WO1991017162A1 - Imidazopyridine paf antagonists - Google Patents

Imidazopyridine paf antagonists Download PDF

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Publication number
WO1991017162A1
WO1991017162A1 PCT/EP1991/000737 EP9100737W WO9117162A1 WO 1991017162 A1 WO1991017162 A1 WO 1991017162A1 EP 9100737 W EP9100737 W EP 9100737W WO 9117162 A1 WO9117162 A1 WO 9117162A1
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formula
alkyl
group
phenyl
chain
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PCT/EP1991/000737
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English (en)
French (fr)
Inventor
Kelvin Cooper
Michael Jonathan Fray
John Steele
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Pfizer Limited
Pfizer Inc.
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Publication of WO1991017162A1 publication Critical patent/WO1991017162A1/en
Priority to FI925054A priority Critical patent/FI925054A0/fi

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    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • This invention relates to imidazopyridines specifically to certain 4-substituted-1-(2-methylimidazo[4,5-c]pyrid-1-yl)-benzene derivatives.
  • the compounds are potent and selective antagonists of platelet activating factor having clinical utility in the treatment of allergic and inflammatory conditions in humans and animals.
  • Platelet activating factor (PAF, 1-0-alkyl-2-acetyl-sn- glyceryl-3-phosphorylcholine) is an ether phopholipid whose structure was first elucidated in 1979. It is produced by, released from and interacts with many pro-inflammatory cells, platelets and the kidney.
  • PAF In addition to potent platelet aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via the release of other powerful mediators such as thromboxane A 2 or the leukotrienes, which make PAF inhib'itors of potential value in the treatment of a variety of conditions including allergic, inflammatory and hypersecretory conditions such as asthma, arthritis, rhinitis, bronchitis and urticaria, the treatment of circulatory shock, gastric ulceration, psoriasis and cardiovascular conditions , including angina , thrombosis and stroke.
  • other powerful mediators such as thromboxane A 2 or the leukotrienes
  • PAF antagonists having the formula: and pharmaceutically acceptable salts thereof,
  • A is a C 1 -C 8 alkyl, perfluoro(C 1 -C 8 )alkyl, C 3 -C 8 cycloalkyl, aryl or heterocyclic group, wherein said aryl or heterocyclic group may be unsubstituted or substituted with from one to three substituents each independently chosen from C 1 -C 4 alkyl, halo, oxo, CO 2 R 4 , CONR 5 R 6 , OH, C 1 -C 4 alkoxy, NH 2 , NO 2 , CN and (CH 3 ) 3 SiCH 2 ;
  • substituents and, in the case where the group A is an aryl or heterocyclic group, the ring may optionally be fused to said aryl or heterocyclic group;
  • each of R 1 , R 2 and R 3 is independently H or CH 3 ;
  • R 4 is H, C 1 -C 4 alkyl or aryl(C 1 -C 4 )alkyl;
  • R 5 and R 6 are each independently H or C 1 -C 4 alkyl, or R 5 is H and
  • R 6 is C 3 -C 8 cycloalkyl or aryl, or the two groups R 5 and R 6 together with the nitrogen atom to which they are attached, form a piperidino, 4-ketopiperidino, morpholino or piperazinyl group;
  • R 7 is H, C 1 -C 4 alkyl, CO 2 (C 1 -C 4 )alkyl, aryl(C 1 -C 4 )alkyl or heteroaryl(C 1 -C 4 )alkyl;
  • A-B is not C 2 H 5 OCOCH 2 CO- or CH 3 COCH 2 CO 2 CH 2 -.
  • aryl includes phenyl, naphthyl, tetrahydronaphthyl and indanyl, each of said groups being optionally substituted as defined in A above; alkyl groups having 3 or more carbon atoms may be straight or branched-chain; and halo means fluoro, chloro, bromo or iodo.
  • heterocyclic group means a 5 or 6 membered ring containing up to four nitrogen atoms, or one or two nitrogen atoms together with a further oxygen or sulphur atom, or up to two oxygen atoms or a sulphur atom, as heteroatom, and said ring may be saturated or unsaturated and substituted with one or more subsitutuents as defined in A above, and may optionally be fused to a phenyl or further 5 or 6 membered heterocyclic ring.
  • heterocyclic groups examples include pyridyl, quinolyl, benzimidazolyl, benzthiazolyl, benzdioxolanyl,
  • benzothienyl triazolyl, imidazolyl, indazolyl, indolinyl, piperidyl and morpholinyl.
  • heteroaryl used in relation to R 7 means a 5 or 6 membered aromatic heterocyclic group including, for example, pyridyl, thienyl and imidazolyl.
  • linking groups B are possible and as well as simple straight-chain or branched alkylene and alkenylene groups, the invention includes groups containing an ether, thioether, amine or amide group and various cyclic variations thereof:
  • the linking group, B is an ether group having an oxygen atom and up to four carbon atoms in the chain linking the group A to the phenyl ring.
  • the linking group may optionally have a further oxygen atom in the chain and said chain may optionally be substituted by hydroxy, oxo (to give an. ester group), C 1 -C 4 alkoxy, C 1 -C 4 alkyl or phenyl.
  • the linking group may also form part of a 5 to 7 membered cyclic ether group containing one or two oxygen atoms in the ring which may optionally be substituted by C 1 -C 4 alkyl hydroxy, oxo, or C 1 -C 4 alkoxy and which may optionally be fused to a phenyl or tetrahydronaphthalene ring.
  • the ring may be for example, a tetrahydropyranyl, dioxolanyl, dioxanyl or dioxepanyl ring.
  • the group, A is preferably a phenyl group which may optionally be substituted as defined in A above.
  • this type include compounds of the following formulae-:
  • R 1 , R 2 and R 3 being preferably H.
  • Cyclic diethers are readily prepared by reaction of a diol with the appropriate aldehyde or ketone.
  • reaction of a diol with the appropriate aldehyde or ketone.
  • ester-linked derivatives may be prepared by reaction of the carboxylic acid of formula HO 2 C-D 1 -X with an alkanol of formula A-D 1 -OH or by reaction of an alkanol of formula HO-D 1 -X with an acid of formula A-D 1 -CO 2 H wherein A, and X are as previously defined and D 1 is as previously defined for D or it may be a direct bond.
  • the linking group B contains an amide group together with up to three further carbon atoms in the chain linking A to the phenyl ring.
  • the nitrogen atom may optionally be substituted by C 1 -C 4 alkyl and the chain may optionally be substituted by C 1 -C 4 alkyl or phenyl, or include a further oxo substituent.
  • the group A may be phenyl, optionally substituted as defined in A above or it may be naphthyl, indanyl, or a heterocyclic group, for example a pyridyl, quinolyl, indazolyl, benzimidazolyl or benzthiazolyl group.
  • this type include:
  • reaction may conveniently be achieved via the acid chloride which may be prepared by reaction of the acid with, for example, oxalyl chloride in accordance with normal practice.
  • the amino substituent R 7 is preferably H, C 1 -C 4 alkyl, CO 2 (C 1 -C 4 )alkyl or aryl(C 1 -C 4 )alkyl.
  • the linking group in this case may optionally be cyclised to form a pyrrolidinyl group or piperidino group, which may optionally be fused to a benzene ring, or it may be an oxazoline ring.
  • group A is preferably phenyl, optionally substituted as previously defined.
  • group A is preferably phenyl, optionally substituted as previously defined.
  • particular and preferred examples include :
  • Further reactions include, for example, reaction of the amine products with n-butyl lithium followed by reaction with a C 1 -C 4 alkylchloroformate to give the N-alkoxycarbonyl derivatives, or alkylation to give the products where R 7 is C 1 -C 4 alkyl, aryl(C 1 -C 4 alkyl) or heteroaryl(C 1 -C 4 )- alkyl.
  • the linking group B is a 7 membered saturated or mono-unsaturated ring containing -NR 7 - wherein R 7 is as previously defined.
  • The. ring may optionally be substituted as previously defined under B; preferred substituents include oxo and CO 2 R 4 , particularly when R 4 is methyl.
  • R 7 is preferably H, C 1 -C 4 alkyl, aryl(C 1 -C 4 ) alkyl or heteroaryl(C 1 -C 4 )- alkyl.
  • A is preferably phenyl or substituted phenyl and said phenyl ring is benzofused to the 7-membered ring
  • R 21 is H, methyl, 4-chlorobenzyl or 2-pyridylmethyl and X is as previously defined.
  • each R 22 is independently H or an aryl group substituent as defined in A above, to give the 3-methoxycarbonyl-tetrahydro- benzazepin-2-one (VIII).
  • a strong base e.g. sodium hydride
  • R 22 is preferably H.
  • the linking group B contains a S(O) m group together with up to four carbon atoms where m is 0-2 .
  • the sulphur atom may be present as a thioether, sulphone or sulphoxide group.
  • the chain may optionally be substituted by C 1 -C 4 alkyl or hydroxy.
  • the group A is preferably phenyl optionally substituted as previously defined in A above. Particular and preferred examples of this type include:
  • the linking group B is a C 1 -C 4 alkylene or alkenylene group which may optionally be substituted by one or more OH, oxo, CO 2 R 4 or perfluoroalkyl groups.
  • the group A is preferably phenyl optionally substituted as defined in A above or is
  • heptafluoropropyl examples include:
  • R 4 is C 1 -C 4 alkyl and X is as previously defined, yields the 3-aryl-2-alkoxycarbonylprop-2-ene-1-one derivative. Reduction gives the 3-aryl-2-alkoxycarbonyl-1-hydroxypropyl derivative where the linking group is-:
  • R 4 is C 1 -C 4 alkyl and D and X are as previously defined, by reaction with, for example, a perfluoroalkyl magnesium iodide, gives the corresponding perfluoroalkyl-carbonyl derivative.
  • the ketone may be further reacted, for example with a further Grignard addition to give further disubstituted-methanol derivatives.
  • the compounds may be purified using conventional methods such as recrystallisation or column chromatography as appropriate, and compounds having acidic or basic centres may be isolated as the free acid or base or in salt form. Compounds having asymmetric centres may be isolated as the racemic mixtures or resolved to give the individual enantiomers.
  • the invention includes all enantiomers whether resolved or not.
  • the pharmaceutically acceptable acid addition salts of the compounds of the formula (I) which form such salts are those formed from acids which form non-toxic acid addition salts, for example the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate,
  • the activity of the compounds of the invention is shown by their ability to inhibit the platelet aggregating activity of PAF in vitro . Testing is performed as follows:
  • Blood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the samples centrifuged for 15 minutes to obtain platelet rich plasma.
  • the plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 mM KH 2 PO 4 , 6mM Na 2 HPO 4 , 100 mM
  • the activity of the compounds of formula (I) is also demonstrated in vivo by their ability to protect mice from the lethal effect of an injection of PAF.
  • a mixture of PAF (50 ⁇ g/kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein into mice.
  • the compounds under test are either injected into the tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier.
  • the compounds are tested at several doses in groups of 5 mice and the dose which reduces mortality to 50% is recorded as the PD 50 value.
  • the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of
  • ком ⁇ онентs for example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • oral dosages of the compounds will generally be in the range of from 2-1000 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
  • administration would typically be within the range 1 to 10 mg per single dose as required.
  • inhalation via a nebuliser or aerosol may be the preferred route of drug administration.
  • Dose levels by this route would be within the range 0.1 to 50 mg per single dose as required.
  • the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the invention provides a
  • composition comprising a compound of the formula (I), without proviso, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compound of the formula (I), without proviso, or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic, inflammatory and hypersecretory conditions in a human being.
  • Methyl 2-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzyloxy]- benzoate (3.73 g, 10 mmol) was dissolved in ethanol (100 ml), 2N sodium hydroxide (20 ml) added and the solution stirred at room temperature for 2 hours. The solvent volume was reduced to 30 ml under reduced pressure and the residue poured into water (100 ml). The aqueous phase was washed with dichloromethane (2 x 50 ml) and acidified with glacial acetic acid.
  • Butyllithium (1.6M in hexane; 0.91 ml, 1.46 mmol) was added in drops to a stirred suspension of 1-[4-(1,3-dihydroxypropyl)- phenyl]-2-methylimidazo[4,5-c]pyridine (0.2 g, 0.7 mmol) in anhydrous tetrahydrofuran. The mixture was heated to reflux for 30 minutes, then cooled and treated with chlorotrimethylsilane (0.22 ml, 1.7 mmol). After stirring for 16 hours, the solvent was evaporated and the residue partitioned between dichloromethane and saturated aqueous sodium bicarbonate, ihe organic layer was dried over magnesium sulphate and concentrated to an oil.
  • 1,2-Bistrimethylsilyloxy-1-phenylethane (from Preparation 6) (0.34 g, 1.2 mmol) was added to a cold (-70°C), stirred solution of trimethylsilyl trifluoromethane-sulphonate (0.23 ml, 1.2 mmol) in dry dichloromethane (2 ml). After 5 minutes, a solution of 4-(2-methylimidazo[4,5-c]-pyrid-1-yl)benzaldehyde (0.24 g, 1 mmol) in 2 ml of dichloromethane was added. The mixture was allowed to warm to 22.24°C then stirred at this temperature for 22 hours.
  • step (a) The above procedure was followed using the appropriate amine in step (a) to yield the following products
  • Glacial acetic acid was added to a stirred solution of
  • diethylazodicarboxylate (6.283 ml, 1.8 mmol). The solution was stirred at ambient temperature for 16 hours then evaporated to dryness and the residual gum chromatographed on silica (230-400 mesh), eluting with 10% - 20% methanol in ethyl acetate.
