EP1435933A1 - Derives de 5'-carbamoyl-2'-methyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38 - Google Patents

Derives de 5'-carbamoyl-2'-methyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38

Info

Publication number
EP1435933A1
EP1435933A1 EP02779491A EP02779491A EP1435933A1 EP 1435933 A1 EP1435933 A1 EP 1435933A1 EP 02779491 A EP02779491 A EP 02779491A EP 02779491 A EP02779491 A EP 02779491A EP 1435933 A1 EP1435933 A1 EP 1435933A1
Authority
EP
European Patent Office
Prior art keywords
methyl
biphenyl
alkyl
compound
dicarboxamide
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02779491A
Other languages
German (de)
English (en)
Inventor
Richard Martyn GlaxoSmithKline ANGELL
Nicola Mary GlaxoSmithKline ASTON
Paul GlaxoSmithKline BAMBOROUGH
Mark J. GlaxoSmithKline BAMFORD
George Stuart GlaxoSmithKline COCKERILL
Suzanne Joy GlaxoSmithKline MERRICK
Kathryn Jane GlaxoSmithKline SMITH
Ann Louise GlaxoSmithKline WALKER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
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 Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1435933A1 publication Critical patent/EP1435933A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • This invention relates to novel compounds and their use as pharmaceuticals, particularly as p38 kinase inhibitors, for the treatment of certain diseases and conditions.
  • R 1 is a phenyl group which may be optionally substituted
  • R 2 is selected from hydrogen, C h alky! and -(CH ⁇ v -C ⁇ cycloalkyl;
  • R 3 is the group -CO-NH-(CH 2 ) q -R 4 ; when q is 0 to 2 R 4 is selected from hydrogen, C h alky!, -C 3 . 7 cycloalkyl, CONHR 5 , phenyl optionally substituted by R 7 and/or R 8 , heteroaryl optionally substituted by R 7 and/or R 8 and heterocyclyl optionally substituted by R 7 and/or R 8 ; and when q is 2 R 4 is additionally selected from C ⁇ alkoxy, NHCOR 5 , NHCONHR 5 , NR 5 R 6 , and OH; R 5 is selected from hydrogen, C h alky! and phenyl wherein the phenyl group may be optionally substituted by up to two substituents selected from C ⁇ alkyl and halogen;
  • R 6 is selected from hydrogen and C ⁇ alkyl; or R 5 and R 6 , together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic or heteroaryl ring optionally containing one additional heteroatom selected from oxygen, sulfur and nitrogen, wherein the ring may be substituted by up to two C h alky! groups;
  • R 7 is selected from C h alky!, d. 6 alkoxy, -CONR 6 R 9 , -NHCOR 9 , -SO 2 NHR 9 , - NHSO R 9 , halogen, trifluoromethyl, -Z-(CH 2 ) s -phenyl optionally substituted by one or more halogen atoms, -Z-(CH 2 ) s -heterocyclyl or -Z-(CH 2 ) s -heteroaryl wherein the heterocyclyl or heteroaryl group may be optionally substituted by one or more substituents selected from C ⁇ . 6 alkyl;
  • R 8 is selected from C ⁇ . 6 alkyl and halogen; or when R 7 and R 8 are adjacent to each other they may, together with the carbon atoms to which they are bound, form a five- or six-membered saturated or unsaturated ring to give a fused bicyclic ring system, wherein the ring that is formed by R 7 and R 8 may optionally contain one or two heteroatoms selected from oxygen, nitrogen and sulfur;
  • R 9 is selected from hydrogen and C h alky!; U is selected from methyl and halogen;
  • W is selected from methyl and chlorine
  • X and Y are each selected independently from hydrogen, methyl and halogen
  • Z is selected from -O- and a bond; m is selected from 0, 1, 2, 3 and 4, and may be optionally substituted with up to two groups selected independently from d- ⁇ alkyl; n is selected from 0, 1 and 2; v is selected from 0, 1 and 2; q and s are selected from 0, 1 and 2; or a pharmaceutically acceptable salt or solvate thereof.
  • a compound of formula (IA) is provided:
  • R 1 , R 2 , R 3 and m are as defined above, or a pharmaceutically acceptable salt or solvate thereof.
  • the molecular weight of a compound of formula (I) does not exceed 1000, more preferably 800, even more preferably 600.
  • the group R 1 may be optionally substituted by up to three substituents, more preferably one or two substituents, selected independently from the group consisting of halogen, C h alky!, d-ealkoxy, trifluoromethyl, benzyloxy, hydroxy, cyano, hydroxyd.
  • R 1 may be optionally substituted by two adjacent substituents which, together with the carbon atoms to which they are bound, form a five- or six-membered saturated or unsaturated ring to give a fused bicyclic ring system.
  • the ring that is fused to the phenyl ring may optionally contain one or two heteroatoms selected from oxygen, nitrogen and sulfur.
  • the group R 1 may also be optionally substituted by three, more preferably one or two, C 3 . 7 cycloalkyl groups.
  • R 10 and R 11 are independently selected from hydrogen, C h alky!, trihalomethyl, benzyl, -(CH 2 ) r OH, -(CH 2 ) r NR 12 R 13 and phenyl optionally substituted by up to three groups selected from C h alky! and d-ealkoxy.
  • R 10 and R 11 may also be independently selected from d- ⁇ alkyl substituted by up to three, more preferably one or two, hydroxy groups.
  • R 12 and R 13 are independently selected from hydrogen and C 1-4 alkyl.
  • A is selected from halogen, -SO 2 NH 2 , -SO 2 -(4-methyl)piperazinyl, -NR ⁇ COC ⁇ alkyl and -NR 10 SO 2 d. 6 alkyl.
  • p is selected from 0, 1 , 2 or 3.
  • t is selected from 0, 1, 2 and 3.
  • r is selected from 2 or 3.
  • the optional substituents on the group R 1 may be located on any position on the phenyl ring.
  • that substituent when there is one substituent on the group R 1 , that substituent is located on the meta- or para-position relative to the amide linkage.
  • these substituents When there are two optional substituents on the group R 1 , these substituents preferably occupy the meta- and para-positions relative to the amide linkage.
