WO2007034278A2 - Antagonistes du recepteur du c3a - Google Patents

Antagonistes du recepteur du c3a Download PDF

Info

Publication number
WO2007034278A2
WO2007034278A2 PCT/IB2006/002561 IB2006002561W WO2007034278A2 WO 2007034278 A2 WO2007034278 A2 WO 2007034278A2 IB 2006002561 W IB2006002561 W IB 2006002561W WO 2007034278 A2 WO2007034278 A2 WO 2007034278A2
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
methyl
imidazo
phenyl
pyrazol
Prior art date
Application number
PCT/IB2006/002561
Other languages
English (en)
Other versions
WO2007034278A3 (fr
Inventor
Michelle Marie Claffey
Steven Wayne Goldstein
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 WO2007034278A2 publication Critical patent/WO2007034278A2/fr
Publication of WO2007034278A3 publication Critical patent/WO2007034278A3/fr

Links

Classifications

    • 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
    • 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
    • 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
    • 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. Additionally, 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 a proteinaceous extracellular deposit composed primarily of an amyloidogen ⁇ c peptide termed A-beta protein, and which is surrounded by dystrophic neurttes.
  • 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 immunosurveilla ⁇ ce , and acquired immunity processes.
  • Complement a phylogenet ⁇ caily old system of enzymes and other proteins that most likely evolved to protect organisms against microbial assault.
  • Complement activation is a praminent 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.
  • 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 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.
  • 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 indude macrophages, neutrophils, eosiniph ⁇ s, 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.
  • 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.
  • chemotaxis and respiratory burst are both host defense mechanism that generate high levels of cytotoxic superoxide.
  • chemotaxis and respiratory burst are both host defense mechanism that generate high levels of cytotoxic superoxide.
  • C3a A key step in this inflammatory response is the formation of C3a, which upon binding to microglial C3a receptors, causes recruitment of microglia to the plaque followed by activation of neurotoxin release. Blocking of C3a receptors would thus be expected to inhibit these deleterious microglial responses and slow the progression of Alzheimer's disease.
  • the C3a receptor belongs to the rhodopsin family of G protein-coupled receptors (see Ernbler 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, eosin ⁇ pnils 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 trie 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 Hunt ⁇ ngton's disease, Pick's disease, and Gullian Barre syndrome.
  • Hunt ⁇ ngton's disease Pick's disease
  • Gullian Barre syndrome See Campos-Tor ⁇ es et aL, (March 2000), Irnmunophamiacology, volume 49, Issues 1-2, page 48; see also, (Vogt, W. (1986) Complement 3, 177-188; Morgan, B. P. (1994) European J. Clin. Investigation, 24, 219-228; and Morgan et al., (1997), Immunopharmacology, 38, 43-50).
  • 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/r ⁇ perfusion injury.
  • disease states such as sepsis, adult respiratory distress syndrome, nephrites, graft rejection, myocardial ischemia/reperfusion injury, and intestinal ischemia/r ⁇ perfusion injury.
  • Such disease states include, but are not limited to: neurological diseases such as Alzheimer's disease, multiple sclerosis, Hunti ⁇ gton'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, hyperlip ⁇ demia, 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, Hunti ⁇ gton'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
  • W is selected from the group consisting of
  • a 1 is O or S
  • a 2 is N or CH, with the proviso that if Ai is O, A ⁇ is N; n is between 3 and 5;
  • the ring containing Z is a 5, 6, or 7-membered heterocyclic or heteroaryl ring containing 1-3 heteroatoms independently selected from the group consisting of O, N and S;
  • R 1 at each occurrence is independently selected from H 1 optionally substituted Cn-C 8 alkyl, optionally substituted C 1 -C 5 alkoxy, halo, SO 2 N(R 6 J 2 , N(R 6 )SO 2 N(Ra) 2 , SO 2 R e ,
  • CONHSO 2 Re CONHSO 2 (NRe) 2 , optionally substituted 3-10-membered heteroCycloalkyl, optionally substituted C 3 -C 10 cycloaikyl, cyano, optionally substituted 5- 10-membered heteroaryl, COR S , CO 2 R 6 , N(R 6 J 2 , NR 6 COR 6 , C0N(R 9 ) 2 , and CONCO(R 6 ) 2 ;
  • R ⁇ at each occurrence is independently selected from H, optionally substituted CI-C B alkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted Ce-C 1 Q aryl, optionally substituted C 3 -C 10 cycloaikyl, and optionally substituted 3-10 membered heterocycloalkyl;
  • 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, hydrobrornide, hydraiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleste, fumarate, gluconate, saccharate, be ⁇ zoate, methanesulfonate, etha ⁇ esulfanate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1 ,1'-methylene- bis-(2-hydroxy-3- ⁇ aphthoate)]
  • 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, Le., 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 (eq., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alka ⁇ lammo ⁇ iurn and other base salts of pharmaceutically acceptable organic amines.
  • pharmacologically acceptable cations such as alkali metal cations (eq., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alka ⁇ lammo ⁇ iurn and other base salts of pharmaceutically acceptable organic amines.
