6- ylmethyl]-6-methyl-nicoti ⁇ amide; .
  • the compounds of the invention and some of the intermediates in the present invention may contain one or more asymmetric carbons.
  • Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art- known procedures.
  • diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods.
  • Enantiomers ⁇ an be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.
  • Pure stereochemically isomeric forms of the compounds of the invention may also be obtained from the pure stereochemical forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
  • the pure and mixed stereochemically isomeric forms of the compounds of the invention are intended to be embraced within the scope of the present invention.
  • the compounds of the invention may operate by more than one mechanism of action, including those unrelated to the Complement cascade, and the utility of the present compounds in the practice of the invention, including for use in treating other disease states not mentioned herein, is not limited by any particular theory of operation or mechanism of action as described herein, or by those theories or mechanisms generally recognized by those skilled in the art.
  • One aspect of the present invention is a method of synthesizing the C3a antagonists described herein.
  • the following reaction schemes are intended to illustrate the preparation of the antagonists of the present invention. It will be appreciated that certain groups represented by letters ("R" groups and the like) in the reaction scheme do not always correspond with similarly defined component groups of the Formula (I) compounds themselves, since certain functionalities of the reactants can be modified when the resulting products are formed.
  • a compound of general formula I can be prepared by the reaction of a compound of general formula A1 with a compound of general formula B1 in the presence or absence of a base such as NaHCO 3 , K 2 CO 3 , tBuOK, NaOH, and Cs 2 CO 3 in solvents such DMF, dioxane, and C1-C6 alkyl alcohols, or mixtures thereof, at temperatures ranging from ambient to the boiling point of said mixtures.
  • a base such as NaHCO 3 , K 2 CO 3 , tBuOK, NaOH, and Cs 2 CO 3
  • solvents such DMF, dioxane, and C1-C6 alkyl alcohols, or mixtures thereof.
  • an additional cyclization step may be necessary to close the . imidazole ring.
  • initial coupling may be performed using conditions exemplified above followed by filtration to isolate a salt intermediate that may be cyclized in acids such as polyphosphoric acid, concentrated HCI, concentrated HBr, or 0.1 M perchloric acid at temperatures ranging from ambient to the boiling point of said mixtures to provide compounds of general formula I.
  • acids such as polyphosphoric acid, concentrated HCI, concentrated HBr, or 0.1 M perchloric acid at temperatures ranging from ambient to the boiling point of said mixtures to provide compounds of general formula I.
  • Scheme 2 Another method of preparation for compounds of general formula I is shown in Scheme 2.
  • Compounds of general formula I may be prepared from compounds of general formula C1 and compounds of general formula D1 in the presence of a catalyst such as dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium and a base such as Na 2 CO 3 in solvents such as toluene, C 1 -C 6 alkyl alcohols, H 2 O, or mixtures thereof, at temperatures ranging from ambient to the boiling point of said mixtures.
  • a compound of general formula C1 may be prepared by coupling and cyclization of an alpha-haloketone with a 2- aminoheterocycle such as 2-aminopyridine using conditions exemplified in Scheme 1.
  • the phenylboronic acids and esters of general formula D1 are commercially available or may be readily synthesized using methods known to those skilled in the art.
  • the R 1 group may or may not be further manipulated to other functional groups by using standard methods known to those skilled in the art.
  • Aryl bromides or triflates of general formula E1 may be treated with bis(pinacol)diborane in the presence of a catalyst such as dichloro[1 ,1'-bis(diphenylphosphino)ferrocene]palladium and a base such as KOAc in solvents such as DMF at temperatures ranging from ambient to refluxing for time periods ranging from 1-24 h followed by the addition of compounds of general formula C1, additional catalyst and base such as Na 2 CO 3 with continued stirring at temperatures ranging from ambient to refluxing of said mixtures to provide compounds of general formula I.
  • the R 1 group may or may not be further manipulated to other functional groups by using standard methods known to those skilled in the art.
  • Compounds of general formula I may also be prepared by the method of Scheme 4.
  • Compounds of general formula C1 may be converted into the corresponding boronic esters of general formula F1 using methods known to those skilled in the art, such as combining mixtures of compounds of general formula C1 with a catalyst such as dichloro[1 ,1'- bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct, a ligand such as bis(diphenylphosphino)ferrocene, a base such as KOAc, and bis(pinacolato)diboron in solvents such DMSO or dioxane at temperatures ranging from ambient to refluxing of said mixtures.
  • a catalyst such as dichloro[1 ,1'- bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct
  • a ligand such as bis(diphenylphosphino)ferrocene
  • boronic esters may be optionally hydrolyzed to the boronic acid by using methods known to those skilled in the art such a treatment of the boronic esters with BBr 3 in methylene chloride at low temperatures such as -78°C to provide boronic acids.
  • Compounds of general formula I may be prepared by the reaction of compounds of general formula F1 with compounds of general formula E1 in the presence of a catalyst such as Pd(PPh 3 ) 4 and a base such as K 3 PO 4 in solvents such as methanol, dioxane, water and combinations thereof at temperatures ranging from ambient temperature to the boiling points of said mixtures.
  • the R 1 group may or may not be further manipulated to other functional groups by using standard methods known to those skilled in the art.
  • compositions comprising substantially enriched enantiomeric forms of the compound(s) of the present invention, or pharmaceutically acceptable addition salts thereof, and a pharmaceutically acceptable carrier.
  • these compositions may be formulated in unit dosage forms.
  • compositions of the present invention are preferably non-pyrogenic, e.g., do not trigger elevation of a patient's body temperature by more than a clinically acceptable amount.
  • Another aspect of the present invention is a pharmaceutical composition comprising a compound(s) of the present invention, or pharmaceutically acceptable addition salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments these compositions may be formulated in unit dosage forms.
  • Plasticizers and stabilizing agents known in the art may be incorporated in the pharmaceutical compositions of the present invention.
  • additives such as plasticizers and stabilizing agents are selected for their biocompatibility.
  • the additives are lung surfactants, such as 1,2-dipalmitoylphosphatidylcholine
  • DPPC DPPC
  • PC L- ⁇ -phosphatidylcholine
  • a composition of this invention may further contain one or more adjuvant substances, such as fillers, thickening agents or the like.
  • a subject composition includes an excipient.
  • a particular excipient may be selected based on its melting point, solubility in a selected solvent (e.g., a solvent that dissolves the therapeutic agent), and the resulting characteristics of the microparticles.
  • Excipients may comprise a few percent, about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or higher percentage of the subject compositions. Buffers, acids and bases may be incorporated in the subject compositions to adjust their pH. Agents to increase the diffusion distance of therapeutic may also be included.
  • compositions as described herein can be administered in various pharmaceutical formulations, depending on the disorder to be treated and the age, condition and body weight of the patient, as is well known in the art.