  • Preferred substituents for the group R 1 are halogen, d ⁇ alkyl, trifluoromethyl, d- 4 alkoxy, phenyloxy optionally substituted by the group A, benzyloxy, hydroxy, cyano, - CH 2 CH 2 OH, -(CH 2 ) P -NHCH 3 , -(CH 2 ) P -N(CH 3 ) 2 , -(CH 2 ) P CONR 10 R 11 , -(CH 2 ) p CO 2 R 10 , - (CH 2 ) P NR 10 COR 11 , -(CH 2 ) p OCOR 10 , -(CH 2 ) P OCONR 0 R 11 , -(CH 2 ) P NR 0 COOR 11 , -
  • substituents for the group R 1 include -CH 2 OH.
  • substituents for the group R 1 include halogen, in particular fluorine or chlorine; C ⁇ alkyl, in particular methyl; d ⁇ alkoxy, in particular methoxy; hydroxy; cyano; hydroxyC ⁇ alkyl, in particular -CH 2 OH or -CH 2 CH 2 OH; - (CH 2 ) p CO(CH 2 ) t NR 10 R ⁇ in particular -CONH 2 or -CH 2 CONH 2 ; -(CH 2 ) P SO 2 NR 10 R 1 ⁇ in particular -SO 2 NH 2 ; -(CH 2 ) P NR 10 SO 2 R 11 , in particular -NHSO 2 CH 3 or -CH 2 NHSO 2 CH 3 ; -SO 2 R 10 , in particular -SO 2 (CH 2 ) 2 OH; and -(CH 2 ) P NR 10 R 11 , in particular -CH 2 N(CH 3 ) 2 .
  • halogen in particular fluorine or chlorine
  • R 2 is selected from hydrogen, d ⁇ alkyl and -CH 2 - cyclopropyl, more preferably hydrogen. In further preferred embodiment, R 2 is selected from hydrogen, methyl and ethyl.
  • R 4 is selected from d ⁇ alkyl, cyclopropyl, -CH 2 - cyclopropyl, pyridinyl and phenyl. In further preferred embodiment, R 4 is selected from
  • C 1-4 alkyl in particular ethyl or isopropyl; -C 3 . 7 cycloalkyl, in particular cyclopropyl, cyclobutyl or cyclopentyl, especially cyclopropyl; phenyl optionally substituted by R 7 and/or R 8 , in particular phenyl optionally substituted by C ⁇ alkyl, C 1 _ 4 alkoxy, -CONH 2 , -
  • heteroaryl is preferably pyridyl, pyrimidyl or oxadiazolyl optionally substituted by C ⁇ alkyl or phenyl optionally substitued with adjacent groups which give a fused bicyclic ring system, especially quinolinyl, isoquinolinyl or tetralonyl; heteroaryl optionally substituted by R 7 and/or R 8 , in particular thienyl, pyridyl or benzofuran optionally substituted by C, ⁇ alkyl and/or -CONH 2 ; and NHCONHR 5 , in particular where R 5 is phenyl.
  • R 5 is selected from hydrogen and d ⁇ alkyl. In a further preferred embodiment, R 5 is selected from phenyl optionally substituted by d_ 4 alkyl, in particular methyl.
  • R 6 is selected from hydrogen and d ⁇ alkyl. In particular, R 6 is selected from hydrogen or methyl.
  • R 7 is selected from C 1 - 4 alkyl, -NHCOCH 3 , pyridinyl, pyrimidinyl and oxadiazolyl.
  • R 7 is selected from d. 4 alkyl, in particular methyl; C 1-4 alkoxy, in particular methoxy; -CONR 6 R 9 , in particular - CONHCH 3 or CONH 2 ; -NHCOR 9 , in particular -NHCOCH 3 ; -SO 2 NHR 9 , in particular - SO2NH2; -NHSO 2 R 9 , in particular -NHSO 2 CH 3 ; halogen, in particular chlorine; and -Z-
  • heteroaryl wherein the heteroaryl is preferably pyridyl, pyrimidyl or oxadiazolyl optionally substituted by C-
  • R 8 is selected from C 1-4 alkyl, fluorine and chlorine.
  • R 8 is selected from methyl and chlorine.
  • R 9 is selected from hydrogen and methyl.
  • R 10 and R 11 are independently selected from hydrogen, trifluoromethyl and phenyl. In a further preferred embodiment, R 10 and R 11 are independently selected from hydrogen; d ⁇ alkyl, in particular methyl or t- butyl; or d ⁇ alkyl substituted by up to three, more preferably one or two, hydroxy groups, in particular 2-hydroxyethyl or 1 ,3-dihydroxyprop-2-yl.
  • R 12 and R 13 are independently selected from hydrogen, C h alky! and trifluoromethyl.
  • W is methyl
  • X and Y are each selected independently from hydrogen, chlorine and fluorine. In a further preferred embodiment, X is fluorine. In a preferred embodiment, Z is a bond.
  • m is selected from 0, 1 and 2.
  • n is selected from 0 and 1. In particular, n is 0.
  • p is selected from 0, 1 and 2.
  • q is selected from 0 and 1. In one embodiment, q is
  • s is selected from 0 and 1.
  • t is selected from 0, 1 and 2.
  • Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts and solvates. Specific examples which may be mentioned include:
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C ⁇ alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl and t-butyl.
  • a d ⁇ alkyl group is preferred, for example methyl, ethyl or isopropyl.
  • the said alkyl groups may be optionally substituted with one or more fluorine atoms, for example, trifluoromethyl.
  • alkoxy refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2- methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.
  • a d ⁇ alkoxy group is preferred, for example methoxy or ethoxy.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms.
  • C ⁇ cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms.
  • Examples of "cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a C 3 . 5 cycloalkyl group is preferred, for example cyclopropyl.
  • heteroaryl ring and “heteroaryl” refer to a monocyclic five- to seven- membered unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur.
  • the heteroaryl ring has five or six ring atoms.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • a particularly preferred heteroaryl ring is pyridyl.
  • the said ring may be optionally substituted by one or more substituents independently selected from d. 6 alkyl and oxy.
  • heteroaryl ring and “heteroaryl” also refer to fused aromatic rings comprising at least one heteroatom selected from oxygen, nitrogen and sulfur. Preferably, the fused ring each have five or six ring atoms. Examples of fused aromatic rings include, but are not limited to, indolyl, benzofuranyl and benzothiophenyl, in particular benzofuranyl.
  • heterocyclic rings and “heterocyclyl” refer to a monocyclic three- to seven-membered saturated or non-aromatic, unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur.
  • the heterocyclyl ring has five or six ring atoms.
