US20040053953A1 - Treatment of chemokine mediated diseases - Google Patents

Treatment of chemokine mediated diseases Download PDF

Info

Publication number
US20040053953A1
US20040053953A1 US10/390,078 US39007803A US2004053953A1 US 20040053953 A1 US20040053953 A1 US 20040053953A1 US 39007803 A US39007803 A US 39007803A US 2004053953 A1 US2004053953 A1 US 2004053953A1
Authority
US
United States
Prior art keywords
group
substituted
compound
unsubstituted
alkyl
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.)
Abandoned
Application number
US10/390,078
Other languages
English (en)
Inventor
Arthur Taveras
Motasim Billah
Daniel Lundell
William Kreutner
James Jakway
Jay Fine
Loretta Bober
Jianhua Chao
Purakkattle Biju
Younong Yu
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.)
Merck Sharp and Dohme Corp
Original Assignee
Schering Corp
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 Schering Corp filed Critical Schering Corp
Priority to US10/390,078 priority Critical patent/US20040053953A1/en
Assigned to SCHERING CORPORATION reassignment SCHERING CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BILLAH, MOTASIM, BOBER, LORETTA A., CHAO, JIANHUA, FINE, JAY S., JAKWAY, JAMES, KREUTNER, WILLIAM, LUNDELL, DANIEL, BIJU, PURAKKATLE J., TAVERAS, ARTHUR G., YU, YOUNONG
Publication of US20040053953A1 publication Critical patent/US20040053953A1/en
Priority to US11/705,929 priority patent/US7960433B2/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • 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
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • 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
    • 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
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61P9/10—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

