WO2006129100A1 - Nouveaux composes - Google Patents

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Publication number
WO2006129100A1
WO2006129100A1 PCT/GB2006/002015 GB2006002015W WO2006129100A1 WO 2006129100 A1 WO2006129100 A1 WO 2006129100A1 GB 2006002015 W GB2006002015 W GB 2006002015W WO 2006129100 A1 WO2006129100 A1 WO 2006129100A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
indazol
ring
compound
phenyl
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PCT/GB2006/002015
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English (en)
Inventor
Francis Louis Atkinson
Michael David Barker
Sebastien Andre Campos
Nigel James Parr
Vipulkumar Kantibhai Patel
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Glaxo Group Limited
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Publication date
Priority claimed from GB0511391A external-priority patent/GB0511391D0/en
Priority claimed from GB0610513A external-priority patent/GB0610513D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2006129100A1 publication Critical patent/WO2006129100A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel bis-anilinopyrimidine compounds which have activity against the spleen tyrosine kinase (Syk kinase), processes for their preparation, pharmaceutically acceptable formulations containing them and their use in therapy.
  • Syk kinase spleen tyrosine kinase
  • Allergic rhinitis and asthma are diseases associated with hypersensitivity reactions and inflammatory events involving a multitude of cell types including mast cells, eosinophils, T cells and dendritic cells.
  • high affinity immunoglobulin receptors for IgE (Fc ⁇ Rl) and IgG (Fc ⁇ RI) become cross-linked and activate downstream processes in mast cells and other cell types leading to the release of pro-inflammatory mediators and airway spasmogens.
  • IgE receptor cross-linking by allergen leads to release of mediators including histamine from pre-formed granules, as well as the synthesis and release of newly synthesised lipid mediators including prostaglandins and leukotrienes.
  • Syk kinase is a non-receptor linked tyrosine kinase which is important in transducing the downstream cellular signals associated with cross-linking Fc ⁇ Rl and or Fc ⁇ RI receptors, and is positioned early in the signalling cascade.
  • the early sequence of Fc ⁇ Rl signalling following allergen cross-linking of receptor-lgE complexes involves first Lyn (a Src family tyrosine kinase) and then Syk kinase.
  • Inhibitors of Syk kinase activity would therefore be expected to inhibit all downstream signalling cascades thereby alleviating the immediate allergic response and adverse events initiated by the release of pro-inflammatory mediators and spasmogens (Wong, B., Grossbard, E. B. Payan, D. G & Masuda, E. S. Expert Opin. Investig. Drugs (2004) 13 (7) 743-762).
  • Rheumatoid Arthritis is an auto-immune disease affecting approximately 1% of the population. It is characterised by inflammation of articular joints leading to debilitating destruction of bone and cartilage.
  • Recent clinical studies with Rituximab, which causes a reversible B cell depletion, (J. CW. Edwards et al 2004, New Eng. J. Med. 350: 2572-2581) have shown that targeting B cell function is an appropriate therapeutic strategy in auto-immune diseases such as RA.
  • Clinical benefit correlates with a reduction in auto-reactive antibodies (or Rheumatoid Factor) and these studies suggest that B cell function and indeed auto-antibody production are central to the ongoing pathology in the disease.
  • WO 03/057695 (Boehringer lngelheim Pharmaceuticals, Inc.) describes substituted [1 ,6]-naphthyridines that inhibit Syk kinase.
  • WO2003/063794, WO2004/014382, WO2005/012294 and WO2005/16893 describes a series of 2,4-pyrimidinediamaine compounds which inhibit Syk kinase, for use in treating autoimmune diseases.
  • WO2005/026158 (Novartis AG) describes 2,4-di (hetero)-arylamino-pyrimidine derivatives which have ZAP-70 and/or Syk inhibitory activities.
  • WO 04/035604 discloses the structural co-ordinates of the human Syk protein.
  • the present invention provides a compound of formula (I):
  • R 1 , R 2 and R 3 is each independently selected from hydrogen, halogen, hydroxy, -C 1-6 alkyl, -NR 5 R 6 , -C 1-6 alkylene-NR 5 R 6 , -CN, -C ⁇ alkylene-COaH, C(O)Ci -6 alkoxy, -C 1-2 alkyl substituted by 1 or more fluorine atoms), -C 1-6 alkoxy, -C(O)C 1-6 alkyl, - C(O)NR 5 R 6 , -C(O)NHR 7 , -OCH 2 C(O)NHR 8 , -OCH 2 C(O)OR 5 , -CH 2 C(O)NHR 8 , -NR 5 C(O)R 6 , -SC 1-6 alkyl, -S(O)C 1-6 alkyl, -S(O) 2 C 1-6 alkyl, -CH 2 S(O) 2 C 1-6 alkyl,
  • R 1 is hydrogen, halogen or C 1-6 alkyl and R 2 and R 3 are attached to adjacent carbon atoms of the phenyl ring and are joined and together to form, in combination with the carbon atoms on the phenyl group to which they are attached, a 5- or 6-membered heteroaryl or heterocyclic ring ; or
  • R 1 is hydrogen, halogen or C 1-6 alkyl and R 2 and R 3 are attached to adjacent carbon atoms of the phenyl ring and are joined together to form, in combination with the carbon atoms on the phenyl group to which they are attached, a 5- or 6-membered carbocyclic ring, and
  • R 7 is phenyl optionally substituted by halogen, C 1-6 alkyl
  • R 8 is hydrogen, C 1-6 alkyl optionally terminally substituted with hydroxy, 2-oxo-1- pyrrolidinyl or 2,5-dioxo-1-pyrrolidinyl, a 5- or 6-membered heteroaryl ring comprising 1 or 2 heteroatoms independently selected from O, N and S and optionally substituted on a ring carbon by C 1-6 alkyl, phenyl optionally substituted by halo, Crealkyl.