  • heterocyclyl groups include, but are not limited to, aziridinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino, and thiomorpholino.
  • the said ring may be optionally substituted by one or more substituents independently selected from d. 6 alkyl and oxy.
  • fused bicyclic ring system refers to a ring system comprising two five- to seven-membered saturated or unsaturated hydrocarbon rings, the ring system optionally containing one or more heteroatoms independently selected from oxygen, nitrogen and sulfur. Preferably, each ring has five or six ring atoms.
  • suitable fused bicyclic rings include, but are not limited to, naphthyl, indolyl, indolinyl, benzothienyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzodioxanyl, indanyl and tetrahydronaphthyl.
  • Each ring may be optionally substituted with one or more substitutents selected from halogen, d. 6 alkyl, oxy, -(CH 2 ) P NR 10 R 11 , -CO(CH 2 ) P NR 10 R 11 , and imidazolyl.
  • Particularly preferred substituents are chlorine, imidazolyl and -CH 2 - N(CH 3 ) 2 .
  • halogen refers to the elements fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. A particularly preferred halogen is fluorine.
  • the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably the solvent used is water.
  • Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
  • compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • Salts of the compounds of the present invention are also encompassed within the scope of the invention and may, for example, comprise acid addition salts resulting from reaction of an acid with a nitrogen atom present in a compound of formula (I).
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,
  • Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • a general method (A) for preparing the compounds of Formula (I) comprises the reactions set out in Scheme 1 below.
  • a general method (B) for preparing the compounds of Formula (I) comprises the reactions set out in Scheme 2 below.
  • a general method (C) for preparing the compounds of Formula (I) comprises the reactions set out in Scheme 3 below.
  • the acid compound (XIII) may be converted to an activated form of the acid, for example the acid chloride, by treatment with, for example, oxalyl chloride, and then the activated acid thus formed reacted with the amine compound (XIV));
  • R 3 , U, W, X, Y and n are as defined above and R 1A and R ⁇ are R 1 and R 2 as defined above or groups convertible to R 1 and R 2 , to give a compound of formula (I).
  • Suitable amide forming conditions are well known in the art and include treating a solution of the acid, in for example THF, with an amine in the presence of, for example, HOBT, HBTU and DIPEA.
  • the compounds, salts or solvates of the present invention are conveniently administered in the form of pharmaceutical compositions.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the compounds of formula (I) and their pharmaceutically acceptable salts and solvates may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration.
  • the pharmaceutical composition may be in a form such that it can effect controlled release of the compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
  • a particularly preferred method of administration, and corresponding formulation, is oral administration.
  • the pharmaceutical composition may take the form of, and be administered as, for example, tablets (including sub-lingual tablets) and capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, emulsions, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the present invention can also be administered in the form of liposome emulsion delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the present invention includes pharmaceutical compositions containing 0.1 to 99.5%, more particularly, 0.5 to 90% of a compound of the formula (I) in combination with a pharmaceutically acceptable carrier.
  • composition may also be administered in nasal, ophthalmic, otic, rectal, topical, intravenous (both bolus and infusion), intraperitoneal, intraarticular, subcutaneous or intramuscular, inhalation or insufflation form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • transdermal administration the pharmaceutical composition may be given in the form of a transdermal patch, such as a transdermal iontophoretic patch.
  • the pharmaceutical composition may be given as an injection or a continuous infusion (e.g. intravenously, intravasculariy or subcutaneously).
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • parenteral administration these may take the form of a unit dose presentation or as a multidose presentation preferably with an added preservative.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle.
  • the compounds of the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the composition may be formulated for topical application, for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
  • Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.
  • Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropan
  • gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • the pharmaceutical compositions generally are administered in an amount effective for treatment or prophylaxis of a specific condition or conditions. Initial dosing in human is accompanied by clinical monitoring of symptoms, such symptoms for the selected condition.
  • the compositions are administered in an amount of active agent of at least about 100 ⁇ g/kg body weight. In most cases they will be administered in one or more doses in an amount not in excess of about 20 mg/kg body weight per day. Preferably, in most cases, dose is from about 100 ⁇ g/kg to about 5 mg/kg body weight, daily.