  • the compounds may be formulated as tablets, capsules, granules, powders or syrups; or for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations or suppositories.
  • injections intravenous, intramuscular or subcutaneous
  • drop infusion preparations or suppositories For application by the ophthalmic mucous membrane route, they may be formulated as eye-drops or eye ointments.
  • formulations can be prepared by conventional means, and, if desired, the active ingredient may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • an excipient such as an excipient, a binder, a disintegrating agent, a lubricant, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • a daily dosage of from 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this may be administere ⁇ in a single dose or in divided doses.
  • the precise time of administration and/or amount of therapeutic agent that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, etc.
  • physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication
  • route of administration etc.
  • the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those therapeutic agents, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent; excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent; excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives; such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and
  • sugars such as lactose, glucose and sucrose
  • agar (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogeri-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
  • buffering agents such as magnesium hydroxide and aluminum hydroxide
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the therapeutic agents. These salts can be prepared in situ during the final isolation and purification of the therapeutic agent, or by separately reacting a purified therapeutic agent in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, besylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate naphthylate
  • mesylate besylate
  • glucoheptonate lactobionate
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic or organic base addition salts of the compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the therapeutic agent, or by separately reacting the purified therapeutic agent in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamide, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, for example, Berge et al., supra).
  • Complement activation in a patient comprising administering to said patient, a therapeutically effective amount of the compounds of the present invention.
  • Another aspect of the present invention is a method for treating or preventing Complement-mediated tissue damage in a patient comprising administering to said patient, a therapeutically effective amount of a compound(s) of the present invention.
  • Another aspect of the present invention is a method for treating diseases characterized by chronic Complement activation comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • these diseases are selected from neurodegenerative diseases and pulmonary diseases.
  • the neurodegenerative diseases may be ones which affect the central nervous system (CNS) or the peripheral nervous system (PNS).
  • the present compounds can be used in a method for treating Complement mediated nerve myeline loss (demyelination).
  • Myelin provides the axonal "insulation" essential for efficient neural signal conduction in both the CNS and PNS.
  • the cell which produces myelin in the CNS is the oligodendrocyte whereas the myelin-producing cell in the PNS is the Schwann cell.
  • Diseases characterized by demyelination occur both in the CNS and the PNS.
  • one aspect of the present invention is a method of treating Complement mediated demyelination of nerves in the CNS or in the PNS comprising administration of a therapeutically effective amount of a compound(s) of the present invention.
  • MS multiple sclerosis
  • one aspect of the present invention is a method of treating MS comprising administration of a therapeutically effective amount of a compound(s) of the present invention.
  • GBS Gulliain-Barre syndrome
  • MFS Miller-Fisher syndrome
  • one aspect of the present invention is a method of treating GBS or MFS comprising administration of a therapeutically effective amount of a compound(s) of the present invention.
  • IgM monoclonal gammopathy and peripheral neuropathy constitute other instances of
  • one aspect of the present invention is a method of treating IgM monoclonal gammopathy and peripheral neuropathy comprising administration of a therapeutically effective amount of a compound(s) of the present invention.
  • Another aspect of the present invention is a method of treating neuromuscular diseases wherein Complement is implicated, comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • An example of such neuromuscular disease is myasthenia gravis. (See Asghar SS. Pasch MC, Frontiers in Bioscience. 5:E63-81 , 2000 Sep 1.]
  • Another aspect of the present invention is a method for treating Alzheimer's disease comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • the pathological hallmark of Alzheimer's disease (AD) is the senile plaque, a proteinaceous extracellular deposit composed primarily of an amyloidogenic peptide termed R-protein, and which is surrounded by dystrophic neurites.
  • Senile plaques are the focus of a robust and chronic inflammatory response mounted by microglia, the brain's endogenous macrophage.
  • Eikenbloom et al. disclose Complement activation in amyloid plaques in Alzheimer's dementia. (See Eikelenboom, P., hack, CE. et al., 1989.
  • HD Huntington's disease
  • Huntington's disease is an autosomal dominant inherited neurodegenerative disease characterized by the onset in mid-life of chorea, dementia, personality disturbance and inexorable progression to death.
  • Singhrao et al. have reported significant presence of Complement factors C1q, C4, C3, iC3b-neoepitope and C9- neoepitope in HD striatum, neurons, myelin and astrocytes. (See Singhrao et al., (1999), Exper. Neurolo., 159, 362-376)
  • PD Pick's disease
  • PD is a neurodegenerative disorder, the histological hallmarks of which is the Pick body, a dense, amorphous body which is strongly stained for tau protein and ubiquitin. Neuronal loss and astrocyte proliferation occur in the areas of disease which appear to be restricted to the frontal and temporal lobes.
  • Yasuhura et al. has shown that Complement in implicated in Pick's dfsease. (See Yasuhura et al., (1994), Brain Res., 652, 346-349).
  • Another aspect of the present invention is a method for treating asthma comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • Asthma is a disease that affects approximately 10% of the population. The overall annual prevalence of cases has increased by 42% in the past decade, and despite the availability of more potent and selective therapy, the annual incidence of asthma mortality has risen by 40% over this same time period.
  • Asthma is an allergenic reaction toward an inhaled antigen, characterized by a strong bronchoconstriction and edema formation with subsequent cell infiltration into the lung parenchyma and alveoli, mainly lymphocytes and eosinophils.
  • IgE mediated histamine release is generally regarded as the major pathophysiological pathway for asthma, other non-lgE mediated mechanisms also contribute to the disease.
  • a major candidate in that respect is the C3a analphylatoxin.
  • Other Complement mediated pulmonary disorders include hypersensitivity pneumonites, " and anaphylaxis. (See Regal, J., (1997), Immunopharmacology, 38, 17-25)
  • Another aspect of the present invention is a method for treating or preventing a selected from sepsis, adult respiratory distress syndrome, nephrites, graft rejection, myocardial ischemia/reperfusion injury, and intestinal ischemia/reperfusion injury, comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • Lipton et al., in U.S. Patent No. 6,503,947 discloses attenuation of cerebral ischemia and reperfusion injury by administrating a Complement inhibitor.
  • compositions of the present invention comprise any one or more of the above-described compounds, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier in accordance with the properties and expected performance of such a carrier, as is well-known in the art.