Definitions

  • This invention relates to the treatment of chemokine mediated diseases using CXC chemokine receptor antagonists in combination (or association) with other pharmaceutical compounds.
  • the CXC-chemokines include interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1), neutrophil-activating protein-2 (NAP-2), GRO ⁇ , GRO ⁇ , GRO ⁇ , ENA-78, GCP-2, IP-10, MIG and PF4.
  • CC chemokines include RANTES, MIP-1 ⁇ , MIP-2 ⁇ , monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin.
  • Individual members of the chemokine families are known to be bound by at least one chemokine receptor, with CXC-chemokines generally bound by members of the CXCR class of receptors, and CC-chemokines by members of the CCR class of receptors.
  • IL-8 is bound by the CXCR-1 and CXCR-2 receptors.
  • CXC-chemokines promote the accumulation and activation of neutrophils
  • these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini et al., FEBS Left. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Fev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341,643(1993).
  • the CXC-chemokine receptors represent promising targets for the development of novel anti-inflammatory agents.
  • This invention provides a method of treating a CXC chemokine mediated disease comprising administering to a patient (i.e., a mammal, e.g. human) in need of such treatment, a therapeutically effective amount of:
  • the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more disease modifying antirheumatic drugs (DMARDs) such as, for example, methotrexate, azathioptrine, luflunomide, penicillamine, gold salts, mycophenolate, mofetil, cyclophosphamide and the like.
  • DMARDs disease modifying antirheumatic drugs
  • the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more nonsteroidal anti-inflammatory drugs (NSAIDS) such as, for example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like.
  • NSAIDS nonsteroidal anti-inflammatory drugs
  • a disease modifying antirheumatic drug such as, for example, methotrexate, azathioptrine, luflunomide, penicillamine, gold salts, mycophenolate, mofetil, cyclophosphamide and the like;
  • a nonsteroidal anitinflammatory drug such as, for example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like;
  • COX-2 selective inhibitors such as, for example, rofecoxib and celecoxib;
  • COX-1 inhibitors such as, for example, piroxicam
  • immunosuppressives such as, for example, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin or sulfasalazine; and
  • steroids such as, for example, betamethasone, cortisone, prednisone or dexamethasone.
  • the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of:
  • a disease modifying antirheumatic drug such as, for example, methotrexate, azathioptrine, luflunomide, penicillamine, gold salts, mycophenolate, mofetil, cyclophosphamide and the like;
  • a nonsteroidal anitinflammatory drug such as, for example, piroxicam, ketoprofen, naproxen, indomethacin, ibuprofen and the like;
  • COX-2 selective inhibitors such as, for example, rofecoxib and celecoxib;
  • COX-1 inhibitors such as, for example, piroxicam
  • immunosuppressives such as, for example, methotrexate, cyclosporin, leflunimide, tacrolimus, rapamycin or sulfasalazine;
  • steroids such as, for example, betamethasone, cortisone, prednisone or dexamethasone;
  • the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I), in combination (or association) with an effective amount of one or more biological response modifiers (BRMs) such as, for example, anti-TNF antagonists including antibodies and/or receptors/receptor fragments, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like.
  • BRMs biological response modifiers
  • the invention provides a method of treating a chemokine mediated disease comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of:
  • anti-inflammatory agents such as, for example, p38 kinase inhibitors, PDE4 inhibitors, and TACE inhibitors;
  • chemokine receptor antagonists such as, for example, thalidomide
  • the invention provides a method of treating a chemokine mediated disease, said disease being a pulmonary disease (e.g., COPD, asthma, or cystic fibrosis) comprising administering to a patient (e.g., a human) in need of such treatment, an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, ⁇ -2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipas
  • a pulmonary disease
  • Agents that belong to these classes include, but are not limited to, beclomethasone, mometasone, ciclesonide, budesonide, fluticasone, albuterol, salmeterol, formoterol, loratadine, desloratadine, tiotropium bromide, MSI-ipratropium bromide, montelukast, theophilline, cilomilast, roflumilast, cromolyn, ZD-4407, talnetant, LTB-019, revatropate, pumafentrine, CP955, AR-C-89855, BAY-19-8004, GW-328267, QAB-149, DNK-333, YM-40461 and TH-9506 (or pharmaceutically acceptable formulations thereof).
  • the invention provides a method of treating a chemokine mediated disease, said disease being multiple sclerosis comprising administering to a patient in need of such treatment a therapeutically effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of methotrexate, cyclosporin, leflunimide, sulfasalazine, ⁇ -methasone, ⁇ -interferon, glatiramer acetate, prednisone, etonercept, infliximab, and formulations thereof.
  • one or more compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of methotrexate, cyclosporin, leflunimide, sulfasalazine, ⁇ -methasone, ⁇ -interferon, glatiramer acetate, prednisone, eto
  • the invention provides a method of treating a chemokine mediated disease, said disease being rheumatoid arthritis comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX inhibitor, an immunosuppressive, a steroid, a PDE IV inhibitor, an anti-TNF- ⁇ compound, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective inhibiitors, other classes of compounds indicated for the treatment of rheumatoid arthritis, and formulations thereof.
  • the invention provides a method of treating a chemokine mediated disease, said disease being rheumatoid arthritis comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of a COX-2 inhibitor, a COX inhibitor, an immunosuppressive, a steroid, a PDE IV inhibitor, an anti-TNF- ⁇ compound, MMP inhibitors, glucocorticoids, chemokine inhibitors, and CB2-selective inhibitors.
  • the invention provides a method of treating a chemokine mediated disease, said disease being stroke and cardiac reperfusion injury comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpIIb/IIIa antagonist, anticoagulants, other compounds indicated for the treatment of rheumatoid arthritis and formulations thereof.
  • one or more compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpIIb/IIIa antagonist, anticoagulants, other compounds indicated for the treatment of rheumatoid arthritis and formulations thereof.
  • the invention provides a method of treating a chemokine mediated disease, said disease being stroke and cardiac reperfusion injury comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpIIb/IIIa antagonist, and anticoagulants.
  • one or more compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of thrombolitics, antiplatelet agents, gpIIb/IIIa antagonist, and anticoagulants.
  • the invention provides a method of treating a chemokine mediated disease, said disease being stroke and cardiac reperfusion injury comprising administering to a patient in need of such treatment an effective amount of one or more (e.g., one) compounds of formula (I) in combination (or association) with an effective amount of one or more compounds selected from the group consisting of an effective amount of one or more compounds selected from the group consisting of tenecteplase, TPA,reteplase, abciximab, eftiifbatide, heparin and formulations thereof.
  • a chemokine mediated disease said disease being stroke and cardiac reperfusion injury
  • This invention also provides novel compounds of formula (I), wherein said novel compounds are selected from the group consisting of:
  • any variable e.g., aryl, R 2
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • an effective amount means a therapeutically effective amount, e.g., an amount that provides a clinical response to the disease being treated.
  • Examples of “one or more” include (a) 1, 2 or 3, (b) 1 or 2, or (c) 1.
  • Examples of “at least one” include (a) 1, 2 or 3, (b) 1 or 2, or (c) 1.
  • Alkyl means a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 20 carbons are intended. Preferred alkyl groups contain 1 to 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to 6 carbon atoms in the chain.
  • Alkoxy means an alkyl-0 group in which alkyl is as previously defined.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched. Where the number of carbon atoms is not specified, 2 to 20 carbons are intended. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 6 carbon atoms in the chain. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. Alkenylalkyl means that the alkenyl group is attached to the parent moiety through an alkyl group.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched. Where the number of carbon atoms is not specified, 2 to 15 carbons are intended. Preferred alkynyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. Alkynylalkyl means that the alkynyl group is attached to the parent moiety through an alkyl group.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • suitable aryl groups include phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl and the like.
  • Arylalkyl means an aryl-alkyl group in which the aryl and alkyl groups are as defined.
  • suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl. The bond to the parent moiety is through the alkyl group.
  • Cycloalkyl means a non-aromatic ring system having 3 to 10 carbon atoms and one to three rings, preferably 5 to 10 carbon atoms. Preferred cycloalkyl rings contain 5 to 7 ring atoms.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and the like.
  • Cycloalkylalkyl means a cycloalkyl group attached to the parent moiety through an alkyl group.
  • Non-limiting examples include cyclopropylmethyl, cyclohexylmethyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain 5 to 7 ring atoms.
  • Non-limiting examples of cycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, norbornenyl and the like.
  • Halo means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.
  • Haloalkyl means an alkyl group as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.
  • Heterocyclyl or “heterocyclic” means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain 5 to 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • heterocyclic acidic functional group is intended to include groups such as, pyrrole, imidazole, triazole, tetrazole, and the like.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