  • the daily dosage level of the active agent will be from 0. 1 mg/kg to 10 mg/kg and typically around 1 mg/kg. It will be appreciated that optimum dosage will be determined by standard methods for each treatment modality and indication, taking into account the indication, its severity, route of administration, complicating conditions and the like. The physician in any event will determine the actual dosage which will be most suitable for an individual and will vary with the age, weight and response of the particular individual. The effectiveness of a selected actual dose can readily be determined, for example, by measuring clinical symptoms or standard anti-inflammatory indicia after administration of the selected dose.
  • the present invention provides a compound of formula (I) or a salt or solvate thereof, for use in therapy.
  • the compounds of the present invention are generally inhibitors of the serine/threonine kinase p38 and are therefore also inhibitors of cytokine production which is mediated by p38 kinase.
  • inhibitors of the serine/threonine kinase p38 are included those compounds that interfere with the ability of p38 to transfer a phosphate group from ATP to a protein substrate according to the assay described below.
  • the compounds of the invention may be selective for one or more of the isoforms of p38, for example p38 ⁇ , p38 ⁇ , p38 ⁇ and/or p38 ⁇ .
  • the compounds of the invention selectively inhibit the p38 ⁇ isoform.
  • the compounds of the invention selectively inhibit the p38 ⁇ isoform.
  • the compounds of the invention selectively inhibit the p38 ⁇ and p38 ⁇ isoforms.
  • Assays for determining the selectivity of compounds for the p38 isoforms are described in, for example, WO 99/61426, WO 00/71535 and WO
  • p38 kinase activity can be elevated (locally or throughout the body), p38 kinase can be incorrectly temporally active or expressed, p38 kinase can be expressed or active in an inappropriate location, p38 kinase can be constitutively expressed, or p38 kinase expression can be erratic; similarly, cytokine production mediated by p38 kinase activity can be occurring at inappropriate times, inappropriate locations, or it can occur at detrimentally high levels.
  • the present invention provides a method for the treatment of a condition or disease state mediated by p38 kinase activity, or mediated by cytokines produced by the activity of p38 kinase, in a subject which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.
  • the present invention also provides a method of inhibiting cytokine production which is mediated by p38 kinase activity in a subject, e.g. a human, which comprises administering to said subject in need of cytokine production inhibition a therapeutic, or cytokine-inhibiting, amount of a compound of the present invention.
  • the compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomers, a single diastereoisomer or a mixture of diastereoisomers.
  • the present invention treats these conditions by providing a therapeutically effective amount of a compound of this invention.
  • therapeutically effective amount is meant a symptom-alleviating or symptom-reducing amount, a cytokine-reducing amount, a cytokine-inhibiting amount, a kinase-regulating amount and/or a kinase- inhibiting amount of a compound.
  • Such amounts can be readily determined by standard methods, such as by measuring cytokine levels or observing alleviation of clinical symptoms. For example, the clinician can monitor accepted measurement scores for anti-inflammatory treatments.
  • the compounds of the present invention can be administered to any subject in need of inhibition or regulation of p38 kinase or in need of inhibition or regulation of p38 mediated cytokine production.
  • the compounds may be administered to mammals.
  • mammals can include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, most preferably, humans.
  • the present invention provides methods of treating or reducing symptoms in a human or animal subject suffering from, for example, rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritable bowel syndrome, muscle degeneration, bone resorption diseases, osteoporosis, diabetes, reperfusion injury, graft vs.
  • rheumatoid arthritis arthritis
  • osteoarthritis asthma
  • psoriasis eczema
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from rheumatoid arthritis, neurodegenerative disease,
  • Alzheimer's disease, Parkinson's disease and epilepsy which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a further aspect of the invention provides a method of treatment of a human or animal subject suffering from any type of pain including chronic pain, rapid onset of analgesis, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain associated with osteoarthritis and rheumatoid arthritis, post operative inflammatory pain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia, post-hepatic neuralgia, inflammatory neuropathies and migraine pain which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a further aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of a condition or disease state mediated by p38 kinase activity or mediated by cytokines produced by p38 kinase activity.
  • a further aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of a condition or disease state selected from rheumatoid arthritis, osteoarthritis, asthma, psoriasis, eczema, allergic rhinitis, allergic conjunctivitis, adult respiratory distress syndrome, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, silicosis, endotoxemia, toxic shock syndrome, inflammatory bowel disease, tuberculosis, atherosclerosis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, aneurism, stroke, irritable bowel syndrome, muscle degeneration, bone resorption diseases, osteoporosis, diabetes, reperfusion injury, graft vs.
  • a condition or disease state selected from rheum
  • a further aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of a condition or disease state selected from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy, and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer.