  • the dosage and dose rate of the compounds identified in the present invention effective for treating or preventing a disease or condition exhibiting, caused by or relating to amyloid formation, or a disease or condition caused by, exhibiting or relating to the activities of microglia or cells of macrophage lineage will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the observations and conclusions of the treating physician.
  • suitable dosage levels may be between about 0.1 ⁇ g/kg and about 50.0 mg/kg body weight per day, preferably between about 1.0 ⁇ g/kg and about 5.0 mg/kg body Weight per day, more preferably between about 10.0 //g/kg and about 1.0 mg/kg of body weight per day, and most preferably between about 20.0 //g/kg and about 0.5 mg/kg of body weight per day of the active ingredient.
  • suitable dosage levels of a compound identified in the present invention will be between about 1.0-10.0 ⁇ g and 500.0-5000.0 mg per day, preferably between about 5.0-50.0 ⁇ g and 5.0-50.0 mg per day, more preferably between about 100.0-1000.0 ⁇ g and 10.0-100.0 mg per day, and most preferably between about 200.0-2000.0 ⁇ g and about 5.0-50.0 mg per day of the active ingredient.
  • These ranges of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient.
  • the number of times per day that a dose is administered will depend upon such pharmacological and pharmacokinetic factors as the half- life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimal and optimal blood plasma or other body fluid levels of said active ingredient attained in the patient that are required for therapeutic efficacy.
  • compositions of formula I include the acid addition and base salts thereof.
  • Suitable acid, addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosy
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, trorhethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • Pharmaceutically acceptable salts of compounds of formula I may be prepared by one or more of three methods:
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. - R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995).
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
  • the solvent or water When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, no ⁇ -stoichiometry will be the norm.
  • multi-component complexes other than salts and solvates
  • complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals.
  • clathrates drug- host inclusion complexes
  • co-crystals The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J.
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
  • references to compounds of formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof.
  • the compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula I.
  • 'prodrugs' of the compounds of formula I are also within the scope of the invention.
  • certain derivatives of compounds of formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • Some examples of prodrugs in accordance with the invention include:
  • the compound of formula I contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula I is/are replaced by (C r C 10 )alkanoyl.
  • replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
  • certain compounds of formula I may themselves act as prodrugs of other compounds of formula I.
  • metabolites of compounds of formula I that is, compounds formed in vivo upon administration of the drug.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation. • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate W
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled persoh.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. When any racemate crystallizes, crystals of two different types are possible.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. . While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as Cl, fluorine, such as F, iodine, such as I and I, nitrogen, such as N and N 1 oxygen, such as 15 0, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • substitution with positron emitting isotopes can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • substitution with 123 I can be useful for Single Photon Emission Computed Tomography (SPECT) studies.
  • Isotopically-labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed. •
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 - DMSO. Also within the scope of the invention are intermediate compounds as hereinbefore defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula I.
  • the invention includes all polymorphs of the aforementioned species and crystal habits thereof.
  • the Drug Product The compounds of formula I should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995). v , Oral Administration
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and and buccal/mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs.
  • Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in -fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, ⁇ (6), 981-986, by Liang and Chen (2001).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets.
  • Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • the formulation of tablets is discussed in Pharmaceutical Dosage Forms: Tablets. Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
  • the compound of formula I may be water-soluble or insoluble.
  • a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
  • the compound of formula I may be in the form of multiparticulate beads.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified controlled release.
  • Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or targeted and programmed release. Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line. 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. '
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include .intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • compositions are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as powdered a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula I used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for use with needle-free injection administration comprise a compound of the invention in powdered form in conjunction with a suitable vehicle such as sterile, pyogen-free water.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified controlled release.
  • Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or tragettedtargeted and programmed release.
  • compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot ⁇ providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(dl-lactic- coglycolic)acid (PGLA) microspheres.
  • the compounds of the invention may also be administered topically, (intra)dermally, or transdermal ⁇ to the skin or mucosa.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). " .
  • Topical administration examples include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection .
  • Topical administration may alsoi be achieved using a patch, such as a transdernal iontophoretic patch.
  • Formulations for topical administration may be formulated to be immediate and/or modified controlled release.
  • Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or vomttedtargeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an, atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1,1,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, or as nasal drops.
  • a dry powder either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1//g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100//I.
  • a typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative ⁇ solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified controlled release using, for example, PGLA.
  • Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or vomttedtargeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing the compound of formula I.
  • the overall daily dose will typically be in the range 50 ⁇ g to 2000 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may also be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • Drug-cyclodextrin complexes for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser.