  • Preferred heteroaryls contain 5 to 6 ring atoms.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imi
  • Heteroarylalkyl means a heteroaryl-alkyl group where the bond to the parent moiety is through an alkyl group.
  • N-oxides can form on a tertiary nitrogen present in an R substituent, or on ⁇ N— in a heteroaryl ring substituent and are included in the compounds of formula I.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • chemokine mediated diseases include: psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs.
  • anti-adhesion molecules include anti-CD11a (efalizumab), CD58-Fc (alefacept), anti-VLA (natalizumab), as well as small molecule antagonists of LFA-1 (such as IC-747), VLA-4 (such as GW559090), and LFA-3.
  • leukotriene inhibitors include LTD4 receptor antagonists (e.g., Singulair), Zileuton, and inhibitors of 5-lipoxygenase.
  • inhibitors of cytokine production include inhibitors of TNF- ⁇ such as thalidomide.
  • TACE TNF- ⁇ converting enzyme
  • methotrexate methotrexate
  • A is selected from the group consisting of:
  • n is 0 to 6;
  • p is 1 to 5;
  • X is 1 to 3;
  • R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —C(O)NHOR 13 , —C(O)NR 13 OH, —S(O 2 )OH, —OC(O)R 13 , an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R 9 groups;
  • each R 3 and R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 17 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —SO (t) R 13 , —C(O)NR 13 OR 14 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
  • each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R 9 groups;
  • each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more (e.g., 1 to 6) substituents on said substituted R 7 and R 8 groups, wherein each substitutent is independently selected from the group consisting of:
  • fluoroalkyl is one non-limiting example of an alkyl group that is substituted with halogen
  • R 8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
  • each R 9 is independently selected from the group consisting of:
  • —OH groups e.g., —(CH 2 ) q OH, wherein q is 1-6, usually 1 to 2, and preferably 1
  • each R 10 and R 11 is independently selected from the group consisting of R 13 , (e.g., hydrogen and alkyl (e.g., C 1 to C 6 alkyl, such as methyl)), halogen, —CF 3 , —OCF 3 , —NR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —OH, —C(O)OR 13 , —SH, —SO (t) NR 13 R 14 , —SO 2 R 13 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —C(O)NR 13 R 14 , —C(O)NR 13 OR 14 , —OC(O)R 13 and cyano;
  • R 13 e.g., hydrogen and alkyl (e.g., C 1 to C 6 alkyl, such as methyl)
  • halogen e.g., hydrogen and alkyl (e.g.
  • R 12 is selected from the group consisting of: hydrogen, —C(O)OR 13 , unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R 12 groups and each substituent is independently selected from the group consisting of: R 9 groups;
  • each R 13 and R 14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein “heterocyloalkyl” means heterocyclic); wherein there are 1 to 6 substituents on said substituted R 13 and R 14 groups and each substituent is independently selected from the group consisting of: alkyl, —CF 3 , —OH, alkoxy, aryl, aryl
  • R 13 and R 14 taken together with the nitrogen they are attached to in the groups —C(O)NR 13 R 14 and —SO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered heterocyclic ring), said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR 18 ; wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups (i.e., there is 1 to 3 substituents on the ring formed when the R 13 and R 14 groups are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)NR 13
  • each R 15 and R 16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
  • R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl;
  • R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ;
  • each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;
  • R 30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO 2 , or —SO 2 R 15 provided that R 15 is not H;
  • each R 31 is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R 31 groups and each substituent is independently selected from the group consisting of: alkyl, halogen and —CF 3 ;
  • each R 40 is independently selected from the group consisting of: H, alkyl and cycloalkyl;
  • g is 1 or 2;
  • t is 0, 1 or 2.
  • R 13 and R 14 are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl).
  • Examples include, but are not limited to (1) —SO 2 NH 2 and (2) —SO 2 NR 13 R 14 wherein R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO 2 N(CH 3 ) 2 .
  • R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO 2 N(CH 3 ) 2 .
  • R 13 and R 14 are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). Examples include, but are not limited to —C(O)NR 13 R 14 wherein each R 13 and R 14 are the same or different alkyl group, e.g., the same alkyl group, such as, for example —C(O)N(CH 3 ) 2 .
  • substituent A is preferably selected from the group consisting of:
  • Substituent A in formula (I) is most preferably selected from the group consisting of:
  • Substituent A in formula (I) is more preferably selected from the group consisting of:
  • Substituent B in formula (I) is preferably selected from the group consisting of:
  • Substituent B in formula (I) is most preferably selected from the group consisting of:
  • Substituent B in Formula (I) is more preferably selected from the group consisting of:
  • Embodiment No. 1 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 2 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 3 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 4 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 5 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 6 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 7 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 8 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 9 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 10 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 11 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 12 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 13 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 14 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 15 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 16 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 17 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 18 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 19 is directed to the methods of this invention using compounds of formula (I) wherein B is selected from the group consisting of:
  • R 3 for this B group is selected from the group consisting of: —C(O)NR 13 R 14 ,
  • Embodiment No. 20 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 21 is directed to the methods of this invention using compounds of formula (I) wherein B is
  • R 13 and R 14 are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents are as defined in formula (I).
  • Embodiment No. 22 is directed to the methods of this invention using compounds of formula (I) wherein B is
  • R 2 is —OH and all other substituents are as defined in formula (I), or
  • R 2 is —OH
  • R 13 and R 14 are independently selected from the group, consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), or
  • R 2 is —OH
  • R 13 and R 14 are the same or different and alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), for example the same alkyl group, for example methyl, and
  • Embodiment No. 23 is directed to the methods of this invention using compounds of formula (I) wherein B is
  • R 3 is selected from the group consisting of:
  • Embodiment No. 24 is directed to the methods of this invention using compounds of formula (I) wherein B is
  • R 3 is selected from the group consisting of:
  • R 2 is —OH, and all other substituents are as defined in formula (I).
  • Embodiment No. 25 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • Embodiment No. 26 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH, and all other substituents are as defined in formula (I).
  • Embodiment No. 27 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is as defined for compounds of formula (I), R 13 and R 14 are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents areas defined for compounds of formula (I).
  • R 13 and R 14 are the same or different alkyl group.
  • R 13 and R 14 are the same alkyl group.
  • R 13 and R 14 are methyl.
  • Embodiment No. 28 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 13 and R 14 are independently selected from the group consisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all other substituents areas defined for compounds of formula (I).
  • R 13 and R 14 are the same or different alkyl group.
  • R 13 and R 14 are the same alkyl group.
  • R 13 and R 14 are methyl.
  • Embodiment No. 29 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in Embodiment No. 23, R 4 is H, R 5 is H, R 6 is H, and all other substituents are as defined for compounds of formula (I).
  • Embodiment No. 30 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in Embodiment No. 24, R 4 is H, R 5 is H, R 6 is H, and all other substituents areas defined for compounds of formula (I).
  • Embodiment No. 31 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in Embodiments Nos. 21, 22, 25 and 26, except that R 13 and R 14 are each methyl, and all other substituents are as defined in formula (I).
  • Embodiment No. 32 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 11 is H, and all other substituents are as defined in formula (I).
  • Embodiment No. 33 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH, and all other substituents are as defined in formula (I).
  • Embodiment No. 34 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 3 is —C(O)NR 13 R 14 , and all other substituents are as defined in formula (I).
  • Embodiment No. 35 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2), and all other substituents are as defined in formula (I).
  • Embodiment No. 36 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —C(O)NR 13 R 14
  • all other substituents are as defined in formula (I).
  • Embodiment No. 37 of this invention is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2), and all other substituents are as defined in formula (I).
  • Embodiment No. 38 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —C(O)NR 13 R 14
  • R 11 is H
  • all other substituents are as defined in formula (I).
  • Embodiment No. 39 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2)
  • R 11 is H
  • all other substituents are as defined in formula (I).