  • C 1-6 alkoxy or trifluoromethyl, or, together with the nitrogen to which it is attached is a C ⁇ alkyl ester of serine;
  • R 9 is Ci -6 alkyl or phenyl optionally substituted by C-,. 6 alkyl;
  • R 10 is Ci -6 alkoxy, Ci -6 alkyl optionally terminally substituted with hydroxyl, 2-oxo-1- pyrrolidinyl or 2,5-dioxo-1-pyrrolidinyl, or R 10 is a 5 or 6-membered heteroaryl ring comprising 1 heteroatom selected from O, N and S or 2 different heteroatoms independently selected from O, N and S and optionally substituted on one or more ring carbons by C 1-6 alkyl;
  • a salt or solvate preferably a pharmaceutically acceptable salt or solvate, thereof.
  • the present invention provides for a compound of formula (I) which is of the formula (Ia):
  • R 1 , R 2a and R 3a is each independently selected from the group of substituents Group A which comprises hydrogen, halogen, hydroxy, -C 1-6 alkyl, -NR 5 R 6 , -Ci. 6 alkylene-NR 5 R 6 , -CN, -Co -3 alkylene-C0 2 H, C(O)C 1-6 alkoxy, -Ci -2 alkyl substituted by 1 or more fluorine atoms, -C 1-6 alkoxy, -CCOJC L ⁇ alkyl, -C(O)NR 5 R 6 , -C(O)NHR 7 , -OCH 2 C(O)NHR 8 , -OCH 2 C(O)OR 5 , -CH 2 C(O)NHR 8 , -NR 5 C(O)R 6 , -SC 1- ⁇ alkyl, -S(O)C 1-6 alkyl, -S(O) 2 C 1-6 alkyl, -
  • R 5 and R 6 are is each independently hydrogen or C 1-6 alkyl
  • R 7 , R 8 , R 9 and R 10 are as hereinbefore defined for formula (I); or
  • a salt or solvate preferably a pharmaceutically acceptable salt or solvate, thereof.
  • Compounds of the present invention are useful as inhibitors of Syk and thus useful in treating diseases resulting from in appropriate mast cell activation, for instance allergic and inflammatory diseases.
  • two of R 1 , R 2 and R 3 are hydrogen.
  • representative values for substituents in Group A include: hydroxy, chloro, methyl, (1-methylethyl), -CONH 2 , -CONHCH 3 , -CONH(C 2 H 5 ), -CON(C 2 Hs) 2 , -CN, -CF 3 , methyloxy, (i-methylethyl)oxy, -CO 2 H, -CH 2 CO 2 H, - C(O)OCH3,-SO 2 NH 2 , and -SO 2 CH 3 .
  • R 1 and R 3 is each hydrogen and R 2 is R 4 .
  • R 1 and R 2 is each hydrogen and R 3 is R 4 .
  • R 4 include: benzimidazol-2-yl, tetrazol-5-yl ;
  • representative examples of the 5- or 6- membered saturated or unsaturated ring formed by R 2a and R 3a , fused with the phenyl ring include:
  • representative examples of the 5- or 6- membered saturated or unsaturated ring formed by R 2a and R 3a , fused with the phenyl ring, and including any substituents which may be present, include:
  • representative examples of the 5- or 6- membered saturated carbocyclic ring formed by R 2a and R 3a include:
  • R 5 and R 6 include: H, methyl, and ethyl.
  • R 7 include phenyl and 4- methyl phenyl.
  • R 8 include: hydrogen, 3- hydroxypropyl, 2,5-dioxo-1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, difluoromethyloxy, methyl serinate (including N);
  • Representative examples of compounds of formula (I) include:
  • heteroaryl includes single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • Representative heteroaryl rings comprise from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heteroaryl ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic includes non-aromatic single or fused rings comprising up to four hetero-atoms in the ring selected from oxygen, nitrogen and sulphur and optionally substituted with up to three substituents.
  • Representative heterocyclic rings comprise from 4 to 7, preferably 5 to 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • Examples of "-C 1-2 alkyl substituted by 1 or more fluorine atoms” include, but is not restricted to, -CF 3 .
  • references to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl. It will be appreciated that references to alkylene and alkoxy shall be interpreted similarly.
  • references to C 3-7 cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl.
  • carbocyclic refers to rings which may be saturated or unsaturated but which are not aromatic, may be branched, which contain 5-7 carbon atoms and which may be optionally substituted with up to three substituents.
  • substituents for such carbocyclic rings include those previously mentioned for heteroaryl and heterocyclic.
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and 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, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts of the compound of the present invention may be prepared.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects.
  • compositions may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts may be preferred over the respective free base or free acid because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form.
  • the compound of the present invention may contain one or more acidic functional groups.
  • suitable pharmaceutically acceptable salts include salts of such acidic functional groups.
  • Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically- acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • Compounds of the present invention are basic and accordingly generally capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids.
  • Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate ⁇ , acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate,
  • the term "compound” refers to one or more compounds.
  • a compound of the present invention refers to one or more compounds of the present invention.
  • the compound of the present invention may exist in solid or liquid form. In the solid state, the compound of the present invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymophs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the compound of the present invention may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereoisomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof.
  • the compound of the present invention containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compound of the present invention may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a centre of geometric asymmetry is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included the compound of the present invention whether such tautomers exist in equilibrium or predominately in one form.
  • the present invention provides a process for preparing a compound of formula (I), or a salt or solvate thereof, which process comprises:
  • Process (a) may be performed in the presence of a solvent (for example, aqueous acetone) and optionally in the presence of dilute acid such as hydrochloric acid at a suitable temperature, preferably in the range of 0-100° C.
  • a solvent for example, aqueous acetone
  • dilute acid such as hydrochloric acid
  • suitable temperature preferably in the range of 0-100° C.
  • suitable leaving groups (L 1 ) include, but are not restricted to, an alky!
  • alkyl and aryl sulfide an alkyl and aryl sulfinyl, an alkyl and aryl sulfonyl, a halide (such as chloride, bromide or iodide), and an alcohol derived leaving group (such as triflate, mesylate, methylsulfonate or tosylate).
  • a halide such as chloride, bromide or iodide
  • an alcohol derived leaving group such as triflate, mesylate, methylsulfonate or tosylate.
  • process (a) may be performed in the presence of a non-nucleophilic base such as triethylamine or diisopropylethylamine, as a melt, at a suitable temperature, preferably in the range of 0-180° C.
  • a non-nucleophilic base such as triethylamine or diisopropylethylamine
  • Process (b) may be performed under conditions analogous to those described for process (a) above. Suitable leaving groups for L 2 are also described above for L 1 .