  • n-Butyl lithium (1.6M in hexane) (1.19 ml, 1.9 mmol) was added dropwise to a stirred solution of l-[4-(2-chlorobenzyl- aminomethyl)phenyl]-2-methylimidazo[4,5-c]pyridine (0.61 g, 1.7 mmol) in anhydrous tetrahydrofuran, under nitrogen, at -30°C.
  • Oxalyl chloride (0.7 ml, 8 mmol) was added to a stirred solution of 2-chlorophenylacetic acid (340 mg, 2 mmol) in anhydrous dichloromethane (6 ml) under nitrogen. Anhydrous dimethylformamide (2 drops) was added and the solution stirred at ambient temperature for 2 hours. The solution was concentrated under high vacuum, then re-dissolved in dichloromethane (10 ml) and a solution of 4-(2-methylimidazo[4,5-c]-pyrid-1-yl)benzylamine (0.6 g, 2.5 mmol) in anhydrous dichloromethane (10 ml) added over 5 minutes.
  • N-Methylmorpholine (1.6 ml, 16 mmol) was added to a stirred suspension of the product from c) above (0.7 g, 1.8 mmol),
  • Example 118 using the appropriate aromatic aldehyde as starting material.
  • Bis(trimethylsilyl)acetamide (5 mmol, 1.24 ml) was dissolved in tetrahydrofuran (15 ml) and cooled to -78°C in a CO 2 /acetone bath.
  • Butyllithium (2.2M, in hexane, 5 mmol, 2.27 ml) was added dropwise over 5 minutes and the solution stirred at -78°C for a further 15 minutes.
  • the aqueous phase was basified with 2N sodium hydroxide then extracted with dichloromethane (3 x 100 ml). The combined organic extracts were dried over Na 2 SO 4 , filtered and evaporated to dryness. Purification was effected by column chromatography on silica eluting with dichloromethane/ methanol/ ammonia 94:6:0.1 and the product-containing fractions evaporated to dryness. The resulting oil was dissolved in a little dichloromethane and the product precipitated with cold ether, (0.24 g, 37%). M.p. 126-128°C. Found: C,63.52; H.4.61; N.13.19. C 22 H 19 ClN 4 O 2 . 0.5 H 2 O requires C.63.54; H,4.81; N,13.47%.
  • Examples 148-151 were prepared by the method of Example 1 using 4-(2-methylimidazo[4,5-c]pyrid-1-yl)benzyl alcohol and the appropriate phenol.
  • Example 152 was prepared similarly using the procedure of Example 147 but isolating the product as the free basee
  • Example 153 The product from Example 153 (2.43 g, 6.54 mmol) was dissolved in a mixture of methanol (60 ml), water (40 ml) and aqueous sodium hydroxide (1M, 3.27 ml, 3.27 mmol) at room temperature with stirring, and then sodium borohydride (254 mg, 6.54 mmol) was added. The mixture was stirred for 18 hours at room temperature, and then parlitioned between dichloromethane (3 x 50 ml) and 0.1M aqueous sodium hydroxide (200 ml).
  • Example 154 was cyclised following the method of Example 157 to give the title compound, m.p. 219-220°C (from methanol). Found: C,70.50; H,4.73; N.11.21. C 22 H 18 FN 3 O 2 requires C,70.38; H,4.83; N,11.19%.
  • Example 155 was cyclised following the method of Example 157 to give the title compound, m.p. 243-246°C (from methanol/dichloromethane). Found: C, 74.94; H.6.05; N.10.90.
  • Example 157 The compound from Example 157 (371 mg, 1.0 mmol) was dissolved in dry dimethylformamide (8 ml) and sodium hydride (48 mg, 60% dispersion, 1.2 mmol) was added at room temperature.
  • Example 37 The method of Example 37 was followed using 4-fluoro-(1,3- dihydroxypropyl)benzene to give the title compound, m.p. 70°C.
  • step (c) The product from step (b) above, (240 mg, 0.76 mmol) was added to a mixture of trifluoroacetic acid (8 ml) and triethyl- silane (145 ⁇ l, 0.91 mmol), and the mixture was stirred at 50°C for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 ml) and rendered basic by the addition of saturated aqueous sodium bicarbonate. The aqueous layer was separated, extracted with dichloromethane (2 x 15 ml), and the combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure.
  • Butyllithium (1.6M in hexane; 19 ml, 30 mmol) was added dropwise to a cold (-20°C), stirred solution of phenylethanediol (2 g, 14.5 uuuol) in tetrahydrofuran (80 ml). After 10 minutes, neat chlorotrimethyl-silane (4.5 ml, 35 mmol) was added. After 30 minutes, all voiatiles were removed under vacuum and the residue was partitioned between hexane and saturated sodium bicarbonate solution. The hexane layer was dried over magnesium sulphate and evaporated to give the title product as a pale-yellow oil (4g, 97%).
  • the creamy coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator.
  • Nickel-aluminium alloy (1 g) was added to a stirred solution of 4-(2-methylimidazof4,5-c]pyrid-1-yl)benzonitrile (1 g, 4.3 mmol) in 90% formic acid (13 ml) and water (3 ml). The mixture was heated to 120°C when an exothermic reaction initiated, then heated under reflux for an additional 1 hour. The solution was cooled and filtered using a filter aid, washing the filter cake with methanol. The filtrate was concentrated and partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to dryness.