  • the subject invention also includes jsotopically-Iabelied 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 that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C 1 14 C 1 15 N, 18 O 1 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • 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, Hunt ⁇ ngton's chorea, Pick's disease, Guill ⁇ an 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 iSGhemia and reperfusion injury, shock and hypertension, hyperlipidern ⁇ a, hypercholesterolemia, edema, obesity; nephritis, graft rejection, and inflammatory conditions generally including without limitation, osteoarthritis, ischemia, iung inflammation and rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of a compound(s) of the present invention.
  • a medical condition selected from the group consisting of Alzheimer's disease, multiple
  • Exemplary conditions that may be treated by the compound of the invention are Alzheimer's disease, multiple sclerosis, Huntingto ⁇ 's chorea, Pick's disease, Guillian Barre syndrome, encephalitis, meningitis, stroke, and hemorrhagic stroke.
  • 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 cornpound(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 compou ⁇ d(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 “subjecf 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 alkyny! 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, alkenyi 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 Ce-C 30 aromatic hydrocarbon may be substituted by one or more subst ⁇ tuents 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.
  • aryl group as used herein, unless otherwise indicated, includes an organic radical derived from a monocyclic or bicylic (C 6 -C 1D ) aromatic hydrocarbon compound by removal of a hydrogen radical from a ring carbon of the aryl compound.
  • 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 1 Q) 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 substitue ⁇ ts, and perferabiy the number of subsfrtuents is between 0 and 3, more preferably between o and 2. It will be appreciated that the preferred number of substituents is determined in part by facility of synthesis.
  • aryl groups are phenyl and naphthyl
  • a heteroaryl group may be substituted by one or more substitue ⁇ ts wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substituents, and perferabiy 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, th ⁇ enyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrralyl, triazolyl, tetrazolyl, ⁇ rnidazolyl, 1 ,3,5-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1 ,3,5-thiadiazolyl, 1 ,2,3-thiadiazolyi, 1 ,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyi, 1 ,3,5-triazinyi, pyrazoio[3,4-b]pyridinyl, cin ⁇ olinyl, pterld ⁇ nyl, purinyl; 6,7
  • a cycloalkyi group may be substituted by one or more substituents wherein, unless otherwise indicated, selection of each substituent is independent of selection of any other substitue ⁇ ts, and perferabiy 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 fadlity of synthesis.
  • cycloalkyi groups include cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclope ⁇ tenyl, cyclohexe ⁇ yl, cyclohepte ⁇ yl, 1,3- cyclobutadienyl, 1 ,3-cydopentadienyl, 1 ,3-cyclohexadienyl, 1,4-cydohexadie ⁇ yl, 1,3- cycloheptadienyl, 1,4-cycIoheptadienyl, 1,3,5-cycloheptatrie ⁇ yl, bicyclo[3.2.1]octane, bicyclo [2.2.1] heptane, and the norborn-2-e ⁇ e unsaturated form thereof.
  • cycloalkyi also includes cycloalkenyl
  • 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 substitue ⁇ ts, 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.
  • Representative heter ⁇ cycloatkyl groups include pyrrolidinyi, tetrahydr ⁇ furanyl, dihydrofuranyl, tetrahydropyranyl, pyra ⁇ yl, thiopyranyl, azir ⁇ dinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, ⁇ sothiazoi ⁇ dinyl, 1 ,3-thiazolidin-3-yI, 1 ,2-pyrazo!idi ⁇ -2-yl, 1,3-pyrazolidin-l-yl, piperidinyl, thiomorpholi ⁇ yl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyi, mo ⁇ holinyl, 1,2-tetrahydrod ⁇ azin ⁇ 2-yl, 1,3-tetra
  • alkyl In connection with the terms “alkyl”, “aryl”, “heteroaryl”, “cycloalkyr 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 1 -C 6 )aIkOXy-, (C 1 -C 6 )acyIoxy-, (C1-C 6 )a!kyiamino-, ((C 1 -C 6 )alky)l 2 amino-, (C 1 - C 6 )acylam ⁇ o-, cyano, nitro, (C 1 C 6 )alkyl-, (C 2 -C 6 )alkenyl-, (C 2 -C 6 )alkynyI-, cyano(C1-C6)alkyl-, trifluoromethyl(C 1 C 6 )alkyl-, ⁇ itro(C 1 C 6 )alkyl- , (C 1 -C 3 )alkyl(mo ⁇ ofliuoroa[kylene)(CrC 3 )alkyl-, (C 1
  • Y 1 , Y 2 , Y 3 , Y 4 are each CH.
  • R 1 is selected from H, optionally substituted C 1 -C 6 alkyl, CO 2 -optionally substituted C 1 -C 6 alkyl, halo, amino, CHO 1 CO-optionally substituted Ci-C 6 alkyl. and cyano.
  • R 1 is a 5-10 membered heteroaryl selected from the group consisting of tetrazolyl, oxadiazolyl optionally substituted withOH, and pyrrolyl optionally substituted with one or two CrC ⁇ alkyl.
  • Y 9 is CR 1 , CHR 1 , N or NR 1 ; Y 10 is C or CH; and Y 11 is NR 1 , N, or S.
  • the dotted bonds indicate that the bond between Y 5 and Y 6, Y 7 and Y 8, and Y 6 and Y 7 , respectively, may be independently single or double.
  • the dotted bonds indicate that the bond between Y 10 and Y 11 , and Y 9 and Y 10 , respectively, may be independently single or double.
  • Y 5 is a divalent group such as CHR 1
  • the bond to Y 8 is a single bond; if it is a trivale ⁇ t group such CR 1 , the bond to Y B is a double bond.
  • At least one R 1 is H.
  • group (A) is selected from the group consisting of
  • R 2 and R 3 are selected independently from H, optionally substituted C 1 -C 5 alkyl, trifiuoromethyl, CO-optio ⁇ ally substituted C 1 -C 6 alkyl, and COa-optionally substituted C 1 -C B alkyl.
  • R 1 at each occurrence is independently selected from preferably optionally substituted C 1 -C 8 alkyl, preferably optionally substituted C 1 -C 6 alkoxy, preferably optionally substituted 3-10-membered heterocycioalkyl, preferably optionally substituted C 3 -C 10 cycloalkyl, and preferably optionally substituted 5- 10-membered heteroaryl.