  • Suitable amine protecting groups include, but are not restricted to, sulphonyl (such as tosyl), acyl (such as benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (such as benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate.
  • Suitable amine protecting groups include trifluoroacetyl (-C(O)CF 3 ), which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) which may be removed by acid catalysed hydrolysis (using, for example, trifluoroacetic acid).
  • a solid phase resin bound benzyl group such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) which may be removed by acid catalysed hydrolysis (using, for example, trifluoroacetic acid).
  • Compounds of formula (II) may be prepared according to a process comprising: (a) reacting a compound of formula (Vl):
  • L 1 and L 3 represent leaving groups, with a compound of formula (V) as defined above.
  • Process (b) may be performed under analogous conditions as those described above for part (a).
  • the product of this particular process is advantageously purified by methods well known to persons skilled in the art, such as flash chromatography or high performance liquid chromatography.
  • Suitable leaving groups L 3 include those mentioned above for L 1 , especially halide.
  • Reduction may be performed using reagents such as, but not limited to, hydrogen gas over palladium, iron metal with hydrochloric acid, stannous chloride and hydrochloric acid, or sodium dithionite, as appropriate under conventional conditions.
  • reagents such as, but not limited to, hydrogen gas over palladium, iron metal with hydrochloric acid, stannous chloride and hydrochloric acid, or sodium dithionite, as appropriate under conventional conditions.
  • Compounds of formula (VIII) may be prepared by reacting an organic nitrite derivative, such as tert-butyl nitrite, with a compound of formula (IX):
  • This reaction may be performed in the presence of an acid, such as acetic acid or hydrochloric acid.
  • Certain compounds of formula (IV) may be prepared by a process comprising reacting a compound of formula (VII) or a protected derivative thereof, wherein L 1 and L 3 represent suitable leaving groups, with a compound of formula (111) or a protected derivative thereof.
  • This process may be performed under basic conditions, such as tert-butanol and potassium carbonate, and advantageously at a temperature in the range of 50 to 150 0 C.
  • Compounds of formula (IV) may also be prepared from an analogous compound where the group L 2 is a hydroxyl group (which can be converted to a halogen by reaction with POCI 3 or PCI 5 ) or a methylthio group (which can be converted to a methylsulfinyl or methylsulfonyl group by oxidation with metachloroperoxybenzoic acid or ozone, for example).
  • Compounds in which L 2 is a hydroxyl group may be prepared from corresponding compounds in which L is a methylthio group by oxidation with hydrogen peroxide in acetic acid.
  • reaction is preferably performed in the presence of an acid, such as acetic acid or hydrochloric acid.
  • the aforementioned reaction may be performed under nitrogen atom protecting conditions (for example, in the presence of acetate) to yield a product in which an indazolyl nitrogen atom is protected.
  • Compounds of formula (X) may be prepared by reducing the corresponding nitro compound using conventional conditions, such as sodium dithionite, hydrogen gas in the presence of palladium, or iron metal with hydrochloric acid. Such corresponding nitro compounds may be prepared by reacting a compound of formula (VII) with a compound of formula (Xl):
  • Compounds of the present invention are useful as inhibitors of Syk and thus useful in treating diseases resulting from inappropriate mast cell activation, for instance allergic and inflammatory diseases.
  • the present invention provides for a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
  • the present invention provides for a method of treating inappropriate mast cell activation which method comprises administering to a patient in need thereof an effective compound of formula I, or a or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method comprising administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to inhibit a Syk kinase.
  • the present invention provides a method of treating an inflammatory disease which comprises administering to a patient in need thereof an effective compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating an allergic disorder which comprises administering to a patient in need thereof an effective compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.
  • Syk kinase diseases and pathological conditions thought to be mediated by Syk kinase include inflammatory and allergic disorders involving mast cell activation, such as chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), asthma, ulcerative colitis, Crohn's Disease, bronchitis, conjunctivitis, psoriasis, sclerodoma, urticaria, dermatitis, and allergic rhinitis. They also include inflammatory conditions which involve B cells, for instance lupus and rheumatoid arthritis. Likely disease targets for compounds of the present invention include chronic obstructive pulmonary disease (COPD), asthma and allergic rhinitis.
  • COPD chronic obstructive pulmonary disease
  • ARDS adult respiratory distress syndrome
  • ARDS adult respiratory distress syndrome
  • ARDS adult respiratory distress syndrome
  • ARDS adult respiratory distress syndrome
  • ARDS adult respiratory distress syndrome
  • ARDS adult respiratory distress syndrome
  • ARDS
  • the present invention provides a method of treating chronic obstructive pulmonary disease which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating asthma which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating allergic rhinitis which comprises administering to a patient in need thereof an effective compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • Compounds of the present invention may also be used in combination with other therapeutic agents, for instance an anti-inflammatory steroid, in particular an antiinflammatory corticosteroid.
  • Anti-inflammatory corticosteroids are well known in the art. Representative examples include fluticasone propionate (e.g. see US patent 4,335,121), beclomethasone 17- propionate ester, beclomethasone 17,21-dipropionate ester, dexamethasone or an ester thereof, mometasone or an ester thereof (e.g. mometasone furoate), ciclesonide, budesonide, and flunisolide.
  • fluticasone propionate e.g. see US patent 4,335,121
  • beclomethasone 17- propionate ester beclomethasone 17,21-dipropionate ester
  • dexamethasone or an ester thereof dexamethasone or an ester thereof
  • mometasone or an ester thereof e.g. mometasone furoate
  • ciclesonide e.g. mometasone furoate
  • ciclesonide esonide
  • anti-inflammatory corticosteroids are described in WO 02/12266 A1 (Glaxo Group Ltd), in particular, the compounds of Example 1 ( 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -[(2-furanylcarbonyl)oxy]-11 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo-androsta-1,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester) and Example 41 (6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -[(4-methyl-1 ,3-thiazole-5- carbonyl)oxy]-3-oxo-androsta-1 ,4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester), or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient, such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from about 0.1 to 99.9 wt.%, depending on the nature of the formulation.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled, such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and would result in pharmaceutically unacceptable compositions are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • dosage forms include those adapted for (1) inhalation, such as aerosols and solutions and (2) intranasal administration, such as solutions or sprays.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound of the present invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: Diluents, fillers, binders, lubricants, glidants, granulating agents, solvents, co-solvents, suspending agents, emulsifiers, anticaking agents, humectants, chelating agents, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • Diluents Diluents, fillers, binders, lubricants, glidants, granulating agents, solvents, co-solvents, suspending agents, emulsifiers, anticaking agents, humectants, chelating agents, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • Oral solid dosage forms such as tablets will typically comprise one or more pharmaceutically acceptable excipients, which may for example help impart satisfactory processing and compression characteristics, or provide additional desirable physical characteristics to the tablet.