  • auxiliary additive i.e. as a carrier, diluent, or solubiliser.
  • alpha-, beta- and gamma-cyclodextrins examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 2000 mg depending, of course, on the mode of administration. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. '
  • 6-Biphenyl-4-yl-1-methyl-1 H-imidazoH .2-a]imidazole hydrochloride Also prepared by the method of Example 1 , but substituting 2-bromo-(1-biphenyl-4- yl)-ethanone and cyclized in concentrated hydrochloric acid. Anal. CaIc. for
  • Examples 30 - 51 were also prepared using the method of Example 29 but with the corresponding phenylboronic acids or esters that were either commercially-available or prepared according to methods outlined in the Preparations section:
  • Anal. CaIc. for C 23 H 26 N 2 (HCI): C, 75.29; H, 7.42; N, 7.63. Found: C, 74.94; H, 7.42; N, 7.34. 2
  • Example 44(C3a 1CTM 141 nM) 2-(2'-Fluoro-4'.5'-dimethyl-biphenyl-4-yl)-5.6.7.8-tetrahvdro-imidazori .2-aipyridine hydrochloride mp 185-197 0 C.
  • Examples 52 - 55 were also prepared using the method of Example 29 with the corresponding bromobenzene intermediates and benzeneboronic acids or esters along with Pd(dppf)Cl2 as the catalyst:
  • 6-(3',4'-Dimethyl-biphenyl-4-yl)-1-ethyl-1H-imidazo ⁇ ,2-a1imidazole To a solution of 6-(3',4'-dimethyl-biphenyl-4-yl)-1 H-imidazo[1 ,2-a]imidazole (87 mg,
  • Examples 70 - 73 were also produced using a procedure analogous to Example 69:
  • Example 70 (C3a IC 5Q 147 nM)
  • Example 101 - C3a ICgn 30 nM 2-(3'.4'-Dimethyl-biphenyl-4-yl)-imidazoH .2-alpyridine
  • Example 102 - C3a ICgn 17 nM 3-f2-(3'.4'-Dimethyl-biphenyl-4-yl.)-imidazo ⁇ ,2-alpyridin-6-vn-ri ,2.41oxadiazol-5-ol
  • reaction mixture was heated at 80 0 C overnight, cooled to rt, concentrated, and chromatographed (preabsorbed to silica; eluted with gradient of 0-2.5% MeOH in CH 2 CI 2 ) to provide 41.7 mg of solid.
  • the solid was combined with azidotrimethylsilane (37 uL, 0.28 mmol), dibutyltin oxide (5 mg, 0.02 mmol), and toluene.
  • the mixture was heated at 90 °C for 18 h, cooled to rt, diluted with MeOH, and concentrated.
  • Example 104 - C3a ICm 32 nM 6-(3',4'-Dimethyl-biphenyl-4-yl)-2,3-dihvdro-imidazof2,1-blthiazole tosylate salt
  • Example 106 - C3a ICm 129 nM 2-Biphenyl-4-yl-7-ethyl-imidazof1 ,2-alpyridine
  • Examples 107 - 111 may be prepared using a method analogous to Example 106:
  • Example 109 - C3a ICm 47 nM r2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo ⁇ ,2-aipyridin-6-yll-methanol
  • Example 110 - C3a IC 50 14 nM [2-(3',4'-Dimethyl-biphenyl-4-yl)-imidazo[1,2-a]pyridin-7-yl]-methanol
  • Example 120 - C3a ICgn 101 nM N-f2-(3',4'-Dimethyl-biphenyl-4-yl)-5.6.7.8-tetrahvdro-imidazo ⁇ .2-alPyridin-6- ylmethyll-4-fluoro-benzamide. . '
  • Example 125 - C3a ICg 2 19 nM 2.5-Dimethyl-1 H-pyrrole-3-carboxylic acid f2- ⁇ 3',4'-dimethyl-biphenyl-4-yl)-5,6,7,8- tetrahvdro-imidazof1.2-alpyridin-6-ylmethvH-amide.
  • Example 129 - C3a ICgn 27 nM 1 H-lndole-5-carboxylic acid f2-(3'.4'-dimethyl-biphenyl-4-yl)-5,6,7,8-tetrahvdro- imidazori ,2-alpyridin-6-ylmethyll-amide.
  • Example 134 - C3a ICm 12 nM 2-Oxo-thiazolidine-4-carboxylic acid r2-(3'.4'-dimethyl-biphenyl-4-yl)-5.6.7.8- tetrahvdro-imidazori .2-aipyridin-6-ylmethvn-amide.
  • Example 138 - C3a ICgn 39 nM N-r2-(3',4'-Dimethyl-biphenyl-4-v ⁇ -5.6.7.8-tetrahvdro-imidazo ⁇ .2-alpyridin-6- ylmethvn-2-(1 H-indol-3-yl)-acetamide.
  • Example 143 - C3a ICgn 38 nM Tetrahvdro-furan-3-carboxylic acid r2-(3',4'-dimethyl-biphenyl-4-yl)-5,6.7.8-tetrahydro- imidazo[1.2-a]pyridin-6-ylmethv ⁇ -amide.
  • Example 147 - C3a IC 52 152 nM N-[2-(3',4'-Dimethyl-biphenyl-4-v ⁇ -5.6,7.8-tetrahvdro-imidazon ,2-alpyridin-6- ylmethv ⁇ -3-(1H-indol-3-yl)-propionamide. •
  • Example 152 - C3a ICgn 26 nM Furan-2-carboxylic acid f2-(3'.4'-dimethyl-biphenyl-4-yl)-5,6,7,8-tetrahvdro- imidazoH,2-a1pyridin-6-ylmethv ⁇ -amide.
  • Example 156 - C3a ICgn 131 nM N-r2-(3'.4'-Dimethyl-biphenyl-4-vn-5.6.7.8-tetrahvdro-imidazori .2-aiPyridin-6- ylmethyll-3-indol-1-yl-propionamide.
  • Example 161 - C3a ICgn 28 nM N-r2-(3',4'-Dimethyl-biphenyl-4-vn-5.6.7.8-tetrahvdro-imidazof1 ,2-a1pyridin-6- ylmethv ⁇ -6-methyl-nicotinamide.
  • Example 165 - C3a ICgn 213 nM 4.5-Dichloro-isothiazole-3-carboxylic acid r2-(3',4'-dimethyl-biphenyl-4-yl)-5.6,7,8- tetrahvdro-imidazo ⁇ ,2-aipyridin-6-ylnnethyll-amide.
  • the reaction was one again evacuated and refilled with nitrogen three times and then heated to reflux. After 90 minutes, the reaction was cooled to room temperature and diluted with ethyl acetate (500 mL) and the aqueous layer was discarded. The organic layer was washed sequentially with aqueous saturated sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL), dried (MgSO 4 ) and concentrated to give a dark oil. This was purified on silica gel utilizing a gradient elution of 40% to 80% CH 2 CI 2 in hexanes to give 9.33 g of the biphenyl methyl ketone as a white solid.
  • 4-lsopropyl-3-methyl-phenylboronic acid 4-lsopropyl-3-methylaniline hydrochloride (3.0 g, 16 mmol) was added portionwise to a dark green solution of cupric bromide (4.0 g, 18 mmol), butyl nitrite (2.3 mL, 19 mmol) and acetonitrile (50 mL). This was then heated to reflux for 15 min, cooled and concentrated. The dark residue was chromatographed on silica gel utilizing hexane a ⁇ eluent to provide 4- isopropyl-3-methylbromobenzene (2.67 g) as a colorless oil.
  • 3'.4'-Dimethyl-biphenyl-4-carboxylic acid hydrazide To a mixture of 3,4-dimethylphenylboronic acid (3.15 g, 26.7 mmol), ethyl 4- bromobenzoate (3.09 g, 13.4 mmol), toluene (30 mL), was added a 2 M solution of sodium carbonate (20.1 mL). . This was then evacuated and refilled with nitrogen three times and then Pd(PPh 3 J 4 (3.09 g, 2.7 mmol) was added in one portion and the degassing repeated.
  • reaction was copied to O 0 C overnight and the resultant solid collected by vacuum filtration and washed with ether. This solid was mixed with polyphosphoric acid (ca. 20 mL) and placed into a 9O 0 C oil bath where it was stirred for 3.5 h. The reaction was then poured into 4 N NaOH (50 mL) and the aqueous mixture was extracted with CHCI 3 (4 x 50 mL). The combined organic layers were dried (Na 2 SO 4 ), concentrated and chromatographed on silica gel (CH 2 Cl 2 /MeOH/NH 4 OH) to give the title compound (176 mg) as a solid.
  • the reaction was cooled to O 0 C overnight and the resultant solid collected by vacuum filtration and washed with methanol. This solid was mixed with polyphosphoric acid (ca. 10 mL) and placed into a 9O 0 C oil bath where it was stirred for 3.5 h. The reaction was then poured into 3 N NaOH -(50 mL), additional based was added until the pH of the solution was about 10 and the aqueous mixture was extracted with CHCI 3 (4 x 50 mL).
  • N,O-dimethyl hydroxylamine hydrochloride (1.07 g, 11 mmol) was added followed by the dropwise addition of diisopropylethyl amine (3.8 mL, 22 mmol).
  • ethyl acetate 50 mL was added and the reaction was washed with water (2 x 20 mL), the organic layer was dried (Na 2 SO 4 ) and concentrated to give 5-phenyl- pyrazine-2-carboxylic acid methoxy-methyl-amide (1.96 g).
  • 6-Chloro-pyridazine-3-sulfonyl chloride freshly prepared . from 1 g of 6-chloro- pyridazine-3-thiol by the method of Petelin-Hudnik et al.; Arch. Pharm. Ber. Dtsch. Pharm. Ges.; 299; 1966; 646-650
  • liquid ammonia 40 mL
  • C3a Receptor Binding Assay utilizes 125 I labeled human C3a peptide (50 pM, New England
  • Non-specific binding is defined as binding measured following quenching with a
  • Soak Printed Filtermat A Glass Fiber Filters (Wallac; 1205-401) in 1 % (20g/L) polyethylenimine (PEI, Sigma; P3143) for 60 min. Air dry overnight. Store until used.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur des composés aryles substitués imidazo[4,5-c] pyridine. Ces composés sont utiles dans des compositions pharmaceutiques comme antagonistes du C3a pour traiter différents états médicaux associés à la cascade du complément. L'invention porte également sur des méthodes de traitement desdits états.
PCT/IB2006/002568 2005-09-19 2006-09-18 Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a WO2007034282A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US71851705P 2005-09-19 2005-09-19
US60/718,517 2005-09-19