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PCT/EP1991/000737 1990-05-09 1991-04-17 Imidazopyridine paf antagonists WO1991017162A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI925054A FI925054A0 (fi) 1990-05-09 1992-11-06 Imidazopyridin paf-antagonister

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GB9010404.3 1990-05-09
GB909010404A GB9010404D0 (en) 1990-05-09 1990-05-09 Therapeutic agents

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IE (1) IE911552A1 (fi)
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WO1993014072A1 (en) * 1992-01-07 1993-07-22 British Bio-Technology Limited Amino acid derivatives as paf-receptor antagonists
US6242461B1 (en) * 2000-01-25 2001-06-05 Pfizer Inc. Use of aryl substituted azabenzimidazoles in the treatment of HIV and AIDS related diseases
US6514965B1 (en) 1999-11-18 2003-02-04 Antex Pharma Inc. Substituted 1-benzazepines and derivatives thereof
WO2005116028A2 (en) * 2004-04-26 2005-12-08 Bristol-Myers Squibb Company Bicyclic heterocycles as kinase inhibitors
EP1666480A1 (en) * 2000-10-19 2006-06-07 Pfizer Pharmaceuticals Inc. Aryl or Heteroaryl Fused Imidazole Compounds as intermediates for Anti-Inflammatory And Analgesic Agents.
US7179839B2 (en) 2001-02-13 2007-02-20 Sanofi-Aventis Deutschland Gmbh Acylated indanyl amines and their use as pharmaceuticals
WO2007034277A1 (en) * 2005-09-19 2007-03-29 Pfizer Products Inc. Aryl substituted imidazo [4,5-c] pyridine compounds as c3a receptor antagonists
EP1809294A2 (en) * 2004-09-21 2007-07-25 Synta Pharmaceuticals Corporation Compounds for inflammation and immune-related uses
US7449481B2 (en) 2004-04-13 2008-11-11 Cephalon, Inc. Thio-substituted biaryl-methanesulfinyl derivatives
US7977338B2 (en) 2006-10-16 2011-07-12 Novartis Ag Phenylacetamides being FLT3 inhibitors
US8030311B2 (en) 2005-04-14 2011-10-04 Novartis Ag Phenylacetamides suitable as protein kinase inhibitors
US8394828B2 (en) 2003-02-03 2013-03-12 Janssen Pharmaceutica, Nv Quinoline-derived amide modulators of vanilloid VR1 receptor
WO2014095548A1 (en) * 2012-12-19 2014-06-26 Basf Se Substituted [1,2,4]triazole compounds and their use as fungicides
KR20190003968A (ko) * 2016-05-04 2019-01-10 비.씨.아이. 파르마 단백질 키나아제 억제제로서의 아데닌 유도체

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EP2651930B1 (en) * 2010-12-16 2015-10-28 Boehringer Ingelheim International GmbH Biarylamide inhibitors of leukotriene production
CA2877474A1 (en) * 2011-06-20 2012-12-27 Myrexis, Inc. Compounds and therapeutic uses thereof
CN114262322A (zh) * 2020-09-16 2022-04-01 中国科学院上海有机化学研究所 一类细胞程序性坏死抑制剂及其制备方法和用途

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EP0330327A2 (en) * 1988-02-25 1989-08-30 Pfizer Limited Dihydropyridines, their preparation and their use as PAF-antagonists
WO1990010632A1 (en) * 1989-03-07 1990-09-20 Pfizer Limited Imidazopyrimidine antiallergy agents
EP0389189A2 (en) * 1989-03-23 1990-09-26 Pfizer Limited Diazepine antiallergy agents

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CA2078007A1 (en) 1991-11-10
FI925054A0 (fi) 1992-11-06
IE911552A1 (en) 1991-11-20

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