  • pharmaceutically acceptable excipients may be selected from diluents, binders, glidants, lubricants, disintegrants, colorants, flavorants, sweetening agents, polymers, waxes or other solubility- modulating materials.
  • Dosage forms for parenteral administration will generally comprise fluids, particularly intravenous fluids, i.e., sterile solutions of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated. Such fluids are typically prepared with water for injection USP. Fluids used commonly for intravenous (IV) use are disclosed in Remington, The Science and Practice of Pharmacy [full citation previously provided]. The pH of such IV fluids may vary, and will typically be from 3.5 to 8 as known in the art. Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, drops, gels or dry powders.
  • Dosage forms for nasal administration may be provided in a metered dose device.
  • the dosage form may be provided as a fluid formulation for delivery from a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations.
  • the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity.
  • the fluid dispenser is of the general type described and illustrated in WO-A-2005/044354.
  • the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation.
  • the housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing.
  • a particularly preferred fluid dispenser is of the general type illustrated in Figures 30-40 of WO-A-2005/044354.
  • the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation.
  • the preferable particle size of the size-reduced (e.g. micronised) compound or salt or solvate is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • Aerosol formulations can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
  • a metering valve metered dose inhaler
  • the dosage form comprises an aerosol dispenser
  • it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a hydrofluorocarbon (HFC).
  • suitable HFC propellants include 1 , 1 ,1 , 2,3,3, 3-heptafluoropropane and 1 ,1 ,1 ,2-tetrafluoroethane.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • the pressurised aerosol may contain a solution or a suspension of the active compound. This may require the incorporation of additional excipients e.g. co-solvents and/or surfactants to improve the dispersion characteristics and homogeneity of suspension formulations. Solution formulations may also require the addition of co-solvents such as ethanol.
  • Other excipient modifiers may also be incorporated to improve, for example, the stability and/or taste and/or fine particle mass characteristics (amount and/or profile) of the formulation.
  • the pharmaceutical composition is a dry powder inhalable composition.
  • a dry powder inhalable composition can comprise a powder base such as lactose, glucose, trehalose, mannitol or starch, the compound of formula (I) or salt or solvate thereof (preferably in particle-size-reduced form, e.g. in micronised form), and optionally a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • the dry powder inhalable composition comprises a dry powder blend of lactose and the compound of formula (I) or salt thereof.
  • the lactose is preferably lactose hydrate e.g. lactose monohydrate and/or is preferably inhalation-grade and/or fine-grade lactose.
  • the particle size of the lactose is defined by 90% or more (by weight or by volume) of the lactose particles being less than 1000 microns (micrometres) (e.g. 10-1000 microns e.g. 30-1000 microns) in diameter, and/or 50% or more of the lactose particles being less than 500 microns (e.g. 10-500 microns) in diameter. More preferably, the particle size of the lactose is defined by 90% or more of the lactose particles being less than 300 microns (e.g.
  • the particle size of the lactose is defined by 90% or more of the lactose particles being less than 100-200 microns in diameter, and/or 50% or more of the lactose particles being less than 40-70 microns in diameter.
  • a suitable inhalation-grade lactose is E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25, 8017 JD Zwolle, Netherlands).
  • a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition can be administered by inhalation via the device such as the DISKUS TM device, marketed by GlaxoSmithKline.
  • the DISKUS TM inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.
  • the compound of the present invention when administered in combination with other therapeutic agents normally administered by the inhaled, intravenous, oral or intranasal route, that the resultant pharmaceutical composition may be administered by the same routes.
  • the compound of the present invention may conveniently be administered in amounts of, for example, 1 ⁇ g to 100 mg.
  • the precise dose will of course depend on the age and condition of the patient and the particular route of administration chosen.
  • Recombinant human Syk was expressed as a His-tagged protein*.
  • the activity of Syk was assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the reaction was incubated for 40 minutes at room temperature, then terminated by the addition of 3 ⁇ l of read reagent containing 60 mM EDTA, 15OmM NaCI, 5OnM Streptavidin APC (Prozyme, San Leandro, California, USA), 0.5nM antiphosphotyrosine antibody labelled with W-1024 europium chelate (Wallac OY, Turku, Finland) in 4OmM HEPES pH 7.4. The reaction was further incubated for 60 minutes at room temperature.
  • the degree of phosphorylation of Biotin-AAAEEIYGEI was measured using a BMG Rubystar plate reader (BMG LabTechnologies Ltd, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.
  • the reaction was incubated for 60min at room temperature, then terminated by the addition of 3 ⁇ l of read reagent containing 60 mM EDTA, 15OmM NaCI, 5OnM Streptavidin APC (Prozyme, San Leandro, California, USA), 0.5nM antiphosphotyrosine antibody labelled with W-1024 europium chelate (Wallac OY, Turku, Finland) in 4OmM HEPES pH 7.4. The reaction was further incubated for 45min at room temperature.
  • the degree of phosphorylation of Biotin-AAAEEIYGEI was measured using a BMG Rubystar plate reader (BMG LabTechnologies Ltd, Aylesbury, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal.
  • Compounds according to the present invention were assayed in this, or a similar Time-resolved fluorescence resonance energy transfer kinase assay, and gave IC 50 values less than 10 ⁇ M.
  • the 30OmM Imidazole fractions were pooled buffer exchanged using G25M (Amersham Biosciences, Buckinghamshire, UK) into 2OmM MES pH 6.0, 2OmM NaCI, 1OmM ⁇ McEtOH,10% glycerol.