  • Embodiment No. 40 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —C(O)NR 13 R 14
  • R 11 is H
  • R 13 and R 14 are independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), unsubstituted heteroaryl and substituted heteroaryl, and all other substituents are as defined in formula (I).
  • R 13 or R 14 is alkyl (e.g., methyl).
  • An example of a substituted heteroaryl group is
  • Embodiment No. 41 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2)
  • R 11 is H
  • R 13 and R 14 are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl, and t-butyl), and all other substituents are as defined in formula (I).
  • R 3 is (1) —SO 2 NH 2 and (2) —SO 2 NR 13 R 14 wherein R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO 2 N(CH 3 ) 2 .
  • R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO 2 N(CH 3 ) 2 .
  • Embodiment No. 42 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 11 is H, and all other substituents are as defined in formula (I).
  • Embodiment No. 43 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH, and all other substituents are as defined in formula (I).
  • Embodiment No. 44 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 3 is —C(O)NR 13 R 14 , and all other substituents are as defined in formula (I).
  • Embodiment No. 45 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2), and all other substituents are as defined in formula (I).
  • Embodiment No. 46 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —C(O)NR 13 R 14
  • all other substituents are as defined in formula (I).
  • Embodiment No. 47 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2), and all other substituents are as defined in formula (I).
  • Embodiment No. 48 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —C(O)NR 13 R 14
  • R 11 is H
  • all other substituents are as defined in formula (I).
  • Embodiment No. 49 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2)
  • R 11 is H
  • all other substituents are as defined in formula (I).
  • Embodiment No. 50 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —C(O)NR 13 R 14
  • R 11 is H
  • R 13 and R 14 are independently selected from the group consisting of: alkyl, unsubstituted heteroaryl and substituted heteroaryl, and all other substituents are as defined in formula (I).
  • one of R 13 or R 14 is alkyl (e.g., methyl).
  • An example of a substituted heteroaryl group is
  • Embodiment No. 51 is directed to the methods of this invention using compounds of formula (I) wherein B is:
  • R 2 is —OH
  • R 3 is —S(O) t NR 13 R 14 (e.g., t is 2)
  • R 11 is H
  • R 13 and R 14 are independently selected from the group consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl, and tbutyl), and all other substituents are as defined in formula (I).
  • R 3 is (1) —SO 2 NH 2 and (2) —SO 2 NR 13 R 14 wherein R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO 2 N(CH 3 ) 2 .
  • R 13 and R 14 are the same or different alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkyl group, such as, for example —SO 2 N(CH 3 ) 2 .
  • Embodiment No. 52 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
  • R 2 to R 6 and R 10 to R 14 are as defined above for the compounds of formula (I).
  • Embodiment No. 53 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 or and —NHSO 2 R 13 ;
  • R 3 is selected from the group consisting of: —SO 2 NR 13 R 14 , —NO 2 , cyano, —C(O)NR 13 R 14 , —SO 2 R 13 ; and —C(O)OR 13 ;
  • R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 , halogen, and —CF 3 ;
  • R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano;
  • R 6 is selected from the group consisting of: H, alkyl and —CF 3 ;
  • each R 10 and R 11 is independently selected from the group consisting of: R 13 , hydrogen, halogen, —CF 3 , —NR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —C(O)OR 13 , —SH, —SO (t) NR 13 R 14 , —SO 2 R 13 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —C(O)NR 13 R 14 , —C(O)NR 13 OR 14 , —OC(O)R 13 , —COR 13 , —OR 13 , and cyano;
  • each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or
  • R 13 and R 14 when taken together with the nitrogen they are attached to in the groups —NR 13 R 14 , —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —OC(O)NR 13 R 14 , —CONR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR 18 ; wherein R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ; wherein each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1
  • Embodiment No. 54 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of: R 5
  • R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
  • R 3 is selected from the group consisting of: —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —NO 2 , cyano, —SO 2 R 13 ; and —C(O)OR 13 ;
  • R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 or —CF 3 ;
  • R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano;
  • R 6 is selected from the group consisting of: H, alkyl and —CF 3 ;
  • R 11 is selected from the group consisting of: H, halogen and alkyl
  • each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or
  • R 13 and R 14 when taken together with the nitrogen they are attached to in the groups —NR 13 R 14 , —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —OC(O)NR 13 R 14 , —CONR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from O, S or NR 18 wherein R 18 is selected from H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 , wherein each R 19 and R 20 is independently selected from alkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups (i
  • Embodiment No. 55 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
  • R 3 is selected from the group consisting of: —C(O)NR 13 R 14 —SO 2 NR 13 R 14 , —NO 2 , cyano, and —SO 2 R 13 ;
  • R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 or —CF 3 ;
  • R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano;
  • R 6 is selected from the group consisting of: H, alkyl and —CF 3 ;
  • R 11 is selected from the group consisting of: H, halogen and alkyl
  • each R 13 and R 14 is independently selected from the group consisting of: H, methyl and ethyl.
  • Embodiment No. 56 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
  • R 2 is —OH
  • R 3 is selected from the group consisting of: —SO 2 NR 13 R 14 and —CONR 13 R 14 ;
  • R 4 is selected form the group consisting of: H, —CH 3 and —CF 3 ;
  • R 5 is selected from the group consisting of: H and cyano
  • R 6 is selected from the group consisting of: H, —CH 3 and —CF 3 ;
  • R 11 is H
  • R 13 and R 14 are independently selected from the group consisting of H and methyl (e.g., for —SO 2 NR 13 R 14 both R 13 and R 14 are H, or both R 13 and R 14 are methyl, also, for example, for —CONR 13 R 14 both R 13 and R 14 are methyl).
  • Embodiment No. 57 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
  • Embodiment No. 58 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
  • Embodiment No. 59 is directed to the methods of this invention using compounds of formula (I) wherein substituent B is selected from the group consisting of:
  • Embodiment No. 60 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R 7 and R 8 substituted groups are selected from the group consisting of: a) cyano, b) —CO 2 R 13 , c) —C(O)NR 13 R 14 , d) —SO 2 NR 13 R 14 ,
  • Embodiment No. 61 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF 3 and —CF 2 CH 3 ), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF 3 , cyano, —OCH 3 , and —NO 2
  • each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF 3 and —CF 2 CH 3 ), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R 8 , is as defined in formula (I), and wherein R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF 3 , cyano, —OCH 3 , and —NO 2 ; each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as,
  • Embodiment No. 62 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • R 7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl
  • R 8 is selected form the group consisting of: H, alkyl, —CF 2 CH 3 and —CF 3
  • R 8a is as defined for formula (I).
  • Embodiment No. 63 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
  • R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula (I).
  • Embodiment No. 64 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
  • R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula IA;
  • Embodiment No. 65 is directed compounds of formula (1) wherein substituent A is selected from the group consisting of:
  • Embodiment No. 66 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • Embodiment No. 67 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • Embodiment No. 68 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is selected from the group consisting of:
  • Embodiment No. 69 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is as defined in any one of the Embodiment Nos. 60 to 68.
  • Embodiment No. 70 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
  • Embodiment No. 71 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
  • R 7 is H
  • R 8 is alkyl (e.g., methyl, ethyl, isopropyl, cyclopropyl and t-butyl), and all other substituents are as defined for formula (I).
  • Embodiment No. 72 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
  • Embodiment No. 73 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is:
  • Embodiment No. 74 is directed to the methods of this invention using compounds of formula (I) wherein B is described in any one of the Embodiment Nos. 1 to 59, and A is
  • Embodiment No. 75 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is
  • furan ring is substituted with at least one (e.g., 1 to 3, or 1 to 2) alkyl group and all other substituents are as defined for formula (I).
  • Embodiment No. 76 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, A is
  • Embodiment No. 77 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is
  • furan ring is substituted with one C 1 to C 3 alkyl group (e.g., methyl or isopropyl), and all other substituents are as defined for formula (I).
  • C 1 to C 3 alkyl group e.g., methyl or isopropyl
  • Embodiment No. 78 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is as defined in any one of the Embodiment Nos. 73 to 77, except that R 7 and R 8 are the same or different and each is selected from the group consisting of: H and alkyl.
  • Embodiment No. 79 is directed to the methods of this invention using compounds of formula (I) wherein B is as described in any one of the Embodiment Nos. 1 to 59, and A is as defined in any one of the Embodiment Nos. 73 to 77, except that R 7 is H, and R 8 is alkyl (e.g., ethyl or t-butyl).
  • Embodiment No. 80 is directed to the methods of this invention using compounds of formula (I) wherein:
  • each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO 2 R 13 , —CONR 13 R 14 , fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein said substituents on said R 7 and R 8 substituted groups are selected from the group consisting of: a) cyano, b) —CO 2 R 13 , c) —C(O)NR 13 R 14 , d) —SO 2 NR 13 R 14
  • R 2 to R 6 and R 10 to R 14 are as defined above for the compounds of formula (I).
  • Embodiment No. 81 is directed to the methods of this invention using compounds of formula (I) wherein:
  • each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF 3 and —CF 2 CH 3 ), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF 3 , cyano, —OCH 3 , and —NO 2
  • each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (such as, —CF 3 and —CF 2 CH 3 ), cycloalkyl (e.g., cyclopropyl, and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); wherein R 8a is as defined in formula (1), and wherein R 9 is selected from the group consisting of: H, halogen, alkyl, cycloalkyl, —CF 3 , cyano, —OCH 3 , and —NO 2 ; each R 7 and R 8 is independently selected from the group consisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl (
  • R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 or and —NHSO 2 R 13 ;
  • R 3 is selected from the group consisting of: —SO 2 NR 13 R 14 , —NO 2 , cyano, —C(O)NR 13 R 14 , —SO 2 R 13 ; and —C(O)OR 13 ;
  • R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 , halogen, and —CF 3 ;
  • R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano;
  • R 6 is selected from the group consisting of: H, alkyl and —CF 3 ;
  • each R 10 and R 11 is independently selected from the group consisting of: R 13 , hydrogen, halogen, —CF 3 , —NR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —C(O)OR 13 , —SH, —SO (t) NR 13 R 14 , —SO 2 R 13 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —C(O)NR 13 R 14 , —C(O)NR 13 OR 14 , —OC(O)R 13 , —COR 13 , —OR 13 , and cyano;
  • each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or
  • R 13 and R 14 when taken together with the nitrogen they are attached to in the groups —NR 13 R 14 , —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —OC(O)NR 13 R 14 , —CONR 13 R 14 , —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from the group consisting of: O, S or NR 18 ; wherein R 18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 ; wherein each R 19 and R 20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl; wherein there are 1
  • Embodiment No. 82 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is even more preferably selected from the group consisting of:
  • R 7 is selected from the group consisting of: H, fluoroalkyl, alkyl and cycloalkyl
  • R 8 is selected form the group consisting of: H, alkyl, —CF 2 CH 3 and —CF 3
  • R 8a is as defined for formula (1).
  • Embodiment No. 83 is directed to the methods of this invention using compounds of formula (1) wherein:
  • R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula (I); and
  • substituent B is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
  • R 3 is selected from the group consisting of: —C(O)NR 13 R 14 , —SO 2 NR 13 R 14 , —NO 2 , cyano, —SO 2 R 13 ; and —C(O)OR 13 ;
  • R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 or —CF 3 ;
  • R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano;
  • R 6 is selected from the group consisting of: H, alkyl and —CF 3 ;
  • R 11 is selected from the group consisting of: H, halogen and alkyl
  • each R 13 and R 14 is independently selected from the group consisting of: H, methyl, ethyl and isopropyl; or
  • R 13 and R 14 when taken together with the nitrogen they are attached to in the groups —NR 13 R 4 , —C(O)NR 13 R 14 , —SO 2 NR 3 R 4 , —QC(O)NR 3 R 4 , —CONR 3 R 14 , —NR 13 C(O)NR 13 R 14 , —SO t NR 13 R 14 , —NHSO 2 NR 13 R 14 form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered ring) optionally having one additional heteroatom selected from O, S or NR 18 wherein R 18 is selected from H, alkyl, aryl, heteroaryl, —C(O)R 19 , —SO 2 R 19 and —C(O)NR 19 R 20 , wherein each R 19 and R 20 is independently selected from alkyl, aryl and heteroaryl, wherein there are 1 to 3 substituents on the substituted cyclized R 13 and R 14 groups (i
  • Embodiment No. 84 is directed to the methods of this invention using compounds of formula (I) wherein:
  • substituent A is selected from the group consisting of:
  • R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
  • R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and R 8a is as defined for formula (I);
  • substituent B is selected from the group consisting of:
  • R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
  • R 3 is selected from the group consisting of: —C(O)NR 13 R 14 —SO 2 NR 13 R 14 , —NO 2 , cyano, and —SO 2 R 13 ;
  • R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 or —CF 3 ;
  • R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano;
  • R 6 is selected from the group consisting of: H, alkyl and —CF 3 ;
  • R 11 is selected from the group consisting of: H, halogen and alkyl
  • each R 13 and R 14 is independently selected from the group consisting of: H, methyl and ethyl.
  • Embodiment No. 85 is directed to the methods of this invention using compounds of formula (I) wherein:
  • substituent A is selected from the group consisting of:
  • substituent B is selected from the group consisting of:
  • R 2 is —OH
  • R 3 is selected from the group consisting of: —SO 2 NR 13 R 14 and —CONR 13 R 14 ;
  • R 4 is selected form the group consisting of: H, —CH 3 and —CF 3 ;
  • R 5 is selected from the group consisting of: H and cyano
  • R 6 is selected from the group consisting of: H, —CH 3 and —CF 3 ;
  • R 11 is H
  • R 13 and R 14 are independently selected from the group consisting of H and methyl (e.g., for —SO 2 NR 13 R 14 both R 13 and R 14 are H, or both R 13 and R 14 are methyl, also, for example, for —CONR 13 R 14 both R 13 and R 14 are methyl).
  • Embodiment No. 86 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 65 and substituent B is as defined in Embodiment No. 57.
  • Embodiment No. 87 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 65 and substituent B is as defined in Embodiment No. 58.
  • Embodiment No. 88 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 65 and substituent B is as defined in Embodiment No. 59.
  • Embodiment No. 89 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 66 and substituent B is as defined in Embodiment No. 57.
  • Embodiment No. 90 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 66 and substituent B is as defined in Embodiment No. 58.
  • Embodiment No. 91 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 66 and substituent B is as defined in Embodiment No. 59.
  • Embodiment No. 92 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 67 and substituent B is as defined in Embodiment No. 57.
  • Embodiment No. 93 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 67 and substituent B is as defined in Embodiment No. 58.
  • Embodiment No. 94 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 67 and substituent B is as defined in Embodiment No. 59.
  • Embodiment No. 95 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 68 and substituent B is as defined in Embodiment No. 57.
  • Embodiment No. 96 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 68 and substituent B is as defined in Embodiment No. 58.
  • Embodiment No. 97 is directed to the methods of this invention using compounds of formula (I) wherein substituent A is as defined in Embodiment No. 68 and substituent B is as defined in Embodiment No. 59.
  • Embodiment No. 98 is directed to the methods of this invention using compounds of formula (I) as defined in any one of the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is a pharmaceutically acceptable salt.
  • Embodiment No. 99 is directed to the methods of this invention using compounds of formula (I) as defined in any one of the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is a sodium salt.
  • Embodiment No. 100 is directed to the methods of this invention using compounds of formula (I) as defined in any one of the Embodiment Nos. 1 to 97 wherein the compound of formula (I) is a calcium salt.
  • Embodiment No. 101 is directed to the methods of this invention using a pharmaceutically acceptable salt of any one of the representative compounds of formula (I) described below.
  • Embodiment No. 102 is directed to the methods of this invention using a sodium salt of any one of the representative compounds of formula (I) described below.
  • Embodiment No. 103 is directed to the methods of this invention using a calcium salt of any one of the representative compounds of formula (I) described below.
  • Embodiment No. 104 is directed to the methods of this invention using a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) compound of formula (I) as described in any one of the Embodiment Nos. 1 to 103 in combination with a pharmaceutically acceptable carrier (or diluent).
  • a pharmaceutically acceptable carrier or diluent
  • Embodiment No. 105 is directed to a pharmaceutically acceptable salt of a novel compound of formula (I), wherein said compound is selected from the group consisting of:
  • Embodiment No. 106 is directed to a calcium salt of any one of the novel compounds of formula (I) described in Embodiment No. 105.
  • Embodiment No. 107 is directed to a sodium salt of any one of the novel compounds of formula (I) described in Embodiment No. 105.
  • Embodiment No. 108 is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) novel compound of formula (I) as described in Embodiment No. 105 in combination with a pharmaceutically acceptable carrier (or diluent).
  • Representative compounds of formula (I) useful in the methods of this invention include but are not limited to:
  • Preferred compounds of formula (I) useful in the methods of this invention include:
  • a more preferred group of compounds of formula (I) useful in the methods of this invention include:
  • a most preferred group of compounds of formula (I) useful in the methods of this invention include:
  • Certain compounds of formula (I) may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers).
  • the invention contemplates all such stereoisomers both in pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional methods.
  • Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
  • Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts.
  • the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
  • Compounds of formula (I) can exist in unsolvated and solvated forms, including hydrated forms.
  • the solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of this invention.
  • This invention also includes Prodrugs of the novel compounds of this invention, and of the compounds of formula (I) useful in the methods of this invention.