Publications (2)

Publication Number Publication Date
WO2007034282A2 true WO2007034282A2 (fr) 2007-03-29
WO2007034282A3 WO2007034282A3 (fr) 2007-05-18

Family

ID=37807741

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/002568 WO2007034282A2 (fr) 2005-09-19 2006-09-18 Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a

Country Status (1)

Country Link
WO (1) WO2007034282A2 (fr)

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008030579A2 (fr) * 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Modulateurs de la kinase associée au récepteur de l'interleukine-1
EP1964841A1 (fr) * 2007-02-28 2008-09-03 sanofi-aventis Imidazo[1,2-a]azine et son utilisation en tant que produit pharmaceutique
WO2009028588A1 (fr) * 2007-08-31 2009-03-05 Eisai R & D Management Co., Ltd. Composé polycyclique
WO2009057577A1 (fr) * 2007-10-30 2009-05-07 Nihon Medi-Physics Co., Ltd. Utilisation d'un nouveau composé présentant une affinité pour les substances amyloïdes et procédé de production dudit composé
US7563797B2 (en) 2006-08-28 2009-07-21 Forest Laboratories Holding Limited Substituted imidazo(1,2-A)pyrimidines and imidazo(1,2-A) pyridines as cannabinoid receptor ligands
US7618960B2 (en) 2005-11-24 2009-11-17 Eisai R&D Management Co., Ltd. Morpholine type cinnamide compound
US7667041B2 (en) 2004-05-26 2010-02-23 Eisai R&D Management Co., Ltd. Cinnamide compound
US7713993B2 (en) 2006-03-09 2010-05-11 Eisai R&D Management Co., Ltd. Multi-cycle cinnamide derivatives
US7737141B2 (en) 2006-07-28 2010-06-15 Eisai R&D Management Co., Ltd. Prodrug of cinnamide compound
CN101861325A (zh) * 2007-09-05 2010-10-13 阿尔伯塔大学理事会 在使用经过邻位取代的芳基硼酸进行的化学反应中对羧酸进行有机催化活化的方法
US7923563B2 (en) 2004-10-26 2011-04-12 Eisai R&D Management Co., Ltd. Amorphous object of cinnamide compound
WO2011048032A1 (fr) 2009-10-21 2011-04-28 F. Hoffmann-La Roche Ag Dérivés du diazépam en tant que modulateurs des récepteurs des chimiokines
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
US8008293B2 (en) 2007-02-28 2011-08-30 Eisai R&D Management Co., Ltd. Bicyclic oxomorpholine derivative
US8048878B2 (en) 2005-11-24 2011-11-01 Eisai R&D Management Co., Ltd. Two cyclic cinnamide compound
WO2012178083A1 (fr) 2011-06-22 2012-12-27 Apellis Pharmaceuticals, Inc. Méthodes de traitement de troubles chroniques au moyen d'inhibiteurs de complément
US20130065884A1 (en) * 2010-03-18 2013-03-14 Zaesung No Anti-Infective Compounds
JP2013523673A (ja) * 2010-03-26 2013-06-17 エフ．ホフマン−ラ ロシュ アーゲー Ｎ−（イミダゾピリミジン−７−イル）−ヘテロアリールアミド誘導体及びｐｄｅ１０ａ阻害剤としてのその使用
EP2685825A1 (fr) * 2011-03-15 2014-01-22 Vanderbilt University Imadazapyrinidin-5(6h)-ones substituées en tant que modulateurs allostériques des récepteurs mglur5
EP2726154A1 (fr) * 2011-06-20 2014-05-07 The University of Queensland Prévention et traitement de conditions inflammatoires aiguës
WO2014121055A3 (fr) * 2013-02-04 2014-10-02 Janssen Pharmaceutica Nv Modulateurs flap
WO2014187762A1 (fr) * 2013-05-23 2014-11-27 F. Hoffmann-La Roche Ag 2-phénylimidazo[1,2-a]pyrimidines en tant qu'agents d'imagerie
US8975276B2 (en) 2011-06-29 2015-03-10 Bristol-Myers Squibb Company Inhibitors of PDE10
US9073876B2 (en) 2013-02-04 2015-07-07 Janssen Pharmaceutica Nv Flap modulators
US9255103B2 (en) 2010-12-08 2016-02-09 Vanderbilt University Substituted pyrazolo[1,5-a]pyrazines as mGluR5 receptor modulators
CN105439965A (zh) * 2015-11-20 2016-03-30 江苏恒安化工有限公司 喹喔啉杂环化合物的合成方法
WO2016191811A1 (fr) 2015-06-03 2016-12-08 The University Of Queensland Agents mobilisateurs et leurs utilisations
CN106588673A (zh) * 2016-12-20 2017-04-26 金凯(辽宁)化工有限公司 一种2‑甲基‑5‑氨基三氟甲苯的制备方法
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
JP2021523231A (ja) * 2018-05-09 2021-09-02 アプリノイア セラピューティクス インコーポレーテッド ヘテロアリール化合物及びその使用
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US11642413B2 (en) 2019-11-13 2023-05-09 Aprinoia Therapeutics Limited Compounds for degrading Tau protein aggregates and uses thereof
US11667628B2 (en) 2012-12-21 2023-06-06 National Institutes For Quantum And Radiological Science And Technology Compounds for imaging tau proteins that accumulate in brain
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2343748A1 (fr) * 1976-03-10 1977-10-07 Metabio Derives de 2,3-dihydro imidazo (2,1-b) thiazole, leur procede de preparation et leur application en therapeutique
EP0404190A1 (fr) * 1989-06-23 1990-12-27 Takeda Chemical Industries, Ltd. Composés hétérocycliques condensés, leur préparation et leur utilisation
WO1999015490A1 (fr) * 1997-09-23 1999-04-01 Smithkline Beecham Corporation Ligands pour recepteurs de c3a
JPH11116481A (ja) * 1997-10-06 1999-04-27 Sumitomo Pharmaceut Co Ltd スタット６活性化阻害剤
WO2001057038A1 (fr) * 2000-02-01 2001-08-09 Basf Aktiengesellschaft Composes heterocycliques et leur utilisation comme inhibiteurs de parp
US6551723B1 (en) * 1998-08-18 2003-04-22 Fuji Photo Film Co., Ltd. Organic electroluminescence element material and organic electroluminescence element comprising same
JP2003277743A (ja) * 2002-03-22 2003-10-02 Idemitsu Kosan Co Ltd 有機エレクトロルミネッセンス素子用材料及びそれを用いた有機エレクトロルミネッセンス素子
WO2004063159A1 (fr) * 2003-01-10 2004-07-29 Idemitsu Kosan Co., Ltd. Derive heterocyclique azote et element electroluminescent organique utilisant ce derive
WO2005043630A1 (fr) * 2003-10-31 2005-05-12 Idemitsu Kosan Co., Ltd. Transistor a couches minces organique