  • the buffer exchanged 6His-Syk was loaded onto a Source15S column (Amersham Biosciences, Buckinghamshire, UK) and the column eluted using a NaCI gradient 0-50OmM over 50 column volumes.
  • the 6His-Syk containing fractions were pooled and concentrated by ultra-filtration. The identity of 6His-Syk was confirmed by peptide mass finger printing and intact LC-MS.
  • Cells of the mouse fibroblast cell line NIH-3T3 are stably transfected with a cFms- SYK chimera.
  • Addition of the ligand (MCSF) produces dimerisation of the chimera resulting in autophosphorylation of the SYK kinase domain.
  • MCSF ligand
  • Cells are plated at a density of 1x10 5 /well in a volume of 200 ⁇ L growth medium (DMEM containing 10% heat inactivated foetal calf serum, 1% L-glutamine, 400 ⁇ g/mL geneticin and 400 ⁇ g/mL zeocin) in 96 well Collagen 1 coated tissue culture plates. Following incubation at 37 0 C, 10% CO 2 , for 20 hours the cell supernatant is removed and replaced with 200 ⁇ L DMEM containing 1 % penicillin/streptomycin (serum free DMEM). The cells are incubated for one hour under the conditions described above. The medium is removed, 50 ⁇ L appropriately diluted compound solution added and the plate incubated for a further hour.
  • DMEM containing 10% heat inactivated foetal calf serum, 1% L-glutamine, 400 ⁇ g/mL geneticin and 400 ⁇ g/mL zeocin
  • Cells are stimulated with 25 ⁇ L MCSF (0.66 ⁇ g/mL final) for 20 minutes at 37°C. After removal of the supernatant, the cells are washed with cold PBS and lysed with 100 ⁇ L lysis buffer for 4 hours at 4 0 C.
  • cFms ELISA 85 ⁇ L cell lysate is transferred to a 96 well ELISA plate coated with goat anti human M-CSF R capture antibody and incubated for 16 hours at 4°C.
  • the plate is washed and a biotinylated anti-phosphotyrosine detection antibody added (100 ⁇ LJwell) for 2 hours at room temperature. This is removed and replaced with 100 ⁇ l_ Streptavidin- HRP for 30minutes.
  • Captured phosphorylated SYK is visualised using 100 ⁇ L TMB substrate. The reaction is terminated with 50 ⁇ L 1M sulphuric acid and the absorbance measured at 450nm.
  • Compound is prepared as a 1OmM stock in DMSO and a dilution series prepared in DMSO using 9 successive 5-fold dilutions. This dilution series is diluted a further 1 :333 with serum free DMEM to give the concentration range to be tested of 1x10 "5 to 1.54x10 "11 M.
  • Compound dilutions are prepared using the Biomek 2000 or Biomek Nx automated robotic pipetting systems.
  • the population of B cells observed in this assay are the naive mature IgM/lgD expressing population. These form at least 70% of the purified B cell population (the rest being isotype switched memory B cells) and are the only cells that proliferate as the cells are stimulated with anti-lgM.
  • Anti-lgM drives signalling through the B cell receptor which is Syk dependant. Proliferation is a functional measure of B cell signalling that can be measured by observing the incorporation of tritiated methyl thymidine into the cells.
  • Purified human tonsillar B cells are resuspended in Buckleys* medium at a concentration of 1.25 x 10 6 ml.
  • 160 ⁇ l of cells re-suspended in Buckley's medium is added to the compound and control wells of a 96 well plate.
  • the control wells are located on column 11 and 12 of the 96 well plate.
  • the background wells are located in column 12 and 20 ⁇ l of 10 ⁇ M control is added to provide an appropriate background control.
  • 20 ⁇ l of 1% DMSO is added to the wells in column 11 for the stimulated control.
  • the compound titrations are located between columns 1 and 10. Three compounds are run in duplicate on each plate and row A and B are used for the control compound titration.
  • the final concentration of DMSO is 0.1% in the assay.
  • the cells are left for 45 minutes, after 45 minutes the proliferative stimulus is added to the first 11 wells of the 96 well plate and 20 ⁇ l of medium is added to column 12.
  • F(ab')2 fragments of a polyclonal goat anti-sera raised to human IgM is used at a final concentration of 15 ⁇ g/ ml to stimulate the cells. (Biosource. Cat no: AMI 4601 ).
  • Tritiated methyl thymidine is added to the cells at a concentration of 1 ⁇ Ci per well. (Amersham, TRK 758). The radioactivity is added 65 hours after the initial stimulus and is left on the cells for 6 to 8 hours. After pulsing with methyl thymidine the cells are harvested on a Skatron 96 well cell harvester onto glass fibre mats. Once these have dried these are counted on a Wallac 1450 Microbeta scintillation counter.
  • Data is downloaded as an XL file and IC50's determined using Activity base.
  • Buckleys Medium 450 mis Iscoves (Sigma I 3390), 5OmIs FCS, 2.5 g BSA, 5mls Pen/ strep, 5mls Glutamine (20OmM), 500 ⁇ l Apo transferrin (50mg/ml) Sigma (T 1147), 100 ⁇ l Bovine Insulin (10mg/ml) Sigma (1 1882).
  • Compound is prepared as a 1OmM stock in DMSO and a dilution series prepared in DMSO using 9 successive 3-fold dilutions.
  • This dilution series is diluted a further 1 :100 with Buckleys medium to give the concentration range to be tested of 100 ⁇ M to 5nM.
  • This is added as 20 ⁇ l to 96 well plates in duplicate to generate two IC50's for each compound tested. Each plate is run in the presence of a control compound, which acts as an internal standard. .
  • LAD2 is a stem cell factor (SCF)-dependent human mast cell line that was established by the NIH from bone marrow aspirates from a patient with mast cell sarcoma/leukaemia.
  • SCF stem cell factor
  • LAD2 cells resemble CD34+-derived human mast cells and express functional Fc ⁇ Rl.
  • the Fc ⁇ RI is up-regulated in the presence of IL-4, SCF and IgE, subsequent cross linking of cell-bound IgE results in degranulation which can be measured as hexosaminidase release.