  • the term “prodrug,” as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20 th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, Md.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of formula (I) may also be deliverable transdermally.
  • the transdermal composition can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compound of formula (I) is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.
  • the amount and frequency of administration of the compounds of formula (I) and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • a typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.
  • the compounds used in combination with the compounds of formula (I) can be administered in their normally prescribed amounts as know by the skilled clinician (see, for example, the Physicians' Desk Reference, 56 th edition, 2002, published by Medical Economics company, Inc. at Montvale, NJ 07645-1742, the disclosure of which is incorporated herein by reference thereto).
  • the amount and frequency of administration of the compounds used in combination with the compounds of formula (I) will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • the compounds of formula (I) are useful in the treatment of CXC-chemokine mediated conditions and diseases. This utility is manifested in their ability to inhibit IL8 and GRO- ⁇ chemokine as demonstrated by the following in vitro assays.
  • a reaction mixture of 10 pg hCXCR1-CHO overexpressing membranes (Biosignal) and 200 ⁇ g/well WGA-SPA beads (Amersham) in 100 ⁇ l was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCl 2 , 1 mM MgCl 2 , 125 mM NaCl, 0.1% BSA) (Sigma).
  • CXCR1 assay buffer 25 mM HEPES, pH 7.8, 2 mM CaCl 2 , 1 mM MgCl 2 , 125 mM NaCl, 0.1% BSA
  • a 0.4 nM stock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1 assay buffer.
  • 20 ⁇ stock solutions of test compounds were prepared in DMSO (Sigma).
  • a 6 ⁇ stock solution of IL-8 was prepared in CXCR2 assay buffer.
  • the assay plates were shaken for 5 minutes on plate shaker, then incubated for 8 hours before cpm/well were determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of Total binding-NSB (250 nM IL-8) was determined for IC 50 values.
  • a working stock of 0.25 ⁇ g/ ⁇ l hCXCR1-CHO over-expressing membranes with a specific activity of 0.05 pmol/mg (Biosignal Packard) and 25 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 0.1 mM CaCl 2 , 1 mM MgCl 2 , 100 mM NaCl) (Sigma). This mixture was incubated on ice for 30 minutes and then centrifuged at 2500 rpm for 5 minutes.
  • a working stock of 0.025 ⁇ g/[l hCXCR1-CHO overexpressing membranes with a specific activity of 3.47 pmol/mg (Euroscreen) and 5 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2.0 mM CaCl 2 , 1 mM MgCl 2 , 125 mM NaCl) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.125 nM stock of ligand, [ 125 I]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR1 assay buffer.
  • Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 13.3-fold in CXCR1 assay buffer.
  • the assay plates were incubated for 4 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC 50 values were quantified using nonlinear regression analysis in GraphPad Prism.
  • a reaction mixture of 4 ⁇ g hCXCR2-CHO overexpressing membranes (Biosignal) and 200 ⁇ g/well WGA-SPA beads (Amersham) in 100 ⁇ l was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2 mM CaCl 2 , 1 mM MgCl 2 ).
  • a 0.4 nM stock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR2 assay buffer.
  • 20 ⁇ stock solutions of test compounds were prepared in DMSO (Sigma).
  • a 6 ⁇ stock solution of GRO- ⁇ (R&D) was prepared in CXCR2 assay buffer.
  • a working stock of 0.031 ⁇ g/ ⁇ l hCXCR2-CHO over-expressing membranes with a specific activity of 0.4 pmol/mg (Biosignal Packard) and 2.5 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCl 2 , 1 mM MgCl 2 ) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.50 nM stock of ligand, [ 125 I]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR2 assay buffer.
  • Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 13.3-fold in CXCR2 assay buffer.
  • the assay plates were incubated for 2 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC 50 values were quantified using nonlinear regression analysis in GraphPad Prism.
  • a working stock of 0.02 ⁇ g/ ⁇ l hCXCR2-CHO overexpressing membranes with a specific activity of 0.6 pmol/mg (Biosignal Packard) and 2 ⁇ g/ ⁇ l WGA-SPA beads (Perkin Elmer Life Sciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0 mM CaCl 2 , 1 mM MgCl 2 ) (Sigma). This mixture was incubated on ice for 5 minutes. A 0.40 nM stock of ligand, [ 125 I]-IL-8 (Perkin Elmer Life Sciences), was prepared in the CXCR2 assay buffer.
  • Test compounds were first serially diluted by half-logs in DMSO (Sigma) and then diluted 20-fold in CXCR2 assay buffer.
  • the assay plates were incubated for 2 hours before cpm/well were determined in a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC 50 values were quantified using nonlinear regression analysis in GraphPad Prism.
  • Carrageenan (0.05 ml of an 1% solution in saline) was injected into one hindpaw of male Sprague-Dawley rats. Paw volumes (ml) were measured by a water displacement plethysmometer prior to and 3 h after the injection of carrageenan. The increase in paw volume that occurred between the two timepoints was determined for each group. Rats received Compound A:
  • a neutralizing rat anti-mouse TNF ⁇ antibody or matched rat IgG isotype control was administered intraperitoneally two hours prior to SCW injection and Compound A or methylcellulose vehicle was orally administered one hour prior to SCW injection.
  • Knee swelling measurements were performed 2 hours after SCW injection using a dial-gauge caliper (Starret, Athol, Mass.) by measuring the difference in swelling between the right and left knee joints.
  • Patellar organ cultures for assessment of synovial cytokine and chemokine and prostaglandin levels were prepared at 2 hours after SCW injection and established as described (Lubberts et al, 1998), using ELISA kits obtained from R&D Systems (Minneapolis, Minn.).
  • Statistical analysis was performed using the Student's t-test, with p ⁇ 0.05 considered to be indicative of statistical significant differences between groups.
  • Combination treatment resulted in a 71% (10 mg/kg Compound A+indomethacin) and 57% inhibition (25 mg/kg Compound A+indomethacin) of IL-1 ⁇ production, consistent with the concept that the effect on IL-1 ⁇ was attributable to the pharmacological action of Compound A.
  • the effect of combination therapy on PGE 2 levels (86% and 85% inhibition, respectively) in patellar organ culture was accounted for by the activity of indomethacin alone (89% inhibition) while Compound A alone had mild activity (34-40% inhibition at 10-25 mg/kg).
  • Step A An amine is condensed (Step A) with a nitrosalicylic acid under standard coupling conditions and the resulting nitrobenzamide is reduced (Step B) under hydrogen atmosphere in the presence of a suitable catalyst.
  • the remaining partner required for the synthesis of the final target is prepared by condensing an aryl amine with the commercially available diethylsquarate to give the aminoethoxysquarate product. Subsequent condensation of this intermediate with the aminobenzamide prepared earlier provides the desired chemokine antagonist (Scheme 1).
  • the aminobenzamide of Scheme 1 is first condensed with commercially available diethylsquarate to give an alternate monoethoxy intermediate. Condensation of this intermediate with an amine gives the desired chemokine antagonist.
  • Benztriazole compounds of Formula (I) are prepared by stirring nitrophenylenediamines with sodium nitrite in acetic acid at 60° C. to afford the nitrobenzotriazole intermediate (Scheme 3). Reduction of the nitro group in the presence of palladium catalyst and hydrogen atmosphere provides the amine compound. Subsequent condensation of this intermediate with the aminooethoxysquarate prepared earlier (Scheme 1) provides the desired chemokine antagonist.
  • Indazole structures of Formula (I) can be prepared according to Scheme 5 by reduction of nitroindazole A ( J. Am. Chem Soc. 1943, 65, 1804-1805) to give aminoindazole B and subsequent condensation with the aminoethoxysquarate prepared earlier (Scheme 1).
  • Indole structures of Formula (I) can be prepared according to Scheme 6 by reduction of nitroindole A ( J. Med. Chem. 1995, 38, 1942-1954) to give aminoindole B and subsequent condensation with the aminoethoxysquarate prepared earlier (Scheme 1).
  • step E The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of Preparative Example 13.19 step D.
  • the aqueous mixture was washed with diethyl ether (40 mL ⁇ 3), adjusted to pH ⁇ 6 using a 1.0 M HCl aqueous solution, and extracted with ethyl acetate (40 mL ⁇ 3).
  • step B alcohol was obtained following a similar procedure set forth in the preparative example 13.35 Step B.
  • Step A product (0.6 g) was reacted following the procedure set forth in the preparative example 13.19 to give the amine product 0.19 g (64%).
  • Step B product (1.0 g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 to give the acid as yellow solid 0.9 g (94%).
  • Step C product (0.35 g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 to give the amino acid as yellow solid 0.167 g (93%).
  • step E The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of WO 02/083624 Preparative Example 513.19step D.
  • Step A The product of Step A (0.6 g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 Step E to give the amine product 0.19 g (64%).
  • Step B The product of Step B (1.0 g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 Step B to give the acid as yellow solid 0.9 g (94%).
  • Step C The product of Step C (0.35 g) was reacted following the procedure set forth in WO 02/083624 Preparative Example 13.19 Step E to give the amino acid as yellow solid 0.167 g (93%).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dermatology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Otolaryngology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
US10/390,078 2002-03-18 2003-03-17 Treatment of chemokine mediated diseases Abandoned US20040053953A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/390,078 US20040053953A1 (en) 2002-03-18 2003-03-17 Treatment of chemokine mediated diseases
US11/705,929 US7960433B2 (en) 2002-03-18 2007-02-14 Treatment of chemokine mediated diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36531402P 2002-03-18 2002-03-18
US10/390,078 US20040053953A1 (en) 2002-03-18 2003-03-17 Treatment of chemokine mediated diseases