  • R ⁇ at each occurrence is independently selected from preferably optionally substituted C 1 -C 6 alkyl, preferably optionally substituted 5- 10 membered heteroaryl, preferably optionally substituted C 6 -C 10 aryl, preferably optionally substituted C 3 -C 10 cycloalkyl, and preferably optionally substituted 3-10 membered heterocycioalkyl.
  • R 2 and R s are selected independently from preferably optionally substituted CrC 6 alKyl.
  • Ci-C 3 alkenyl preferably optionally substituted C 3 -C 10 cycloalkyl, CO- preferably optionally substituted C 1 -C 5 alkyl, CO 2- preferably optionally substituted C 1 -C 8 alkyl, preferably optionally substituted C 1 - C 6 alkoxy, and preferably optionally substituted C r C 6 alkylthio.
  • Exemplary compounds according to the invention include
  • Pure stereochemical ⁇ isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures, For example, d ⁇ astere ⁇ isomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods.
  • E ⁇ antiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastere ⁇ meric 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 e ⁇ antiomers.
  • Diastereomers and enantiomers may alternatively be separated from mixtures using chiral high pressure liquid chromatographic techniques known to one skilled in the art.
  • Pure stereochemically isomeric forms of the compounds of Formula (I) 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 Formula (I) 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 ⁇ ot 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.
  • Gertai ⁇ 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 reacta ⁇ ts can be modified when the resulting products are formed.
  • Compounds of the invention can be prepared using a variety of methods as outlined below in Schemes 1-3. As shown in Scheme 1, a compound of general Formula I can be prepared by the reaction of a compound with the genera!
  • the resulting compounds of general formula I can be converted, according to methods well known in the art such as oxidation, reduction, catalyst coupling reaction, alkylation, amide formation, to another compound of general formula I.
  • a compound of general Formula I can also be prepared by method shown in Scheme 2.
  • Compounds of general formula B2 are commercially available or can be prepared by procedures that are well known to one of skilled in the art of organic chemistry.
  • Compounds of general formula C1 can be prepared by the reaction of 3 compound with the general formula A1 with a compound of general formula B2 in the presence of base such as NaHCO 3 , K 2 CO 3 , fBuOK, and Cs 2 CO 3 in solvents such 1,2-DCE, xylenes, C1-C6 alkyl alcohols, or mixtures thereof, at temperatures ranging from ambient to the boiling point of said mixtures.
  • a compound of general formula C1 can be reacted with a pyrazoloboronic acid or pyrazoloboronic ester compound of general formula D1 in the presence of a catalyst suGh as PdCI 2 (dppf>CH 2 CI 2 in the presence of a ligand such as 1,1 '-bis(diphenylphosphino)ferrocene (dppf) and an inorganic base such as K 3 PO 4 in a solvent such as THF or dioxane at temperatures ranging from ambient to the boiling point of said solvents.
  • the resulting compounds of general formula I can be converted, according to methods well known in the art such as oxidation, reduction, catalyst coupling reaction, aikylation, amide formation, etc. to another compound of general formula I.
  • Scheme 3 outlines the method of preparation of compounds of general formula B1.
  • An acetophenone compound of genera! formula E1 is treated with a base such as fBuOK in a solvent such as THF or MTBE at temperatures ranging from -20 °C to ambient temperature followed by the addition of an ester.
  • the said mixture is continued stirring at temperatures ranging from 0 0 C to ambient temperature for reaction times ranging from 2-24 hours.
  • the resulting 1 ,3-diketones of general formula F1 are treated with hydrazine hydrate to form a pyrazole ring.
  • the pyrazole ring of compounds of general formula G1 can be N-alkylated by treatment with an alkylating agent such as (C1-C ⁇ alkyl) halide, (C1-C6 alkyl) tosyiate, (C1- C6 alkyl) mesylate, and dimethyl sulfate in the presence or absence of a base such as trialkylamine, alkoxides, and K 2 CO 3 in a solvent such as THF, toluene, MTBE, and CH 2 CI 2 at temperatures ranging from ambient temperature to the boiling point of said mixtures to provide a compound of general formula H1, which may generate along with the other N- aikylated regio ⁇ somer.
  • an alkylating agent such as (C1-C ⁇ alkyl) halide, (C1-C6 alkyl) tosyiate, (C1- C6 alkyl) mesylate, and dimethyl sulfate in the presence or absence of
  • a compound of general formula H1 can be converted to compounds of general formula B1 using a variety of methods known to one skilled in the art of organic chemistry.
  • One such method is shown below in Scheme 3 where compounds of general formula H1 are treated with an alkyilithium reagent such as ⁇ BuL ⁇ , .BuLi, and 5BuLi in a solvent such as THF 1 MTBE, toluene, and combinations thereof, at temperatures below 0 "C with subsequent addition of an acylating agent such as 2-chloro-N-methoxy-N- methylacetamide, 2-bromo-N-methoxy-N-methylacetamide, and N-methoxy-N- methylacetam ⁇ de.
  • Compounds of general formula B1 where X is H can be treated with a brominati ⁇ g or chlorinating agent such as N-chlorosuccinamide, N-bromosuccinamide, and bromine in a solvent such as THF, MTBE, ether, and CH 2 Ci 2 at temperatures ranging from ambient temperature to the boiling point of said mixtures to provide compounds of general formula B1 where X is chloro or bromo.
  • a brominati ⁇ g or chlorinating agent such as N-chlorosuccinamide, N-bromosuccinamide, and bromine
  • a solvent such as THF, MTBE, ether, and CH 2 Ci 2
  • compositions comprising substantially enriched enantiomeric forms of the compou ⁇ d(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-pyro ⁇ enic, 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 cornpound(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.