  • a condition or disease state selected from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis, Crohn's disease, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, epilepsy, and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer.
  • a further aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of a condition or disease state selected from rheumatoid arthritis, asthma, psoriasis, chronic pulmonary inflammation, chronic obstructive pulmonary disease, chronic heart failure, systemic cachexia, glomerulonephritis,
  • Crohn's disease and cancer including breast cancer, colon cancer, lung cancer and prostatic cancer.
  • a further aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of a condition or disease state selected from rheumatoid arthritis, neurodegenerative disease, Alzheimer's disease, Parkinson's disease and epilepsy.
  • a further aspect of the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for the treatment of any type of pain including chronic pain, rapid onset of analgesis, neuromuscular pain, headache, cancer pain, acute and chronic inflammatory pain associated with osteoarthritis and rheumatoid arthritis, post operative inflammatory pain, neuropathic pain, diabetic neuropathy, trigeminal neuralgia, post-hepatic neuralgia, inflammatory neuropathies and migraine pain.
  • the compounds of formula (I) and their salts, solvates and physiologically functional salts and solvates may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions.
  • Combination therapies thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other pharmaceutically active agent.
  • the compound(s) of formula (I) or pharmaceutically acceptable salt(s) or solvate(s) thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur separately or sequentially in any order.
  • the amounts of the compound(s) of formula (I) or pharmaceutically acceptable salt(s) or solvate(s) thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • Examples of other pharmaceutically active agents which may be employed in combination with compounds of formula (I) and their salts and solvates for rheumatoid arthritis therapy include: immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone; anti-TNF ⁇ agents such as etanercept, infliximab, diacerein; tyrosine kinase inhibitors such as leflunomide; kallikrein antagonists such as subreum; interleukin 11 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interleukin 1 receptor antagonists such as anakinra; CD8 antagonists such as amiprilose hydrochloride; beta amyloid precursor protein antagonists such as reumacon; matrix metalloprotease inhibitors such as cipemastat and other disease modifying anti-rheumatic drugs (DMARDs)
  • LCMS was conducted on a column (3.3cm x 4.6mm ID, 3um ABZ+PLUS), at a Flow Rate of 3ml/min, Injection Volume of 5 ⁇ l, at room temperature and UV Detection Range at 215 to 330nm.
  • DIPEA 44 ⁇ l was added to a mixture of benzoic acid (0.084mmol), HOBT (0.084mmol), PyBOP (0.084mmol) and amine (O.lmmol) in DMF (0.5ml) and the reaction was stirred at room temperature for 17hours. The DMF was evaporated under vacuum and the residue partitioned between DCM (5ml) and aqueous sodium carbonate solution (1M, 5ml).
  • the organic fraction was chromatographed on a silica SPE (5g) eluting with DCM, chloroform, diethyl ether, ethyl acetate, acetonitrile, acetone, ethanol and methanol or DCM/ethanol/ammonia (1:0:0, 300:8:1, 200:8:1, 100:8:1).
  • the product fractions were combined and evaporated to dryness to give the amide.
  • DIPEA (44 ⁇ l) was added to a mixture of benzoic acid (0.084mmol), PyBOP (0.084mmol) and amine (O.lmmol) in DCM (2ml) and the reaction was stirred at room temperature for 18hours.
  • the reaction was washed with aqueous sodium carbonate solution (1M, 2ml) and the organic fraction was chromatographed on a silica SPE (5g) eluting with DCM, chloroform, diethyl ether, ethyl acetate, acetonitrile, acetone, ethanol, methanol and DCM/ethanol/ammonia (20:8:1 then 15:8:1).
  • the product fractions were combined and evaporated to dryness to give the amide.
  • N 4 -(3-Cyanophenyl)-6-methyl-N 3 -(pyrid-4-ylmethyl)-1 , 1 '-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1,1'-biphenyl-3-yl)carboxylic acid and 4-aminomethylpyridine using method A.
  • N 3 -(2-Benzof uran-2-ylethyl)-N 4' -(3-cyanophenyl)-6-methyl-1 , 1 '-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1,1'-biphenyl-3-yl)carboxylic acid and 2-(2-aminoethyl)benzofuran using method A.
  • N 4' -(3-Cyanophenyl)-6-methyl-N 3 -[2-(3-phenylureido)ethyl]-1 , 1 '-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1,1 '-biphenyl-3-yl)carboxylic acid and 1 -(2-aminoethyl)-3-phenylurea using method A.
  • N 4' -(3-Cyanophenyl)-6-methyl-N 3 -(4-sulphamoylbenzyl)-1,1'-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1,1'-biphenyl-3-yl)carboxylic acid and 4-(aminomethyl)benzenesulphonamide using method A.
  • Example 5 N 4' -(3-Cvanophenyl)-6-methyl-N 3 -(2- f(4- methylphenyl)amino1carbonyl)ethyl)-1.1'-biphenyl-3.4'-dicarboxamide N 4' -(3-Cyanophenyl)-6-methyl-N 3 -(2- ⁇ [(4-methylphenyl)amino]carbonyl ⁇ ethyl)-1 , 1 '- biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]- carbonyl ⁇ -6-methyl-1J'-biphenyl-3-yl)carboxylic acid and 3-amino-N-(4- methylphenyl)propanamide using method A. NMR: ⁇ H [ 2 H 6 ] - DMSO 10.63,(1 H, s),
  • N ' -(3-Cyanophenyl)-6-methyl-N 3 - ⁇ 3-[(methylamino)carbonyl]benzyl ⁇ -1 , 1 '-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1 J'-biphenyl-3-yl)carboxylic acid and 3-(aminomethyl)-N-methylbenzamide using method A.
  • N 3 -(4-Carbamoylbenzyl)-N 4 -(3-cyanophenyl)-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1J'-biphenyl-3- yl)carboxylic acid and 4-(aminomethyl)benzamide using method A.