  • LAD2 cells are re-suspended at 1x10 5 /ml in complete stem pro-34SFM (Gibco Cat 10640-019 media containing Stem Pro-34 nutrient supplement (1 :40), glutamine (2mM), penicillin (100u/ml), streptomycin (100 ⁇ g/ml)) with additional supplements of human recombinant SCF (100ng/ml; R&D systems), human recombinant Interleukin- 4 (6ng/ml; R&D Systems) and IgE (100 ⁇ g/ml; Calbiochem). Cells are then maintained for 5 days at 37 0 C, 5% CO2 in a humidified atmosphere.
  • Primed LAD2 cells are centrifuged (30Og, 5min), the supernatant discarded and the cell pellet re-suspended at 1x10 4 cells/ml in RPMI supplemented with glutamine (2mM). Following a further centrifugation (30Og, 5min) the cells are re-suspended in fresh RPMI with glutamine (2mM), adjusted to a density of 2.85x10 5 /ml, and pipetted into sterile V-well plates (70 ⁇ l_/well; Greiner) containing 20 ⁇ l diluted compound (prepared as detailed above).
  • Cells are then incubated for 1h (37 0 C, 5% CO 2 in a humidified atmosphere) before activating with a sub-maximal concentration of anti- lgE (10 ⁇ l volume to give a final assay dilution of 1 :2700; Sigma).
  • a sub-maximal concentration of anti- lgE 10 ⁇ l volume to give a final assay dilution of 1 :2700; Sigma.
  • plates are centrifuged (120Og, 10 min, 4 0 C) and the supernatant removed for hexosaminidase assay.
  • the cell pellet is lysed in 100 ⁇ l/well triton-X (0.5% in RPMI 2mM glutamine) at 37 0 C for 30 minutes.
  • Beta-hexosaminidase activity is measured by the conversion of 4-methylumbelliferyl N-acetyl- ⁇ -D glucosaminide (Sigma) to a fluorescent product.
  • a useful screening strategy comprises assay 1 (enzyme assay (pKi), assay 2 and then assay 3 (B Cell Proliferation) or assay 4 (LAD2). Intermediates and Examples
  • DMSO dimethylsulfoxide
  • DMF refers to ⁇ /, ⁇ /-dimethylformamide
  • THF refers to tetrahydrofuran
  • HPLC refers to high performance liquid chromatography.
  • ADDP refers to 1 ,1'(azodicarbonyl)dipiperidine
  • SPE refers to solid phase extraction cartridges marketed by lsolute
  • TBTU refers to O-benzotriazol-1-yl- ⁇ /, ⁇ /, ⁇ /', ⁇ /',-bis(tetramethylene)uronium tetrafluoroborate
  • HOBt refers to N-hydroxybenzotriazole hydrate
  • “Hydrophobic frits” refers to filtration tubes sold by Whatman. SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd.
  • TLC thin layer chromatography
  • LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm x 4.6 mm ID) eluting with 0.1% HCO2H and 0.01 M ammonium acetate in water (solvent A) and 0.05% HCO2H 5% water in acetonitrile (solvent B), using the following elution gradient 0.0-7min 0%B, 0.7-4.2 min 100%B, 4.2-5.3 min 0%B, 5.3-5.5min 0%B at a flow rate of 3ml/min.
  • the mass spectra were recorded on a Fisons VG Platform spectrometer using electrospray positive and negative mode (ES+ve and ES-ve).
  • Flashmaster refers to an automated multi-user flash chromatography system, available from Argonaut Technologies Ltd, which utilises disposable, normal phase, SPE cartridges (2 g to 100 g). It provides quaternary on-line solvent mixing to enable gradient methods to be run. Samples are queued using the multi-functional open access software, which manages solvents, flow-rates, gradient profile and collection conditions.
  • the system is equipped with a Knauer variable wavelength uv-detector and two Gilson FC204 fraction-collectors enabling automated peak cutting, collection and tracking.
  • Preparative mass directed HPLC was conducted on a Waters FractionLynx system comprising of a Waters 600 pump with extended pump heads, Waters 2700 autosampler, Waters 996 diode array and Gilson 202 fraction collector on a 10 cm 2.54 cm ID ABZ+ column, eluting with either 0.1% formic acid or trifluoroacetic acid in water (solvent A) and 0.1% formic or trifluoroacetic acid in acetonitrile (solvent B) using the appropriate elution gradient.
  • Mass spectra were recored on Micromass ZMD mass spectrometer using electrospray positive and negative mode, alternate scans. The software used was MassLynx 3.5 with OpenLynx and FractionLynx options.
  • Ethyl chloroformate (136ml) was added dropwise to a chilled solution of 2,3-dihydro- 1,2-benzisothiazol-1 ,1 -dioxide (68.Og) in pyridine (340ml) over 1h, maintaining the temperature below 18 0 C.
  • the slurry was stirred for 10min at 2O 0 C, diluted dropwise with water (1000ml) over 75min and stirred for a further 30min.
  • the mixture was chilled to 0-5 0 C, aged for 1 h and isolated by filtration.
  • the cake was washed with cold water (2x250ml), and dried in vacuo to give the title compound as a white solid (72.35g).
  • a suspension of the above 6-nitro-2,3-dihydro-1 ,2-benzisothiazol-1,1 -dioxide (10.0g), 5%Pd/C (1.0g, 50%wet) and methanesulfonic acid (4.5ml) in propan-2-ol (100ml) was hydrogenated under hydrogen at 2bar pressure at 5O 0 C.
  • the mixture was purged with nitrogen, cooled to 2O 0 C and treated with a mixture of 2M sodium hydroxide (90ml) and 10M sodium hydroxide (10ml).
  • the reaction was stirred for 2h at ambient temperature and filtered through a filter pad, washing the pad with water (20ml).
  • Zinc dust (2.4g) was added portion wise to a stirred suspension of 5-amino-1 ,2- benzisothiazol-3(2H)-one 1 ,1-dioxide (820mg) in concentrated hydrochloric acid (10ml). The mixture was stirred at room temperature for 20 hours before saturated aqueous sodium hydrogen carbonate solution was added to the mixture until the pH of the solution was 8. The mixture was filtered and extracted with ethyl acetate (4x150ml). The combined organic phases were dried (MgSO 4 ), filtered and the solvents evaporated in vacuo to give the title compound as a yellow solid (230mg). LC/MS: Rt 0.82min, MH + 185.