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/705,929 Division US7960433B2 (en) 2002-03-18 2007-02-14 Treatment of chemokine mediated diseases

Publications (1)

Publication Number Publication Date
US20040053953A1 true US20040053953A1 (en) 2004-03-18

Family

ID=28454639

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/390,078 Abandoned US20040053953A1 (en) 2002-03-18 2003-03-17 Treatment of chemokine mediated diseases
US11/705,929 Expired - Fee Related US7960433B2 (en) 2002-03-18 2007-02-14 Treatment of chemokine mediated diseases

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/705,929 Expired - Fee Related US7960433B2 (en) 2002-03-18 2007-02-14 Treatment of chemokine mediated diseases

Country Status (14)

Country Link
US (2) US20040053953A1 (zh)
EP (1) EP1485089B1 (zh)
JP (1) JP4733350B2 (zh)
CN (1) CN100444839C (zh)
AR (1) AR040400A1 (zh)
AU (1) AU2003220384B2 (zh)
BR (1) BR0308739A (zh)
CA (1) CA2479126C (zh)
MX (1) MXPA04009127A (zh)
NO (1) NO20044402L (zh)
NZ (1) NZ535314A (zh)
TW (2) TW200808314A (zh)
WO (1) WO2003080053A1 (zh)
ZA (1) ZA200407339B (zh)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040185081A1 (en) * 2002-11-07 2004-09-23 Donald Verlee Prosthesis with multiple drugs applied separately by fluid jet application in discrete unmixed droplets
US20060025453A1 (en) * 2003-12-22 2006-02-02 Schering Corporation And Pharmacopeia Drug Discovery, Inc. Isothiazole dioxides as CXC- and CC-chemokine receptor ligands
US20060030579A1 (en) * 2004-03-30 2006-02-09 Boehringer Ingelheim International Gmbh Compounds for the treatment of proliverative processes
US20060099662A1 (en) * 2004-04-16 2006-05-11 Genentech, Inc. Assay for antibodies
US20060223864A1 (en) * 2003-12-19 2006-10-05 Schering Corporation And Pharmacopeia Drug Discovery, Inc. Thiadiazoles AS CXC- and CC- chemokine receptor ligands
US20070004682A1 (en) * 2005-06-29 2007-01-04 Schering Corporation Di-substituted oxadiazoles as CXC-chemokine receptor ligands
US20070015731A1 (en) * 2005-06-29 2007-01-18 Biju Purakkattle J 5,6-Di-substituted oxadiazolopyrazines and thiadiazolopyrazines as CXC-chemokine receptor ligands
US20070021494A1 (en) * 2001-04-16 2007-01-25 Schering Corporation And Pharmacopeia, Inc. 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
US20070189915A1 (en) * 2002-11-07 2007-08-16 Sanjay Shrivastava Method of integrating therapeutic agent into a bioerodible medical device
US20070191943A1 (en) * 2002-11-07 2007-08-16 Sanjay Shrivastava Integration Of Therapeutic Agent Into A Bioerodible Medical Device
US20070248594A1 (en) * 2004-05-12 2007-10-25 Schering Corporation Cxcr1 and cxcr2 chemokine antagonists
US20070264230A1 (en) * 2002-10-09 2007-11-15 Schering Corporation Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands
US20080045489A1 (en) * 2006-07-07 2008-02-21 Jianhua Chao 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
US20080132526A1 (en) * 2004-05-24 2008-06-05 Glaxo Group Limited Purine Derivative
US20080200523A1 (en) * 2007-02-21 2008-08-21 Murthi Krishna K Derivatives of squaric acid with anti-proliferative activity
WO2010131145A1 (en) * 2009-05-12 2010-11-18 Pfizer Limited Cyclobutenedione derivatives
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
WO2012125413A2 (en) * 2011-03-12 2012-09-20 Vicus Therapeutics, Llc Compositions for ameliorating systemic inflammation and methods for making and using them
US8865723B2 (en) 2012-10-25 2014-10-21 Tetra Discovery Partners Llc Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury
US9763992B2 (en) 2014-02-13 2017-09-19 Father Flanagan's Boys' Home Treatment of noise induced hearing loss