  • N 4' -(3-Cyanophenyl)-6-methyl-N 3 -[3-(methylsulphonamido)benzyl]-1 , 1 '-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1J'-biphenyl-3-yl)carboxylic acid and N-[3-(aminomethyl)phenyl]methanesulphonamide using method A.
  • N 4 -(3-Cyanophenyl)-N 3 -cyclopropylmethyl-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1,1'-biphenyl-3- yl)carboxylic acid and cyclopropylmethylamine using method A.
  • Example 10 N 4 -(3-Cvanophenyl)-N 3 -cvclopropyl-6-methyl-1.1 '-biphenyl-3.4'- dicarboxamide N 4 -(3-Cyanophenyl)-N 3 -cyclopropyl-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1 , 1 '-biphenyl-3- yl)carboxylic acid and cyclopropylamine using method A.
  • Example 11 N 4 -(3-Cvanophenyl)-6-methyl-N 3 -(quinolin-5-ylmethvO-1.1 '-biphenyl- 3.4'-dicarboxamide N 4 -(3-Cyanophenyl)-6-methyl-N 3 -quinolin-5-ylmethyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1,1'-biphenyl-3- yl)carboxylic acid and 5-aminomethylquinoline using method B.
  • Example 12 N ' -(3-Cvanophenyl)-6-methyl-N 3 -tetralon-6-yl -1.r-biphenyl-3,4'- dicarboxamide
  • N 4 -(3-Cyanophenyl)-6-methyl-N 3 -tetralon-6-yl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1,1'-biphenyl-3- yl)carboxylic acid and 6-aminotetralone using method C and purified by preparative HPLC.
  • LCMS retention time 3.74min, MH + 500.
  • N 3 -(3-Chlorophenyl)-N 4 -(3-cyanophenyl)-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1 , 1 '-biphenyl-3- yl)carboxylic acid and 3-chloroaniline using method C and purified by preparative HPLC.
  • Example 16 N 3 -(2-Chlorophenvn-N ' -(3-cvanophenyl)-6-methyl-1.1 '-biphenyl-3.4'- dicarboxamide N 3 -(2-Chlorophenyl)-N 4 -(3-cyanophenyl)-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1 , 1 '-biphenyl-3- yl)carboxylic acid and 2-chloroaniline using method C. Purified by preparative HPLC. LCMS: retention time 3.93min, MH + 466.
  • N 4 -(3-Cyanophenyl)-6-methyl-N 3 -(3-methylpyrid-4-yl)-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1J'-biphenyl-3- yl)carboxylic acid and 4-amino-3-methylpyridine using method C. Purified by preparative HPLC.
  • Example 18 N 3 -(3-Acetylaminophenyl)-N 4 -(3-cvanophenyl)-6-methyl-1 , 1 '-biphenyl-
  • N 3 -(3-Acetylaminophenyl)-N 4 -(3-cyanophenyl)-6-methyl-1 , 1 '-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1J'-biphenyl-3-yl)carboxylic acid and 3'-aminoacetanilide using method C. Purified by preparative HPLC. NMR: ⁇ H [ 2 H 6 ] - DMSO 10.67,(1 H, s), 10.25,(1 H, s), 9.96,(1 H, s),
  • N 4' -(3-Cyanophenyl)-6-methyl-N 3 -[3-(2-methylpyrimidin-4-yl)phenyl]-1 , 1 '-biphenyl-3,4'- dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl- 1J'-biphenyl-3-yl)carboxylic acid and 4-(3-aminophenyl)-2-methylpyrimidine using method C. Purified by preparative HPLC. NMR: ⁇ H [ 2 H 6 ] - DMSO 10.66,(1 H, s),
  • N 4 -(3-Cyanophenyl)-N 3 -(isoquinolin-5-yl)-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1,1'-biphenyl-3- yl)carboxylic acid and 5-aminoisoquinoline using method C. Purified by preparative HPLC.
  • Example 22 N 4' -(3-Cvanophenyl)-N 3 -(isoquinolin-6-yl)-6-methyl-1.1 '-biphenyl-3.4'- dicarboxamide
  • N 4 -(3-Cyanophenyl)-N 3 -(isoquinolin-6-yl)-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from (4'- ⁇ [(3-cyanophenyl)amino]carbonyl ⁇ -6-methyl-1 ,1 '-biphenyl-3- yl)carboxylic acid and 6-aminoisoquinoline using method C. Purified by preparative HPLC. NMR: ⁇ H [ 2 H 6 ] - DMSO 10.66,(1 H, s), 10.63,(1H, s), 9J9,(1 H, s), 8.53,(1 H, d),
  • Example 24 N 4' -(3-Cvanophenyl)-6-methyl-N 3 -(2-methylpyridin-3-yl)-1.1 '-biphenyl- 3.4'-dicarboxamide (4'- ⁇ [(3-Cyanophenyl)amino]carbonyl ⁇ -6-methyl-1 , 1 '-biphenyl-3-yl)carbonyl chloride
  • Example 27 N 4, -(3-Cvanophenyl)-6-methyl-N 3 -f3-(pyrid-2-yl)phenyl1-1.1 '-biphenyl- 3,4'-dicarboxamide
  • Example 28 N 4' -(3-Cvanophenyl)-6-methyl-N 3 -f3-(5-methyl-1.2.4-oxadiazol-3- yl)phenyl1-1.1 '-biphenyl-3.4'-dicarboxamide
  • N 3 -Cyclopropyl-N 4 -(3-methoxybenzyl)-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from 3'-[(cyclopropylamino]carbonyl]-6'-methyl-1J'-biphenyl-4-yl)carboxylic acid and 3-methoxybenzylamine using method D. Purified by chromatography on silica, eluting with a toluene/methanol (9:1).
  • N 3 -Cyclopropyl-N 4 -(4-methoxyphenyl)-6-methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide was synthesised from 3'-[(cyclopropylamino]carbonyl]-6'-methyl-1J'-biphenyl-4-yl)carboxylic acid and 4-methoxyaniline using method D. Purified by chromatography on silica, eluting with a toluene/methanol (19:1).
  • Example 36 N 3 -Cvclopropyl-N 4 '-f2-(4-methoxyphenyl)ethvH-6-methyl-1.1 '- biphenyl-3,4'-dicarboxamide
  • Example 37 N 3 -Cyclopropyl-6-methyl-N 4 '-(3-f (methylsulfonyl)amino]benzyl)-1.1 '- biphenyl-3,4'-dicarboxamide
  • Example 38 N 3 -Cvclopropyl-N 4 '-f3-r(dimethylamino)methyl1-1 H-indol-5-yl>-6- methyl-1J'-biphenyl-3.4'-dicarboxamide
  • HATU (6mg, 0J7mmol) was added to a solution of 3'-[(cyclopropylamino)carbonyl]-6'- methyl-biphenyl-4-carboxylic acid (50mg, 0.17mmol) in DMF (2ml). After 5 minutes HOBT (23mg, 0J7mmol), the chosen amine (0.17mmol) and DIPEA (0.087ml, 0.51 mmol) were added and the reaction mixture stirred at 80°C under nitrogen for 16 hours. The DMF was removed in vacuo and the residue partitioned between DCM (5ml) and aqueous sodium carbonate solution (1M, 5ml).
  • the layers were separated and the organic layer purified by SPE cartridge (Si, 5g) eluting in turn with DCM, chloroform, ether, ethyl acetate, acetonitrile, acetone, ethanol, methanol and DCM:ethanol:ammonia (20:8:1) to give the desired products.
  • HATU (1.29g, 3.39mmol) was added to a solution of 3'-[(cyclopropylamino)carbonyl]-6'- methyl-biphenyl-4-carboxylic acid (1g, 3.39mmol) in THF (20ml). After 5 minutes HOBT (0.46g, 3.39mmol), 3-bromobenzylamine hydrochloride (0.905g, 4.07mmol) and DIPEA (2.5, 14.24mmol) were added and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The THF was removed in vacuo. The residue was partitioned between ethyl acetate (50ml) and water (50ml).