  • 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) and L- ⁇ -ph ⁇ sphatidyichoii ⁇ e (PC).
  • DPPC 1,2-dipalmitoylphosphatidylcholine
  • PC L- ⁇ -ph ⁇ sphatidyichoii ⁇ e
  • a composition of this invention may further contain one or more adjuvant substances, such as fillers, thickening agents or the IiKe.
  • 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-
  • the pharmaceutical 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 solubilizi ⁇ g 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 solubilizi ⁇ g 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 administered 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 soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, ms ⁇ nitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydro
  • 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, oieate, 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
  • oieate 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, diethylamine, ethylenediamine, ethanolamine, diethgnolamine, piperazine and the like (see, for example, Berge et al., supra).
  • 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 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 myelins loss (demyelinatio ⁇ ).
  • Myelin provides the axo ⁇ a! "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 myel in-producing cell in the PNS is the Schwann cell.
  • Diseases characterized by demyelination occur both in the CNS and the PNS. Accordingly, 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.
  • 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 ⁇ eurites.
  • 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., Help, CE. et al., 1989.
  • 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
  • Another aspect of the present invention is a method for treating Pick's disease (PD) comprising administering to a patient a therapeutically effective amount of a com ⁇ ound(s) of the present invention.
  • 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 disease. (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 compou ⁇ d(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 ceil infiltration into the iung 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 analphylatoxi ⁇ .
  • Other Complement mediated pulmonary disorders include hypersensitivity pneumonites, and anaphylaxis. (See Regal, J., (1997), Immunopharrnacoiogy, 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.
  • Upton et aL in U.S. Patent No. 6,503,947 discloses attenuation of cerebral ischemia and reperfus ⁇ on 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 ⁇ glkg and about 50.0 mg/kg body weight per day, preferably between about 1.0 jwg/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 rng 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.
  • Pharmaceutically acceptable salts of the compounds 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/suiphate, borate, camsylate, citrate, cyclamate, edisylate, esylat ⁇ , formate, fumarate, gluceptate, gluconate, glucur ⁇ ate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, maionate, mesylate, methylsulphate, naphthylate, 2- ⁇ apsyIate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethyiamine, diolamine, glycine, lysine, magnesium, meglumine, oiamine, potassium, sodium, tromethamine and zinc salts. H ⁇ misalts of acids and bases may also be formed, for example, hemisuiphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts:
  • compositions of formula I may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • 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 ('melting point').
  • 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, etha ⁇ ol.
  • 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. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In 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. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/sumble content will be dependent on humidity and drying conditions. In such cases, non-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.
  • 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 Commu ⁇ , .17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004).
  • 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).
  • Mesomorphi ⁇ m 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 1 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, Higuch ⁇ and W. Stella) and Bioreversible Carriers in Drug Design. P ⁇ rgamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs iri 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: (i) where the compound of formula I contains a carboxylic acid functionality (-
  • 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 formuia I is/are replaced by (C 1 -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.
  • Some examples of metabolites in accordance with the invention include:
  • Compounds of formula 1 containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula 1 contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism Otautomerism') can occur.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • racemate or the racemate of a sait or derivative
  • HPLC high pressure liquid chromatography
  • the racemate or a racemic precursor
  • 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-phenylethylami ⁇ e 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 ena ⁇ tiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in e ⁇ a ⁇ tiomerically-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 alkylami ⁇ , typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • 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 alkylami ⁇ , typically 0.1% diethylamine.
  • 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 ⁇ nantiomer.
  • 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