  • Triethylamine (1.97g, 19.46mmol) was added to an ice-cooled solution of 2-amino-4- nitrophenol (3g, 19.46mmol) in THF (30ml).
  • Bromodifluoroacetylbromide (2.48ml, 19.46mmol) was added dropwise to the solution and the mixture stirred at O 0 C for 45min.
  • the reaction was quenched with water and extracted with ethyl acetate (3x 50ml).
  • the crude product was purified by chromatography on a Flashmaster cartridge (Si, 7Og), eluting with a MeOH/DCM/triethylamine gradient (0-15% MeOH, 1% triethylamine) and then washing the column with further MeOH/DCM/triethylamine (10% MeOH, 1% triethylamine.
  • the product fractions were reduced to dryness under vacuum to give 6-amino-2,2-difluoro-2H-1 ,4-benzoxazin-3(4H)-one (857mg) as a brown solid.
  • LC/MS Rt 2.25min, [M-H]- 199.
  • N,N,N'-diethylethylenediamine (Aldrich, 2.1g, 18.0mmol) was added to an ice-cooled solution of 3-nitrobenzenesulphonylchloride (2g, 9.0mmol) in DCM (15ml) and the reaction stirred at room temperature for 17hrs. Water (15ml) was added to the mixture, the phase separated (frit) and the organic phase applied directly to a biotage column (Si, 4Og).
  • Iron powder (1.22g, 22.0mmol) was added in portions to an ice-cooled solution of N- [2-(diethylamino)ethyl]-3-nitrobenzenesulfonamide (1.66g, 5.5mmol) in acetic acid (60ml).
  • the reaction was stirred at room temperature for 18hrs, diluted with water (250ml) and ethyl acetate (100ml) and solid sodium hydrogen carbonate added to the mixture until pH7 was achieved.
  • the organic phase was separated, the aqueous extracted with ethyl acetate (3x 100ml).
  • the combined organic phases were washed with water and brine, dried (magnesium sulphate) and reduced to dryness in vacuo.
  • reaction mixture was was allowed to warm to room temperature overnight, then diluted with methylene chloride (100ml), washed with hydrochloric acid (1N, 3 x 150ml) and a solution of saturated sodium bicarbonate (3 x 150ml). The organic layer was dried over anhydrous sodium sulfate, gravity filtered, and concentrated under reduced pressure to afford 2-(3-nitrophenyl)- ⁇ /-[3-(2- oxo-1-pyrrolidinyl)propyl]acetamide as a yellow oil which was used, without purification, in the next reaction.
  • Example 1 formic acid - 5- ⁇ [4-(1H-indazol-4-ylamino)-2-pyrimidiny ⁇ amino)-1 ,3- dihvdro-2H-indol-2-one (1 :1)
  • Method A (default) - on a Supelcosil LCABZ+PLUS column (3um, 3.3cm x 4.6mm ID) eluting with 0.1% HCO 2 H and 0.01 M ammonium acetate in water (solvent A), and 95% acetonitrile and 0.05% HCO 2 H in water (solvent B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0 ⁇ 100%B, 4.2-5.3 minutes 100%B, 5.3-5.5 minutes 100 ⁇ 0%B, flow 3 ml/min.
  • Mass spectra were recorded on a Fisons VG Platform mass spectrometer using electrospray positive ionisation [(ES+ve to give MH + and M(NH 4 ) 4" molecular ions] or electrospray negative ionisation [(ES-ve to give (M-H) " molecular ion] modes, or on a Perkin Elmer Sciex 100 atmospheric pressure ionization (APCI) mass spectrometer, or a Finnigan LCQ Duo LC/MS Ion Trap electrospray ionization (ESI) mass spectrometer. Retention time in LC/MS is referred to as "Rt" (time in minutes).
  • Mass directed autoprep refers to methods where the material was purified by high performance liquid chromatography on a HPLCABZ+ 5 ⁇ m column (5cm x 10mm i.d.) with 0.1% HCO 2 H in water and 95% MeCN, 5% water (0.5% HCO 2 H) utilizing the following gradient elution conditions: 0-1.0 minutes 5%B, 1.0-8.0 minutes 5 ⁇ 30%B, 8.0-8.9 minutes 30%B, 8.9-9.0 minutes 30 ⁇ 95%B, 9.0-9.9 minutes 95%B, 9.9-10 minutes 95 ⁇ 0%B at a flow rate of 8ml minutes "1 (System 2).
  • the Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the mass of interest.
  • BiotageTM chromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 4Oi or Flash 15Oi) and cartridges pre-packed with KPSiI.
  • Example 105 ⁇ /-(3-hvdroxypropyl)-2-IY4-(r4-(1 H-indazol-4-ylamino)-2- DvrimidinvliaminolphenvOoxvlacetamide:
  • Example 106 Methyl ⁇ /- ⁇ [(4-(r4-(1H-indazol-4-ylamino)-2- pyrimidinyl1amino)phenyl)oxylacetyl) serinate
  • the reaction mixture was stirred at room temperature for 15min before a solution of methyl serinate (Aldrich, 0.19g, 1.2mmol) and ⁇ /, ⁇ /-diisopropylethylamine (0.1Og, O. ⁇ mmol) in ⁇ /, ⁇ /-dimethylformamide (1.5ml) was added via syringe. After stirring for 15 h, the reaction mixture was diluted with ethyl acetate (100ml) and washed with water (3 x 50ml) and a 5% lithium chloride solution (50ml).
  • Example 107 ⁇ /-(3-hvdroxypropyl)-1-(3-(r4-(1H-indazol-4-ylamino)-2- pyrimidinyl1amino ⁇ phenyl)methanesulfonamide
  • reaction mixture was concentrated under reduced pressure, the residue diluted with methylene chloride (5ml), and trifluoroacetic acid (1 ml) was added. After stirring at room temperature for 30min, the reaction mixture was diluted with methylene chloride (50ml), and carefully neutralized by saturated sodium bicarbonate solution. The solid which had formed was collected by vacuum filtration, dissolved in methanol and the combined organic solvents were concentrated under reduced pressure.