  • HATU (6mg, 0J7mmol) was added to a solution of 3'-[(cyclopropylamino)carbonyl]-6'- methyl-biphenyl-4-carboxylic acid (50mg, 0J7mmol) in DMF (2ml). After 5 minutes HOBT (23mg, 0J7mmol), N-(4-aminophenyl)methanesulphonamide (0J7mmol) and DIPEA (0.087ml, 0.51 mmol) were added and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The reaction was partitioned between ethyl acetate (50ml) and hydrochloric acid (1M, 50ml).
  • Example 41 N 3 -Cyclopropyl-6-methyl-N 4 '-(4- ⁇ r(methylsulfonyl)amino1methyl)phenyl)-1.1 '-biphenyl-3,4'-dicarboxamide HATU (65mg, 0J7mmol) was added to a solution of 3'-[(cyclopropylamino)carbonyl]-6'- methyl-biphenyl-4-carboxylic acid (50mg, 0J7mmol) in DMF (2ml).
  • the crude material was purified by SPE cartridge (Si, 5g) eluting in turn with DCM:ethanol:ammonia (400:8:1), ethyl acetate, acetonitrile, acetone and ethanol to yield the N 3 -cyclopropyl-6-methyl-N 4 '-(4- ⁇ [(methylsulfonyl)amino]methyl ⁇ phenyl)-1 , 1 '-biphenyl-3,4'-dicarboxamide.
  • Example 42 N 4 '-[4-(Aminosulfonyl)benzv ⁇ -N -cvclopropyl-6-methyl-1,1'-biphenyl- 3,4'-dicarboxamide HATU (65mg, 0.17mmol) was added to a solution of 3'-[(cyclopropylamino)carbonyl]-6'- methyl-biphenyl-4-carboxylic acid (50mg, 0.17mmol) in DMF (2ml).
  • the layers were separated and the organic layer purified by SPE cartridge (Si, 5g) eluting in turn with DCM, chloroform, ether, ethyl acetate, acetonitrile, acetone, ethanol, DCM:ethanol:ammonia (40:8:1) DCM:ethanol:ammonia (20:8:1) and DCM:ethanol:ammonia (10:8:1) to give N 4 '-[4-(aminosulfonyl)benzyl]-N 3 -cyclopropyl-6- methyl-1 , 1 '-biphenyl-3,4'-dicarboxamide.
  • HATU (6mg, 0.17mmol) was added to a solution of 3'-[(cyclopropylamino)carbonyl]-6'- methyl-biphenyl-4-carboxylic acid (50mg, 0J7mmol) in DMF (2ml). After 5 minutes HOBT (23mg, 0.17mmol), 3-(dimethylaminomethyl)benzylamine (Intermediate 3, 0J7mmol) and DIPEA (0.087ml, 0.51 mmol) were added and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The DMF was removed in vacuo and the residue partitioned between DCM (5ml) and aqueous sodium carbonate solution (1M, 5ml).
  • Triethylamine (21.27ml, 152.6mmol) was added to a suspension of 3- chloromethylbenzylamine hydrochloride (Intermediate 6, 167.92mmol) in dry THF (180ml).
  • a solution of di-tert-butyl dicarbonate (14.75g, 67.58mmol) in dry THF (50ml) was added dropwise at 0°C. Once the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (250ml) and washed with water (150ml). The aqueous layer was extracted with ethyl acetate (50ml).
  • Example 45 N 3 -Cvclopropyl-N 4 '-(2-hvdroxybenzyl)-6-methyl-1.1 '-biphenyl-3,4'- dicarboxamide
  • Example 46 N 4 '-[3-(Aminosulfonyl)phenyll-N -cvclopropyl-6-methyl-1.1 '-biphenyl- 3,4'-dicarboxamide
  • Example 47 N 3 -Cvclopropyl-N 4 '-(2.6-difluorobenzyl)-6-methyl-1.1 '-biphenyl-3,4'- dicarboxamide
  • Example 48 N 3 -Cvclopropyl-N 4 '-(2.6-dimethoxybenzyl)-6-methyl-1 J'-biphenyl-
  • Example 50 N 3 -Cvclopropyl-N 4 '-(4-fluorobenzyl)-6-methyl-1.1 '-biphenyl-3.4'- dicarboxamide
  • Example 51 N 3 -Cvclopropyl-N '-(2.6-dimethylphenyl)-6-methyl-1.r-biphenyl-3.4'- dicarboxamide
  • Example 55 N -Cvclopropyl-N '- ⁇ 4-r(dimethylamino)methyllbenzylV6-methyl-1.1'- biphenyl-3,4'-dicarboxamide
  • Example 56 N '-(2-Chlorobenzyl)-N 3 -cvclopropyl-6-methyl-1.r-biphenyl-3.4'- dicarboxamide
  • Example 60 N 3 -Cvclopropyl-N 4 '-(3-([ethyl(methyl)amino1methyl>benzyl)-6-methyl- 1.1 '-biphenyl-3,4'-dicarboxamide
  • Example 61 N 3 -Cvclopropyl-N 4 '-(3-hvdroxymethylphenyl)-6-methyl-1.1 '-biphenyl-
  • Example 62 N 4 '-r3-(2-Amino-2-oxoethyl)phenvn-N 3 -cvclopropyl-6-methyl-1.1 '- biphenyl-3.4'-dicarboxamide
  • Example 63 N '-Benzyl-N 3 -cvclopropyl-N '-ethyl-6-methyl-1.r-biphenyl-3.4'- dicarboxamide
  • Example 65 N 3 -Cvclopropyl-N 4 '-f3-(2-hvdroxyethyl)phenyl1-6-methyl-1.1 '-biphenyl- 3,4'-dicarboxamide
  • Example 70 N 3 -Ethyl-N 4 '-(4-metho ⁇ yphenyl)-6-methyl-1.1 '-biphenyl-3,4'- dicarboxamide
  • Methyl ⁇ 3'-[(cyclobutylamino)carbonyl]-6'-methyl-1 , 1 '-biphen-4-yl ⁇ carboxylate (Intermediate 8, 123mg, 0.38mmol) in methanol (2ml) was mixed with aqueous sodium hydroxide (2N, 1ml) and stirred at room temperature for 24hours. The methanol was evaporated, the reaction diluted with water (2ml) and extracted with chloroform (3ml). The aqueous was acidified with hydrochloric acid (2N, 3ml) and extracted with chloroform (2x 4ml).
  • Methyl ⁇ 3'-[(isopropylamino)carbonyl]-6'-methyl-1 , 1 '-biphen-4-yl ⁇ carboxylate (Intermediate 12, 0.36mmol) in methanol (2ml) was mixed with aqueous sodium hydroxide (2N, 1ml) and stirred at room temperature for 24hours. The methanol was evaporated, the reaction diluted with water (2ml) and extracted with chloroform (3ml). The aqueous was acidified with hydrochloric acid (2N, 3ml) and extracted with chloroform (2x 4ml).
  • the peptide substrate used in the p33 assay was biotin-IPTSPITTTYFFFRRR- amide.
  • the p3 ⁇ and MEK6 proteins were purified to homogeneity from E.coli expression systems.
  • the fusion proteins were tagged at the N-terminus with Glutathione-S-Transferase (GST).
  • the maximum activation was achieved by incubating 20uL of a reaction mixture of 30nM MEK6 protein and 120nM p3 ⁇ protein in the presence of 1.5uM peptide and 10mM Mg(CH 3 CO 2 ) 2 in 100mM HEPES, pH 7.5, added to 15uL of a mixture of 1.5uM ATP with O.O ⁇ uCi [g- 33 P]ATP, with or without 15uL of inhibitor in 6%DMSO.
  • the controls were reactions in the presence (negative controls) or absence (positive controls) of 50 mM EDTA. Reactions were allowed to proceed for
  • ⁇ P36 Fluorescence Polarisation Method ⁇ P3 ⁇ was prepared in house.
  • SB4777790-R Ligand was diluted in HEPES containing MgCI 2 , CHAPS, DTT and DMSO. This was added to blank wells of a Black