  • the present invention includes all pharmaceutically acceptable isot ⁇ pically-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 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 1B O, phosphorus, such as 32 P, and sutphur, such as 33 S.
  • isotop ⁇ cally-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 isotopicaHy substituted, e.g. D 2 O, d ⁇ -acetone, d ⁇ - DMSO.
  • the compounds of formula I should be assessed for their biopharmaceut ⁇ cal properties, such as solubility and solution stability (across pH), permeability, etc., m " 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. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof).
  • 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).
  • 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 hydroxypropyir ⁇ ethylcellulose) 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, H (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
  • dis ⁇ ntegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl celiulose, croscarmellose sodium, crospovido ⁇ e, polyvinylpyrrolidone, methyl cellulose, m ⁇ cracrystalline 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 Gohesive qualities to a tablet formulation. Suitable binders include microcrystalli ⁇ e 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
  • 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 contaln 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 antioxidants, colourants, flavouring agents, preservatives and taste-masKing agents.
  • Tablets contain up to about 80% drug, from about 1 o weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disi ⁇ tegrant, 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 Dosa ⁇ e Forms: Tablets.
  • Consumable oral films for human or veterinary use are typically pliable water-soluble or water-sweliable 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 hydracolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • 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, intrasternal, 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 steriie 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(di-lactic- coglycolic)acid (PGLA) microspheres.
  • PGLA poly(di-lactic- coglycolic)acid
  • the compounds of the invention may also be administered topically, (i ⁇ tra)dermally, or tr ⁇ ansdermally to the skin or mucosa.
  • Typical formulations for this purpose tio 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 Fi ⁇ nin and Morgan (October 1999).
  • Topical administration may also be achieved using a patch, such as a transdemal jontophoretic 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 intra ⁇ asally 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 i ⁇ haier, 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 propella ⁇ t, 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, chitosa ⁇ 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 etha ⁇ ol, or a suitable alternative agent for dispersing, solubilisi ⁇ g, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligoiactic 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 homogenisatio ⁇ , or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethyicellulose
  • 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-ieucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextra ⁇ , 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 Vg to 20mg of the compound of the invention per actuation and the actuation volume may vary from "I ⁇ l to 100//),
  • 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/i ⁇ tranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified controlled release using, for example, PGL-A
  • Controlled release formulations include Modified release formulations include delayed-, sustained-, pulsed-, controlled-, or tragettedtargeted 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 cyclod ⁇ xtrin 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 solubiiiser.
  • 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.
  • 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.
  • the HCI salt was formed in CH 2 Cl 2 by addition of a solution of aq. HCI in Et 2 O, concentration, and trituration with EtOAc.
  • the Parr bottle was purged with N 2 and then filtered through a plug of celite and rinsing with CH 2 Cl 2 and followed by a mixture of 25% MeOH in CH 2 CI 2 .
  • the filtrate was concentrated and the resulting solid was purified by chromatography (preabsorbed to silica gel, eluted with a gradient of 2.5-10% MeOH in CH 2 CI 2 ) to provide 572.8 mg of ⁇ 2-[4-(1-methyl-5- trifluoromethyI-iH-pyrazoI-3-yI)-phenyl]-5,6,7,8-tetrahydro-imida2 ⁇ t1,2-a]pyridin-6-yl ⁇ - methanol as a pale-yellow solid.
  • the tosylate salt was formed using the general procedure.
  • EtOAc/EtOH 200 mL was placed in a Parr shaker under a H 2 atmosphere (50 psi) at rt for 3 h.
  • the Parr bottle was purged with N 2 , additional 10% Pd on carbon (200 mg) was added, and the Parr bottle was placed back under H 2 atmosphere (50 psi).
  • the reaction mixture was purged with N 2 and filtered through a plug of celite, which was rinsed with 1:1 CH 2 Cl 2 /MeOH. The filtrate was concentrated and then redissolved in CH 2 CI 2 /MeOH and filtered to remove insoluble material.
  • the tosylate salt was formed using the general procedure to provide 74,5 mg of 2-[4-(1-methyl-5-trifluoromethyl-1H- pyrazol-3-yl)-phenyl]-S,6,7,8 ⁇ tetrahydro-irnidazo[1,2-b]pyridaz ⁇ ne toluene sulfonic acid salt as a white solid.
  • Example 13 2-[4-(1 -Methyl-5-trifluoromethyl-1 H-Pyrazol-3-vl-phenyl]-imidazoH .2-alpyridine-6- carbaldehyde
  • ⁇ 2-[4-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-imidazo[1,2- a]pyrid ⁇ n-6-yl ⁇ -metha ⁇ ol (105.2 mg, 0.2825 mmol) in CH 2 CI 2 (10.0 mL) at rt was added Dess- Marti ⁇ per ⁇ odina ⁇ e (150 mg, 0.353 mmol).
  • Example 15 1 -f2-r4-(1 -Methyl-5-trif luoromethyl-1 H-PVrazol-3-yl)-phenvn-5.6.7,8-tetrahydro- imidazori.2-alpyridin-6-yl)etha ⁇ o]