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2343748A1 (fr) * 1976-03-10 1977-10-07 Metabio Derives de 2,3-dihydro imidazo (2,1-b) thiazole, leur procede de preparation et leur application en therapeutique
EP0404190A1 (fr) * 1989-06-23 1990-12-27 Takeda Chemical Industries, Ltd. Composés hétérocycliques condensés, leur préparation et leur utilisation
WO1999015490A1 (fr) * 1997-09-23 1999-04-01 Smithkline Beecham Corporation Ligands pour recepteurs de c3a
JPH11116481A (ja) * 1997-10-06 1999-04-27 Sumitomo Pharmaceut Co Ltd スタット６活性化阻害剤
US6551723B1 (en) * 1998-08-18 2003-04-22 Fuji Photo Film Co., Ltd. Organic electroluminescence element material and organic electroluminescence element comprising same
WO2001057038A1 (fr) * 2000-02-01 2001-08-09 Basf Aktiengesellschaft Composes heterocycliques et leur utilisation comme inhibiteurs de parp
JP2003277743A (ja) * 2002-03-22 2003-10-02 Idemitsu Kosan Co Ltd 有機エレクトロルミネッセンス素子用材料及びそれを用いた有機エレクトロルミネッセンス素子
WO2004063159A1 (fr) * 2003-01-10 2004-07-29 Idemitsu Kosan Co., Ltd. Derive heterocyclique azote et element electroluminescent organique utilisant ce derive
WO2005043630A1 (fr) * 2003-10-31 2005-05-12 Idemitsu Kosan Co., Ltd. Transistor a couches minces organique

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
A. ANDREANI, M.RAMBALDI, A. LOCATELLI, AM. ISETTA: "synthesis and mitogenic activity of new imidazo[2,1-b]thiazoles" EUR. J. MED., vol. 26, 1991, pages 335-337, XP009080499 *
B. MEKONNEN, G. CRANK, D. CRAIG: "a new and facile synthesis of imidazo[2,1-b]oxazoles" J. HETEROCYCLIC CHEM., vol. 34, 1997, pages 589-599, XP002424348 *
BARLIN G B ET AL: "IMIDAZO1,2-BPYRIDAZINES. XXI. SYNTHESES OF SOME 3-ACYLAMINOMETHYL-6-(CHLORO AND IODO)-2-(SUBSTITUTED PHENYL) IMIDAZO1,2-BPYRIDAZINES AND -IMIDAZO 1,2-APYRIDINES AND THEIR INTERACTION WITH CENTRAL AND MITOCHONDRIAL BENZODIAZEPINE RECEPTORS" AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 50, 1997, pages 61-67, XP001007026 ISSN: 0004-9425 *
BUU-HOI, NG. PH. ET AL: "Biphenyl analogs of p-hydroxypropiophenone" RECUEIL DES TRAVAUX CHIMIQUES DES PAYS-BAS ET DE LA BELGIQUE , 72, 774-80 CODEN: RTCPB4; ISSN: 0370-7539, 1953, XP002016690 *
DATABASE BEILSTEIN [Online] BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002424408 Database accession no. beilstein RN : 1022905 *
F. BARBA, B. BATANERO: "a novel and convenient electrochemical synthesis of 3,7-diaryl-2H-imidazo[2,1-b][1,3,4]oxadiaz ines" JOURNAL OF ORGANIC CHEMISTRY, vol. 58, no. 24, 1993, pages 6889-6891, XP009080473 *
FANG, CHONGBO ET AL: "Synthesis and luteal cell killing activity of 2-substituted phenyl-1,2,4- triazolo [5,1-a]pyridine derivatives" ZHONGGUO YAOWU HUAXUE ZAZHI , 12(3), 134-137, 163 CODEN: ZYHZEF; ISSN: 1005-0108, 2002, XP009080425 *
G. B. BARLIN, L.P. DAVIES, S.J. IRELAND, J. ZHANG: "Imidazo1,2-b]pyridazines. part XIII" AUST. J. CHEM., vol. 45, 1992, pages 1281-1300, XP009080477 *
GRANT E B ET AL: "Design, synthesis, and biological activity of diiminoisoindolines as complement component 3a antagonists" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 11, no. 21, 2001, pages 2817-2820, XP002984323 ISSN: 0960-894X *
ISMAIL, MOHAMED A. ET AL: "Novel Dicationic Imidazo[1,2-a]pyridines and 5,6,7,8-Tetrahydro- imidazo[1,2-a]pyridines as Antiprotozoal Agents" JOURNAL OF MEDICINAL CHEMISTRY , 47(14), 3658-3664 CODEN: JMCMAR; ISSN: 0022-2623, 2004, XP002424347 *
LIU, TAO ET AL: "Non-steroidal pregnancy-terminating agents: design, synthesis and structure-activity relationships of 2-aryl-1,2,4- triazolo [1,5-a]pyridine" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS , 12(17), 2411-2413 CODEN: BMCLE8; ISSN: 0960-894X, 2002, XP002424346 *
PAUCHARD, JEAN PAUL ET AL: "Anil synthesis. 17. Preparation of styryl derivatives of 2-phenyl-4H-1,2,4- triazolo [1,5-a]pyridine" HELVETICA CHIMICA ACTA , 61(1), 142-70 CODEN: HCACAV; ISSN: 0018-019X, 1978, XP002424345 *
S.N. SAWHNEY, D.R. KODALI, G.S. DHINDSA, S.P. SINGH: "synthesis & antiinflammatory activity of some arylimidazo[2,1-b]thiazolyl- & arylimidazo[2,1-b]benzothiazolyl-acetic acids" INDIAN JOURNAL OF CHEMISTRY, vol. 21b, February 1982 (1982-02), pages 134-138, XP009080136 *