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Emergency Medicine (AREA)
  • AIDS & HIV (AREA)
  • Toxicology (AREA)
  • Endocrinology (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I), ou leurs sels ou solvates acceptables sur le plan pharmaceutique, ainsi que leur utilisation comme produits pharmaceutiques, en particulier comme inhibiteurs de la kinase p38.
EP02779491A 2001-10-17 2002-10-16 Derives de 5'-carbamoyl-2'-methyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38 Withdrawn EP1435933A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0124928.3A GB0124928D0 (en) 2001-10-17 2001-10-17 Chemical compounds
GB0124928 2001-10-17
PCT/EP2002/011570 WO2003032970A1 (fr) 2001-10-17 2002-10-16 Derives de 5'-carbamoyl-2'-methyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38

Publications (1)

Publication Number Publication Date
EP1435933A1 true EP1435933A1 (fr) 2004-07-14

Family

ID=9924024

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02779491A Withdrawn EP1435933A1 (fr) 2001-10-17 2002-10-16 Derives de 5'-carbamoyl-2'-methyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38

Country Status (4)

Country Link
EP (1) EP1435933A1 (fr)
JP (1) JP2005509622A (fr)
GB (1) GB0124928D0 (fr)
WO (1) WO2003032970A1 (fr)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0124933D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0209891D0 (en) 2002-04-30 2002-06-05 Glaxo Group Ltd Novel compounds
GB0308186D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0308201D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
JP2006526656A (ja) 2003-06-03 2006-11-24 ノバルティス アクチエンゲゼルシャフト ５員ヘテロ環ベースのｐ−３８阻害剤
GB0314488D0 (en) * 2003-06-20 2003-07-23 Glaxo Group Ltd Therapeutically useful compounds
NZ544230A (en) 2003-06-26 2009-07-31 Novartis Ag 5-Membered heterocycle-based P38 kinase inhibitors
ES2315703T3 (es) 2003-07-25 2009-04-01 Novartis Ag Inhibidores de la quinasa p-38.
GB0318814D0 (en) * 2003-08-11 2003-09-10 Smithkline Beecham Corp Novel compounds
GB0402138D0 (en) * 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
US7326732B2 (en) * 2004-02-12 2008-02-05 Pharmagene Laboratories Limited EP2 receptor agonists
KR20150090263A (ko) 2004-09-02 2015-08-05 제넨테크, 인크. 헤지호그 신호전달에 대한 피리딜 억제제
PE20060493A1 (es) * 2004-10-05 2006-09-03 Smithkline Beecham Corp Compuestos derivados de bifenil (di o tri) carboxamidas como inhibidores de serina/treonina quinasa p38
WO2006083477A2 (fr) * 2005-01-07 2006-08-10 Synta Pharmaceuticals Corp. Composes utilises pour des etats inflammatoires et immunitaires
BRPI0607308A2 (pt) 2005-01-25 2009-08-25 Synta Pharmaceuticals Corp compostos, composições farmacêuticas e usos dos referidos compostos
RU2452729C2 (ru) * 2005-09-16 2012-06-10 Арроу Терапьютикс Лимитед Бифенильные производные и их применение при лечении гепатита с
SI1940786T1 (sl) 2005-09-16 2010-11-30 Arrow Therapeutics Ltd Bifenilni derivati in njihova uporaba pri zdravljenju hepatitisa C
JP2009538890A (ja) * 2006-05-30 2009-11-12 アロー セラピューティクス リミテッド ビフェニル誘導体及びｃ型肝炎の治療におけるそれらの使用
EP2083816A2 (fr) 2006-10-27 2009-08-05 Brystol-Myers Squibb Company Composés d'amide hétérocyclique utiles comme inhibiteurs de kinase
EP2751080B1 (fr) * 2011-08-31 2015-10-28 Amakem NV Nouveaux inhibiteurs doux de rock
MX2016010777A (es) 2014-02-19 2016-10-26 H Lundbeck As 2-amino-3,5,5-trifluoro-3,4,5,6-tetrahidropiridinas como inhibidores de bace1 para el tratamiento de la enfermedad de alzheimer.
MA40941A (fr) 2014-11-10 2017-09-19 H Lundbeck As 2-amino-5,5-difluoro-6-(fluorométhyl)-6-phényl-3,4,5,6-tétrahydropyridines comme inhibiteurs de bace1
CR20170187A (es) 2014-11-10 2018-02-01 H Lundbeck As 2-Amino-3,5-difluoro-6-metil-6-fenil-3,4,5,6-tetrahidropiridinas en calidad de inhibidores de BACE1 para el tratamiento de la enfermedad de Alzheimer
JO3458B1 (ar) 2014-11-10 2020-07-05 H Lundbeck As 2- أمينو-6- (دايفلوروميثيل) – 5، 5- ديفلورو-6-فينيل-3،4، 5، 6-تيتراهيدروبيريدين كمثبطات bace1
TW201717948A (zh) 2015-08-10 2017-06-01 Ｈ 朗德貝克公司 包括給予２－胺基－３，５，５－三氟－３，４，５，６－四氫吡啶的聯合治療
BR112017007472A2 (pt) 2015-08-12 2018-01-23 H Lundbeck As 2-amino-3-fluoro-3-(fluoro metil)-6-metil-6-fenil- 3,4,5,6-tetra-hidropiridinas como inibidores de bace1
US20190060286A1 (en) 2016-02-29 2019-02-28 University Of Florida Research Foundation, Incorpo Chemotherapeutic Methods
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
CN114748622A (zh) 2017-10-05 2022-07-15 弗尔康医疗公司 P38激酶抑制剂降低dux4和下游基因表达以用于治疗fshd

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE39088E1 (en) * 1995-08-22 2006-05-02 Japan Tobacco, Inc. Amide compounds and use of the same
EP1158985B1 (fr) * 1999-01-13 2011-12-28 Bayer HealthCare LLC DIPHENYLE UREES A SUBSTITUTION OMEGA-CARBOXY ARYLE EN TANT QU'INHIBITEURS DE LA KINASE p38

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03032970A1 *

Also Published As

Publication number Publication date
GB0124928D0 (en) 2001-12-05
JP2005509622A (ja) 2005-04-14
WO2003032970A1 (fr) 2003-04-24

Similar Documents

Publication Publication Date Title
EP1435933A1 (fr) Derives de 5'-carbamoyl-2'-methyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38
US7208629B2 (en) 5′-Carbamoyl-1,1-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7396843B2 (en) 5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US7384963B2 (en) 2′-Methyl-5-(1,3,4-oxadiazol-2-yl)1, 1′-biphenyl-4-carboxaide derivatives and their use as p38 kinase
EP1436272B1 (fr) Derives d'amide biphenylcarboxilique utilises comme inhibiteurs de la kinase p38
US7183297B2 (en) Biphenyl-derivatives as p38-kinase inhibitors
EP1864975B1 (fr) Dérivés de nicotinamide utiles comme inhibiteurs de P38
EP1709046B1 (fr) Inhibiteurs de la kinase p38
US7166623B2 (en) 2′-Methyl-5′-(1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US20040242868A1 (en) 5-acylamino-1,1'-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
WO2003033482A1 (fr) Oxadiazolyl-biphenylcarboxamides et leur utilisation comme inhibiteurs de la kinase p38
WO2004089876A1 (fr) Derives d'amide biphenylcarboxylique utilises en tant qu'inhibiteurs de la kinase p38

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040419

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20090713

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20091124