  • the starting material for this procedure was a portion (600 mg) of the impure orange solid that was isolated from the chromatography in the preparation of ⁇ 2-[4-(1-methyl-5- trifluoromethyl-IH-pyrazol-S-yO-phenylJ-imidazofi ⁇ -aJpyr ⁇ clin ⁇ -ylJ-methanol.
  • This material was slurried in CH 2 CI 2 (40 mL) at rt and Dess-Martin periodtnane (854 mg, 2.01 mmol) was added. After 55 min, additional Dess-Martin periodinane (300 rng, 0.707 mmol) was added.
  • reaction mixture was stirred at rtfor another 40 min and then poured into 1 M NaOH (150 mL) and extracted with CH 2 CI 2 (3 x 75 mL). The combined extracts were dried (Na 2 SO 4 ), filtered and cone The resulting solid was dissolved in THF (40 mL) at 0 0 C and MeMgBr (4.0 mL of a 1.4 M solution in 3:1 toluene/THF, 5.638 mmol) was added. After 45 min the reaction mixture was poured into sat. NaHCO 3 (150 mL) and extracted with CH 2 Cl 2 (3 x 75 mL).
  • Example 26 2-[4-( 1 -Methyl-5-trifluoromethyl-1 H-pyrazol-3-yl)-phenyl]-imidazo[1.,2-alpyridin-6- ylamine bis-p-toluenesulfonic acid salt
  • 6-(2,5-dimethyl-pyrrol-l-yi)-2-[4-(1-methyl-5-trifluoromethyl-iH- pyrazol-3-yl)-phenyl]-imidazo[1,2-a]pyr ⁇ dine (4.696 g, 10.78 mrn ⁇ l) in EtOH (200 mL) was added hydrazine hydrate (10 mL) and cone. HCI (20 mL). The mixture was heated at reflux for 2 d, cooled, poured into 1 M NaOH (400 mL) and H2O (200 mL), and extracted with
  • Example 27 6-(2.5-Dimethyl-pyrrol-1 -vl)-2-[4-(1 -methyl-5-trif luorornethyl-1 H-pyrazol-3-yl)-phenv ⁇ - imidazo ⁇ 1.2-alpyridine
  • the isolated solid (300 mg) was dissolved in 250 mL EtOH with 12 M HCl (0.10 mL) in a Parr bottle.
  • the bottle was placed under a N 2 atmosphere, charged with 10% Pd/C (350 mg), and then place under an H 2 atmosphere (50 psi) at rt on a Parr shaker for 2 h.
  • the bottle was purged with N 2 and additional 12 M HCI (0.10 mL) and 10% Pd/C (1.0 g) were added.
  • the bottle was placed back under an H ⁇ atmosphere (50 psi) for 20 h and then purged with N 2 -
  • the mixture was diluted with CH 2 CI 2 (200 mL), filtered through a plug of celite, and concentrated to provide 310 mg of C- ⁇ 2-[4-(1-r ⁇ ethyl-5-trifiuoromethyl-1H- ⁇ yrazol- 3-yl)-phenyl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridi ⁇ -6-yl ⁇ -methylamine as the bis-HCI salt as a pale yellow solid.
  • the HCI salt was free based by partitioning between 1 M NaOH and CH 2 CI 2 .
  • Example 36 l3-n/lethyl-5-f4-f1-methyl-5-trifluoromethv>-iH- ⁇ yrazol-3-.yl)-phenylT-3H-imidazofl2» biri.2.4Ttriazol-Z-yl ⁇ -metha ⁇ ol p-toluenesulf ⁇ ic acid satt
  • 5-benzyloxymethyl-4-methyl-4H-[1 ,2,43triazol-3-y ⁇ amine (1.76 g, 8.06 mmol) in /-propanol (60 mL) and 1,2-DCE (30 mL) was added 2-brom ⁇ -i-[4-(1-methyl-5- trfflu ⁇ romethvi-1 H-pyrazol-3-yl)-phenyl]-ethanone (3.36 g, 9.68 mmol).
  • the mixture was dried (Na 2 SO 4 ), filtered, concentrated, and chromatographed (preadsorbed to silica; eluted with a gradient of 0-10% MeOH in CH 2 CI 2 ) to provide a mixture of regioisomers (23.6 mg), which were separated by HPLC (Chiralpak AD column; 75/25 hepta ⁇ e//PrOH) and identified structurally by NMR NOe experiments.
  • the reaction mixture was degassed with a stream of nitrogen bubbles, and then paltadium(dppf) (60 mg, 10 mol%) was added and heated to reflux for 16 h.
  • the reaction was cooled to rt, concentrated and purified sequentially on silica gel utilizing a methanol/ chloroform gradient as elue ⁇ t and then on reverse phase silica gel utilizing a methanol/water gradient as eluent.
  • the resultant oil was dissolved in a minimum amount of ethanol, treated with a few drops of concentrated aqueous HCl and then concentrated to dryness, mp 190-191 0 C.
  • PREPARATIONS General procedure fortosylate salt formation: To a solution of free base (1 mmol) in EtOAc (15 mL) at rt was added p-TsOH » H 2 O (1 mmol for monobasic compounds and 2 mmol for dibasic compounds). The mixture was stirred for 1 - 24 h, filtered and rinsed with EtOAc to provide the tosylate salt as a solid.
  • the aqueous layer was acidified to pH 3-4 with 6M aq HCl and then extracted with EtOAc (3 x 500 mL). The extracts were combined, dried (Na 2 SO 4 ), filtered and concentrated. The resulting yellow oil was concentrated from toluene and then dissolved in toluene (500 mL), Hydrazine hydrate (50 mL) was added over 5 min and the resulting solution was heated at 95 0 C for 14 h. The mixture was cooled and concentrated. The yellow/orange solid was purified by stirring in hot hexanes (300 mL).
  • the resulting black oil was triturated with benzene/Et 2 O to provide 36.6 g of white solid.
  • the solid (36.5 g) was suspended in CH 2 CI 2 (719 mL) and cooled to -5 *C.
  • Et 3 N 47.4 g, 0.468 mol
  • frifluoromethanesulfo ⁇ ic anhydride 132.1 g, 0.468 mo!
  • the reaction mixture was warmed to rt, stirred for 1 h, and poured into H ⁇ O (600 mL).
  • the CH 2 CI 2 layer was separated and the aqueous layer was extracted with CH 2 CI 2 (2 x).
  • N-(6-chloro-pyridazin-3-yl)-2,2-dimethyl-propionamide (Turck. Alain; PIe, Nelly; Ndzi, Bruno; Queguiner, Guy; Haider, Norbert Schuller, Herbert; Heinisch, Gottfried. Tetrahedron. 1993, 49, 599-606.) (500 mg, 2.34 mmol), Pd(PPh 3 ) 4 (811 mg, 0.701 mmol), and Zn(CN) 2 (192 mg, 1.64 mmol) and placed under a nitrogen atmosphere. DMF (25 mL) was added to the flask and the reaction mixture was heated at 100 o C for 2.5 h.
  • N-(6-chloro-pyridazin-3-yl)-2,2-dimethyl-propionamide (Turck. Alain; PIe, Nelly; Ndzi, Bruno; Queguiner, Guy; Haider, Norbert Schuller, Herbert; Heinisch, Gottfried. Tetrahedron
  • the present assay utilizes 125 I labeled human C3a peptide (50 pM, New England Nuclear) with detection of binding to a human B-cell line (L1.2) that has been stably transfected with a human C3a receptor construct.
  • the C3aR tra ⁇ sfected cell line was generated in the laboratory of Dr. Craig Gerard (Harvard Univ.)-
  • 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) polyethyle ⁇ imine (PEI, Sigma; P3143) for 60 min. Air dry overnight. Store until used- Hot Cocktail: 0.2 ⁇ M stock 125 l-C3a (NEN; NEX-356) in L.