Cited By (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7880009B2 (en) 2004-05-26 2011-02-01 Eisai R&D Management Co., Ltd. Cinnamide compound
US7667041B2 (en) 2004-05-26 2010-02-23 Eisai R&D Management Co., Ltd. Cinnamide compound
US7687640B2 (en) 2004-05-26 2010-03-30 Eisai R&D Management Co., Ltd. Cinnamide compound
US7923563B2 (en) 2004-10-26 2011-04-12 Eisai R&D Management Co., Ltd. Amorphous object of cinnamide compound
US8048878B2 (en) 2005-11-24 2011-11-01 Eisai R&D Management Co., Ltd. Two cyclic cinnamide compound
US7618960B2 (en) 2005-11-24 2009-11-17 Eisai R&D Management Co., Ltd. Morpholine type cinnamide compound
US7973033B2 (en) 2006-03-09 2011-07-05 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
US7897632B2 (en) 2006-03-09 2011-03-01 Eisai R&D Management Co., Ltd. Multi-cyclic cinnamide derivatives
US7713993B2 (en) 2006-03-09 2010-05-11 Eisai R&D Management Co., Ltd. Multi-cycle cinnamide derivatives
US7737141B2 (en) 2006-07-28 2010-06-15 Eisai R&D Management Co., Ltd. Prodrug of cinnamide compound
US7563797B2 (en) 2006-08-28 2009-07-21 Forest Laboratories Holding Limited Substituted imidazo(1,2-A)pyrimidines and imidazo(1,2-A) pyridines as cannabinoid receptor ligands
WO2008030579A2 (fr) * 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Modulateurs de la kinase associée au récepteur de l'interleukine-1
WO2008030579A3 (fr) * 2006-09-07 2009-02-26 Biogen Idec Inc Modulateurs de la kinase associée au récepteur de l'interleukine-1
US8044050B2 (en) 2007-02-28 2011-10-25 Sanofi-Aventis Imidazo[1,2-a]azines and their use as pharmaceuticals
US8008293B2 (en) 2007-02-28 2011-08-30 Eisai R&D Management Co., Ltd. Bicyclic oxomorpholine derivative
WO2008104279A1 (fr) * 2007-02-28 2008-09-04 Sanofi-Aventis Imidazo[1,2-a]azines et leur utilisation comme médicaments
EP1964841A1 (fr) * 2007-02-28 2008-09-03 sanofi-aventis Imidazo[1,2-a]azine et son utilisation en tant que produit pharmaceutique
US9453000B2 (en) 2007-08-31 2016-09-27 Eisai R&D Management Co., Ltd. Polycyclic compound
WO2009028588A1 (fr) * 2007-08-31 2009-03-05 Eisai R & D Management Co., Ltd. Composé polycyclique
US7935815B2 (en) 2007-08-31 2011-05-03 Eisai R&D Management Co., Ltd. Imidazoyl pyridine compounds and salts thereof
JP5433418B2 (ja) * 2007-08-31 2014-03-05 エーザイ・アール・アンド・ディー・マネジメント株式会社 多環式化合物
EP2559693A1 (fr) * 2007-08-31 2013-02-20 Eisai R&D Management Co., Ltd. Composé polycyclique
CN101815713A (zh) * 2007-08-31 2010-08-25 卫材R&D管理有限公司 多环化合物
CN101861325A (zh) * 2007-09-05 2010-10-13 阿尔伯塔大学理事会 在使用经过邻位取代的芳基硼酸进行的化学反应中对羧酸进行有机催化活化的方法
US8822720B2 (en) 2007-09-05 2014-09-02 The Governors Of The University Of Alberta Method for the organocatalytic activation of carboxylic acids for chemical, reactions using orthosubstituted arylboronic acids
WO2009057577A1 (fr) * 2007-10-30 2009-05-07 Nihon Medi-Physics Co., Ltd. Utilisation d'un nouveau composé présentant une affinité pour les substances amyloïdes et procédé de production dudit composé
JPWO2009057577A1 (ja) * 2007-10-30 2011-03-10 日本メジフィジックス株式会社 新規アミロイド親和性化合物の使用及び製造方法
WO2011048032A1 (fr) 2009-10-21 2011-04-28 F. Hoffmann-La Roche Ag Dérivés du diazépam en tant que modulateurs des récepteurs des chimiokines
US8865734B2 (en) * 2010-03-18 2014-10-21 Institut Pasteur Korea Anti-infective compounds
US20130065884A1 (en) * 2010-03-18 2013-03-14 Zaesung No Anti-Infective Compounds
JP2013523673A (ja) * 2010-03-26 2013-06-17 エフ．ホフマン−ラ ロシュ アーゲー Ｎ−（イミダゾピリミジン−７−イル）−ヘテロアリールアミド誘導体及びｐｄｅ１０ａ阻害剤としてのその使用
US9255103B2 (en) 2010-12-08 2016-02-09 Vanderbilt University Substituted pyrazolo[1,5-a]pyrazines as mGluR5 receptor modulators
EP2685825A1 (fr) * 2011-03-15 2014-01-22 Vanderbilt University Imadazapyrinidin-5(6h)-ones substituées en tant que modulateurs allostériques des récepteurs mglur5
EP2685825A4 (fr) * 2011-03-15 2014-09-10 Univ Vanderbilt Imadazapyrinidin-5(6h)-ones substituées en tant que modulateurs allostériques des récepteurs mglur5
EP2726154A4 (fr) * 2011-06-20 2014-12-03 Univ Queensland Prévention et traitement de conditions inflammatoires aiguës
EP2726154A1 (fr) * 2011-06-20 2014-05-07 The University of Queensland Prévention et traitement de conditions inflammatoires aiguës
EP3524258A1 (fr) 2011-06-22 2019-08-14 Apellis Pharmaceuticals, Inc. Méthodes de traitement de troubles chroniques au moyen d'inhibiteurs de complément
WO2012178083A1 (fr) 2011-06-22 2012-12-27 Apellis Pharmaceuticals, Inc. Méthodes de traitement de troubles chroniques au moyen d'inhibiteurs de complément
US8975276B2 (en) 2011-06-29 2015-03-10 Bristol-Myers Squibb Company Inhibitors of PDE10
US11667628B2 (en) 2012-12-21 2023-06-06 National Institutes For Quantum And Radiological Science And Technology Compounds for imaging tau proteins that accumulate in brain
US9073876B2 (en) 2013-02-04 2015-07-07 Janssen Pharmaceutica Nv Flap modulators
WO2014121055A3 (fr) * 2013-02-04 2014-10-02 Janssen Pharmaceutica Nv Modulateurs flap
US10047101B2 (en) 2013-02-04 2018-08-14 Janssen Pharmaceautica NV Flap modulators
US9079866B2 (en) 2013-02-04 2015-07-14 Janssen Pharmaceutica Nv Flap modulators
US9732093B2 (en) 2013-02-04 2017-08-15 Janssen Pharmaceutica Nv FLAP modulators
US9926333B2 (en) 2013-02-04 2018-03-27 Janssen Pharmaceutica Nv Flap modulators
US9884878B2 (en) 2013-02-04 2018-02-06 Janssen Pharmaceutica Nv FLAP modulators
US9745328B2 (en) 2013-02-04 2017-08-29 Janssen Pharmaceutica Nv Flap modulators
JP2016520091A (ja) * 2013-05-23 2016-07-11 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 造影剤としての２−フェニルイミダゾ［１．２−ａ］ピリミジン
US20170128598A1 (en) * 2013-05-23 2017-05-11 Hoffmann-La Roche Inc. 2-phenylimidazo[1,2-a]pyrimidines as imaging agents
US9801961B2 (en) * 2013-05-23 2017-10-31 Hoffmann-La Roche Inc. 2-phenylimidazo[1,2-a]pyrimidines as imaging agents
RU2665580C2 (ru) * 2013-05-23 2018-08-31 Ф. Хоффманн-Ля Рош Аг 2-фенилимидазо[1,2-а]пиримидины в качестве визуализирующих средств
WO2014187762A1 (fr) * 2013-05-23 2014-11-27 F. Hoffmann-La Roche Ag 2-phénylimidazo[1,2-a]pyrimidines en tant qu'agents d'imagerie
CN105229009A (zh) * 2013-05-23 2016-01-06 豪夫迈·罗氏有限公司 作为成像剂的2-苯基咪唑并[1,2-a]嘧啶
WO2016191811A1 (fr) 2015-06-03 2016-12-08 The University Of Queensland Agents mobilisateurs et leurs utilisations
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
CN105439965A (zh) * 2015-11-20 2016-03-30 江苏恒安化工有限公司 喹喔啉杂环化合物的合成方法
US11866435B2 (en) 2015-12-22 2024-01-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
CN106588673A (zh) * 2016-12-20 2017-04-26 金凯(辽宁)化工有限公司 一种2‑甲基‑5‑氨基三氟甲苯的制备方法
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US11787793B2 (en) 2016-12-22 2023-10-17 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US11339149B2 (en) 2016-12-22 2022-05-24 Incyte Corporation Heterocyclic compounds as immunomodulators
US10800768B2 (en) 2016-12-22 2020-10-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11124511B2 (en) 2018-03-30 2021-09-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
EP3790883A4 (fr) * 2018-05-09 2022-08-24 Aprinoia Therapeutics Limited Composés hétéroaryles et leurs utilisations
IL278579B1 (en) * 2018-05-09 2024-05-01 Aprinoia Therapeutics Inc Heteroaryl compounds and uses thereof
JP2021523231A (ja) * 2018-05-09 2021-09-02 アプリノイア セラピューティクス インコーポレーテッド ヘテロアリール化合物及びその使用
JP7293343B2 (ja) 2018-05-09 2023-06-19 アプリノイア セラピューティクス リミテッド ヘテロアリール化合物及びその使用
US11414433B2 (en) 2018-05-11 2022-08-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US10906920B2 (en) 2018-05-11 2021-02-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11642413B2 (en) 2019-11-13 2023-05-09 Aprinoia Therapeutics Limited Compounds for degrading Tau protein aggregates and uses thereof
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof

Also Published As

Publication number Publication date
WO2007034282A3 (fr) 2007-05-18

Similar Documents

Publication Publication Date Title
WO2007034282A2 (fr) Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a
US10016406B2 (en) Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof
US7557110B2 (en) Pyrazolo[1,5-A] pyrimidine derivatives
EP3080120B1 (fr) Dérivés imidazole et pyrazole condenses utilisables en tant que modulateurs de l'activité tnf
EP3305073B1 (fr) 1h-pyrazolo [3,4-b] pyridines et leurs utilisations thérapeutiques
NL1029016C2 (nl) Tetrahydronafthyridinederivaten.
WO2007034279A2 (fr) Antagonistes de c3a et leurs compositions pharmaceutiques
WO2007034277A1 (fr) Composés de type imidazo[4,5-c]pyridine arylsubstitués en tant qu'antagonistes du récepteur c3a
WO2007034278A2 (fr) Antagonistes du recepteur du c3a
US20060111416A1 (en) Octahydropyrrolo[3,4-C]pyrrole derivatives
US20060040940A1 (en) Imidazopyridines pyrimidines and triazines for enhancing cognition as gaba-a-alphas 5 receoptor subtype ligands
CA3166358A1 (fr) Antagonistes de sting a petites molecules
CA2897469A1 (fr) Derives de pyridine comme modulateurs allosteriques positifs de recepteur muscarinique m1
CA3150508A1 (fr) Derives de pyridazin-3(2h)-one fusionnes par un azole
GB2572526A (en) Heterocyclic small molecule modulators of human STING
WO2023017452A1 (fr) Dérivés d'urée à petites molécules en tant qu'antagonistes de sting
AU2022325543A1 (en) Small molecule sting antagonists
WO2023227696A1 (fr) Nouveaux dérivés pour le traitement de troubles médiés par trpm3
CN118159535A (zh) 小分子sting拮抗剂
CA2542720A1 (fr) Azabenzodiazepines a titre d'inhibiteurs de la phosphodiesterase-4

Legal Events

Date Code Title Description
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06820755

Country of ref document: EP

Kind code of ref document: A2