  • Example 108 ⁇ /-[3-(2,5-dioxo-1 -pyrrolidinyl)propy ⁇ -2-(4-(r4-(1 /-/-indazol-4-ylaminoV2- pyrimidinyllamino) phenvQacetamide
  • reaction mixture was concentrated under reduced pressure, the residue diluted with methylene chloride (6ml), and trifluoroacetic acid (1ml) was added. After stirring at room temperature for 30min, the reaction mixture was agitated with a solution of saturated sodium bicarbonate (100ml).
  • Example 109 2-(3-(f4-(1 /-/-indazol-4-ylamino)-2-pyrimidinyllamino)phenyl)-A/-r3-(2- oxo-1-pyrrolidinyl)propyllacetamide
  • reaction mixture was concentrated under reduced pressure, the residue diluted with methylene chloride (6ml), and trifluoroacetic acid (1 ml) was added. After stirring at room temperature for 30min, the reaction mixture was agitated with a solution of saturated sodium bicarbonate (100ml).
  • Example 110 1 ,1 -dimethylethylf(4- ⁇ f4-(1 H-indazol-4-ylamino)-2-pyrimidinv ⁇ amino) phenyQoxylacetate
  • Example 111 1-(4- ⁇ r4-(1H-indazol-4-ylamino)-2-pyrimidinyllamino)phenvn-/V- methylmethanesulfonamide
  • Example 114 r(4- ⁇ f4-(1/-/-indazol-4-ylamino)-2-pyrimidinyllamino)phenyl)oxylacetic acid hydrochloride
  • Example 116 ⁇ /-(3,4-dimethyl-5-isoxazolyl)-1-(4- ⁇ f4-(1H-indazol-4-ylamino)-2- pyrimidinyllamino)phenyl)methanesulfonamide
  • Example 117 ⁇ /-(4,5-dimethyl-1.3-thiazol-2-ylV1-f4-ff4-(1 Wndazol-4-ylamino)-2- pyrimidinvnamino ⁇ phenyl)methanesulfonamide
  • Example 118 1-(4- ⁇ f4-(1f/-indazol-4-ylamino)-2-pyrimidinyllamino)phenyl)-A/-f3-(2- oxo-1-pyrrolidinyl)propyllmethanesulfonamide
  • Example 119 ⁇ /-(3-hvdroxypropyl)-1-(4- ⁇ f4-(1/-/-indazol-4-ylamino)-2- pyrimidinyllamino ⁇ phenyl)methanesulfonamide
  • Example 120 2-[(4-([4-(I /-/-indazol-4-ylamino)-2-pyrimidinyllamino ⁇ phenyl)oxy1-A/-r3- (2-oxo-1-pyrrolidinyl)propyllacetamide
  • Example 121 ⁇ /-(3,4-dimethyl-5-isoxazolyl)-2-(4-ff4-(1 A7-indazol-4-ylamino)-2- pyrimidinv ⁇ aminolphenvPacetamide
  • N-(2-chloro-4-pyrimidinyl)-1 H-indazol-4-amine (280mg, 1.1mmol) and 2-(4- aminophenyl)-/v-(3,4-dimethyl-5-isoxazolyl)acetamide (280mg, 1.1 mmol) were dissolved in IPA (7 ml) with a few drops of 2N HCI in ether. The reaction was heated for 3 days and then concentrated in vacuo. The mixture was dissolved in methylene chloride (5ml) treated with TFA (3ml) and stirred at room temperature for 1h and then quenched with NaHC ⁇ 3. The resulting solid was filtered and purified by flash chromatography to yield the title compound.
  • Example 123 N- ⁇ 4-r(difluoromethv0oxylphenyl)-2-(4- ⁇ l4-(1 /-/-indazol-4-ylamino)-2- Pyrimidinyllamino)phenvOaceta ⁇ iide
  • Example 124 ⁇ /M H-indazol-4-yl- ⁇ / 2 -(4-r(methylsulfonyl)methyllphenyl>-2,4- pyrimidinediamine
  • Example 125 2-(4-(K-(I H-indazol-4-ylamino)-2-pyrimidinyllamino
  • Example 127 4- ⁇ r4-(1/-/-indazol-4-ylaminoV2-pyrimidinyl1amino)benzoic acid
  • Example 129 2-(4-(F4-(1 f/-indazol-4-ylamino)-2-pyrimidinvnamino ⁇ phenyl)- ⁇ /-f4- (trifluoromethyl)phenyllacetamide
  • Example 131 ⁇ /-(3-chlorophenvO-2-(4-(r4-(1 /-/-indazol-4-ylamino)-2- pyrimidinyliaminolphenyPacetamide
  • Example 132 ⁇ /-(4-chlorophenvP-2-(4-(r4-(1 H-indazol-4-ylamino)-2- pyrimidinvnamino)phenyl)acetamide
  • Example 133 ⁇ /-(4,5-dimethyl-1.3-thiazol-2-ylV2-(4- ⁇ f4-(1H-indazol-4-ylamino)-2- pyrimidinv ⁇ amino ⁇ phenyl)acetamide
  • Example 134 2-(4- ⁇ f4-f1 H-indazol-4-ylamino)-2-pyrimidinyllamino)phenyl)- ⁇ /-r3-(2- oxo-1-pvrrolidinyl)propvllacetamide
  • Example 136 ⁇ /-(4-(r4-(1/-/-indazol-4-ylamino)-2- pyrimidiny ⁇ amino)phenyl)methanesulfonamide
  • Example 138 2-(4- ⁇ r4-(1H-indazol-4-ylamino)-2-pyrimidinyl1amino)phenyl)- ⁇ /-3- pyridinylacetamide
  • Example 140 ⁇ /M H-indazol-4-yl- ⁇ / 2 -r4-(1 H-tetrazol-5-ylmethvnphenvn-2.4- pyrimidinediamine

Abstract

L'invention concerne des composés bis-anilinopyrimidine de la formule (I), qui sont utilisés comme inhibiteurs de la tyrosine kinase de la rate (Syk) et qui sont par conséquent utiles dans le traitement de maladies causées par une activation inappropriée des mastocytes, par exemple dans les maladies allergiques et inflammatoires.
PCT/GB2006/002015 2005-06-03 2006-06-02 Nouveaux composes WO2006129100A1 (fr)

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