Abstract

L'invention porte sur des composés imidazo[4,5-c] pyridine à substitution aryle. Ces composés sont utiles dans des compositions pharmaceutiques comme antagonistes du C3a pour traiter différentes affections médicales associées à la cascade du complément. L'invention porte également sur des méthodes de traitement correspondantes.
PCT/IB2006/002561 2005-09-19 2006-09-18 Antagonistes du recepteur du c3a WO2007034278A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US71845105P 2005-09-19 2005-09-19
US60/718,451 2005-09-19

Publications (2)

Publication Number Publication Date
WO2007034278A2 true WO2007034278A2 (fr) 2007-03-29
WO2007034278A3 WO2007034278A3 (fr) 2007-05-18

Family

ID=37779396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/002561 WO2007034278A2 (fr) 2005-09-19 2006-09-18 Antagonistes du recepteur du c3a

Country Status (1)

Country Link
WO (1) WO2007034278A2 (fr)

Cited By (10)

* 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
WO2009059162A1 (fr) * 2007-11-02 2009-05-07 Hutchison Medipharma Enterprises Limited Inhibiteurs de la cytokine
US8022075B2 (en) * 2005-11-30 2011-09-20 Fujifilm Ri Pharma Co., Ltd. Diagnostic and remedy for disease caused by amyloid aggregation and/or deposition
WO2011137587A1 (fr) * 2010-05-06 2011-11-10 Hutchison Medipharma Limited Inhibiteurs de cytokines
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
WO2014172190A1 (fr) 2013-04-15 2014-10-23 E. I. Du Pont De Nemours And Company Amides fongicides
US8946234B2 (en) 2008-11-05 2015-02-03 Bayer Cropscience Ag Halogen-substituted compounds
WO2016191811A1 (fr) 2015-06-03 2016-12-08 The University Of Queensland Agents mobilisateurs et leurs utilisations
CN115745848A (zh) * 2022-12-07 2023-03-07 上海优合生物科技有限公司 一种氨基胍的加工合成工艺

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001030778A1 (fr) * 1999-10-27 2001-05-03 Novartis Ag Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique
EP1104762A1 (fr) * 1998-08-03 2001-06-06 Laboratorios S.A.L.V.A.T., S.A. Imidazo 1,2a]azines substituees servant d'inhibiteurs selectifs de la cox-2
WO2001057038A1 (fr) * 2000-02-01 2001-08-09 Basf Aktiengesellschaft Composes heterocycliques et leur utilisation comme inhibiteurs de parp
WO2003051890A1 (fr) * 2001-12-14 2003-06-26 Aegera Therapeutics Inc. Imidazo [2,1-b]-1,3,4-thiadiazole sulfonamides
WO2004111061A1 (fr) * 2003-06-13 2004-12-23 Aegera Therapeutics Inc. Imidazo[2,1-b]-1,3,4,-thiadiazole-2-sulfonamides acyles et non acyles, et utilisations associees
WO2004111060A1 (fr) * 2003-06-13 2004-12-23 Aegera Therapeutics Inc. Imidazo[2,1-b]-1,3,4-thiadiazole sulfoxydes et sulfones

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1104762A1 (fr) * 1998-08-03 2001-06-06 Laboratorios S.A.L.V.A.T., S.A. Imidazo 1,2a]azines substituees servant d'inhibiteurs selectifs de la cox-2
WO2001030778A1 (fr) * 1999-10-27 2001-05-03 Novartis Ag Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique
WO2001057038A1 (fr) * 2000-02-01 2001-08-09 Basf Aktiengesellschaft Composes heterocycliques et leur utilisation comme inhibiteurs de parp
WO2003051890A1 (fr) * 2001-12-14 2003-06-26 Aegera Therapeutics Inc. Imidazo [2,1-b]-1,3,4-thiadiazole sulfonamides
WO2004111061A1 (fr) * 2003-06-13 2004-12-23 Aegera Therapeutics Inc. Imidazo[2,1-b]-1,3,4,-thiadiazole-2-sulfonamides acyles et non acyles, et utilisations associees
WO2004111060A1 (fr) * 2003-06-13 2004-12-23 Aegera Therapeutics Inc. Imidazo[2,1-b]-1,3,4-thiadiazole sulfoxydes et sulfones

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8022075B2 (en) * 2005-11-30 2011-09-20 Fujifilm Ri Pharma Co., Ltd. Diagnostic and remedy for disease caused by amyloid aggregation and/or deposition
WO2008030579A3 (fr) * 2006-09-07 2009-02-26 Biogen Idec Inc Modulateurs de la kinase associée au récepteur de l'interleukine-1
WO2008030579A2 (fr) * 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Modulateurs de la kinase associée au récepteur de l'interleukine-1
RU2485113C2 (ru) * 2007-11-02 2013-06-20 Хатчисон Медифарма Энтерпрайзис Ингибиторы цитокинов
WO2009059162A1 (fr) * 2007-11-02 2009-05-07 Hutchison Medipharma Enterprises Limited Inhibiteurs de la cytokine
US7868001B2 (en) 2007-11-02 2011-01-11 Hutchison Medipharma Enterprises Limited Cytokine inhibitors
JP2011502996A (ja) * 2007-11-02 2011-01-27 ハッチソン メディファーマ エンタープライジズ リミテッド サイトカインインヒビター
TWI419692B (zh) * 2007-11-02 2013-12-21 Hutchison Medipharma Entpr Ltd 細胞激素抑制劑
US8946234B2 (en) 2008-11-05 2015-02-03 Bayer Cropscience Ag Halogen-substituted compounds
US20130065884A1 (en) * 2010-03-18 2013-03-14 Zaesung No Anti-Infective Compounds
US8865734B2 (en) * 2010-03-18 2014-10-21 Institut Pasteur Korea Anti-infective compounds
WO2011137587A1 (fr) * 2010-05-06 2011-11-10 Hutchison Medipharma Limited Inhibiteurs de cytokines
WO2012178083A1 (fr) 2011-06-22 2012-12-27 Apellis Pharmaceuticals, Inc. Méthodes de traitement de troubles chroniques au moyen d'inhibiteurs de complément
EP3524258A1 (fr) 2011-06-22 2019-08-14 Apellis Pharmaceuticals, Inc. Méthodes de traitement de troubles chroniques au moyen d'inhibiteurs de complément
WO2014172190A1 (fr) 2013-04-15 2014-10-23 E. I. Du Pont De Nemours And Company Amides fongicides
WO2016191811A1 (fr) 2015-06-03 2016-12-08 The University Of Queensland Agents mobilisateurs et leurs utilisations
CN115745848A (zh) * 2022-12-07 2023-03-07 上海优合生物科技有限公司 一种氨基胍的加工合成工艺

Also Published As

Publication number Publication date
WO2007034278A3 (fr) 2007-05-18

Similar Documents

Publication Publication Date Title
US10016406B2 (en) Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof
WO2007034278A2 (fr) Antagonistes du recepteur du c3a
WO2007034282A2 (fr) Composes de biphenylimidazole utilises comme antagonistes du recepteur du c3a
TWI458723B (zh) １，２－雙取代雜環化合物
US8450340B2 (en) 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof
WO2007034279A2 (fr) Antagonistes de c3a et leurs compositions pharmaceutiques
JP2024045225A (ja) 複素環式化合物、中間体、その製造方法及び応用
US20060111416A1 (en) Octahydropyrrolo[3,4-C]pyrrole derivatives
WO2007034277A1 (fr) Composés de type imidazo[4,5-c]pyridine arylsubstitués en tant qu'antagonistes du récepteur c3a
EP2993169B1 (fr) Dérivés de l'arylpyridine comme inhibiteurs de l'aldosterone synthase
EP2943198A2 (fr) Inhibiteurs de 3-(benzoimidazol-2-yl)-indazole de la voie de signalisation par wnt et leurs utilisations thérapeutiques
AU2019228568A1 (en) Piperidinyl-3-(aryloxy)propanamides and propanoates
CA2897469A1 (fr) Derives de pyridine comme modulateurs allosteriques positifs de recepteur muscarinique m1
JP2008520644A (ja) オクタヒドロピロロ［３，４−ｃ］ピロール誘導体
KR20160050080A (ko) 트라이아졸로피리딘 화합물, 이의 조성물 및 사용 방법
CA3150508A1 (fr) Derives de pyridazin-3(2h)-one fusionnes par un azole
JP6496246B2 (ja) アルドステロンシンターゼインヒビター関連用途としてのインドリン化合物
WO2007045989A1 (fr) Dérivés de pyridyle pouvant être employés en tant que ligands h3
TWI295926B (en) Triazolopyridinylsulfanyl derivatives as p38 map kinase inhibitors
JPH06510027A (ja) 血小板活性化因子拮抗剤
JP2007509127A (ja) ホスホジエステラーゼ−４阻害剤としてのアザベンゾジアゼピン
EP1671972A1 (fr) Dérivés d' octahydropyrrolo[3,4-c]pyrrole

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06808851

Country of ref document: EP

Kind code of ref document: A2