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MXPA03009441A (es) * 2001-04-16 2004-02-12 Schering Corp Ciclobuteno-1,2-dionas 3,4-disustituidas como ligandos del receptor de quimocina cxc.
US7132445B2 (en) 2001-04-16 2006-11-07 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
CN1599734A (zh) 2001-10-12 2005-03-23 先灵公司 作为cxc趋化因子受体拮抗剂的3,4－二取代的马来酰亚胺化合物
US6878709B2 (en) 2002-01-04 2005-04-12 Schering Corporation 3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists
JP4440917B2 (ja) * 2003-04-18 2010-03-24 シェーリング コーポレイション ２−ヒドロキシ−ｎ，ｎ−ジメチル−３−［［２−（１（ｒ）−５−メチル−２−フラニル）プロピル］アミノ］−３，４−ジオキソ−１−シクロブテン−１−イル］アミノ］ベンズアミドの合成
NZ548499A (en) * 2004-01-30 2010-06-25 Schering Corp Crystalline polymorphs of a CXC-chemokine receptor ligand
CL2007001714A1 (es) 2006-06-12 2008-01-18 Schering Corp Composicion farmaceutica que comprende 2-hidroxi-n,n-dimetil-3-[[2-[[1(r)-5-metil-2-furanil)propil]amino]-3,4-dioxi-1-ciclobuteno-1-il]amino]benzamida y al menos un excipiente seleccionado de un agente humectante, un aglutinante, un disolvente y un desintegrante, util para tratar una enfermedad inflamatoria tal como artritis y asma.
JP2010529079A (ja) 2007-06-06 2010-08-26 ノバルティス アーゲー 抗炎症性置換シクロブテンジオン化合物
WO2009005801A1 (en) * 2007-07-03 2009-01-08 Schering Corporation Process and intermediates for the synthesis of 1,2-substituted 3,4-dioxo-1-cyclobutene compounds
UA103198C2 (en) 2008-08-04 2013-09-25 Новартис Аг Squaramide derivatives as cxcr2 antagonists
FR2961695B1 (fr) * 2010-06-29 2012-07-06 Galderma Res & Dev Utilisation de composes dans le traitement ou la prevention de troubles cutanes
CN103842330B (zh) 2011-09-02 2016-10-19 诺华股份有限公司 抗炎的取代的环丁烯二酮化合物的胆碱盐
FR2981934B1 (fr) * 2011-10-28 2013-12-20 Galderma Res & Dev Nouveaux composes di-substitues de la diamino-3,4-cyclobutene-3-dione-1,2 utiles dans le traitement de pathologies mediees par des chimiokines.
KR101306199B1 (ko) * 2012-01-31 2013-09-09 부산대학교 산학협력단 포스포리파아제 ｄ 억제제를 유효성분으로 포함하는 골다공증 예방 및 치료용 약학적 조성물
TWI734715B (zh) 2015-11-19 2021-08-01 美商卡默森屈有限公司 趨化因子受體調節劑
TWI724056B (zh) 2015-11-19 2021-04-11 美商卡默森屈有限公司 Ｃｘｃｒ２抑制劑
JP2020530848A (ja) * 2017-08-14 2020-10-29 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ ３，４−二置換３−シクロブテン−１，２−ジオンおよびその使用
KR102616949B1 (ko) * 2017-09-14 2023-12-22 다이이찌 산쿄 가부시키가이샤 고리형 구조를 갖는 화합물
MA50424A (fr) 2018-01-08 2020-08-26 Chemocentryx Inc Méthodes de traitement du psoriasis pustuleux généralisé avec un antagoniste de ccr6 ou cxcr2
MX2021003318A (es) 2018-09-21 2021-05-14 Pfizer Dioxociclobutenilamino-3-hidroxi-picolinamidas n-sustituidas utiles como inhibidores de ccr6.
CN112851635B (zh) * 2019-11-28 2022-09-16 中国医学科学院药物研究所 环状砜类化合物及其制备方法、用途和药物组合物
EP3868368A1 (en) * 2020-02-21 2021-08-25 Dompe' Farmaceutici S.P.A. Cxcl8 (interleukin-8) activity inhibitor and corticosteroid combination and pharmaceutical composition and use thereof

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4170588A (en) * 1976-08-28 1979-10-09 Chemische Werke Huls Aktiengesellschaft Synthetic resin stabilizers based on quadratic acid amides
US4639523A (en) * 1984-06-01 1987-01-27 Ikeda Mohando Co., Ltd. Aminoalkylphenoxy derivatives
US5206252A (en) * 1992-05-08 1993-04-27 American Home Products Corporation Thiadiazolyl-amino derivatives of benzopyrans and indanes
US5354763A (en) * 1993-11-17 1994-10-11 American Home Products Corporation Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones
US5466712A (en) * 1994-11-04 1995-11-14 American Home Products Corporation Substituted n-aryl-1,2-diaminocyclobutene-3,4-diones
US5506252A (en) * 1993-11-17 1996-04-09 American Home Products Corporation Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones
US5840764A (en) * 1997-01-30 1998-11-24 American Home Products Corporation Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones
US20010018447A1 (en) * 1997-09-05 2001-08-30 Widdowson Katherine L. Il-8 receptor antagonists
US6300325B1 (en) * 1997-01-23 2001-10-09 Smithkline Beecham Corporation IL-8 receptor antagonists
US6376555B1 (en) * 1998-12-04 2002-04-23 American Home Products Corporation 4-substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones and analogs thereof as novel potassium channel openers
US6420396B1 (en) * 1998-12-16 2002-07-16 Beiersdorf Ag Biphenyl and biphenyl-analogous compounds as integrin antagonists

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1669798A1 (de) 1966-07-28 1971-08-26 Huels Chemische Werke Ag Verfahren zum Stabilisieren markomolekularer Polyacetale
FR1531943A (fr) 1966-07-28 1968-07-05 Huels Chemische Werke Ag Procédé pour stabiliser des poly-acétals macromoléculaires
DE2638855C3 (de) 1976-08-28 1980-04-24 Chemische Werke Huels Ag, 4370 Marl Verwendung von Quadratsäureamiden als Stabilisierungsmittel für geformte oder nicht geformte Kunststoffe
DE3309655A1 (de) 1983-03-17 1984-09-20 Bayer Ag, 5090 Leverkusen 1,2,5-thiadiazol-1-oxide und 1,1-dioxide, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
HU198696B (en) 1987-01-20 1989-11-28 Nissan Chemical Ind Ltd Process for producing 3/2h/-pyridazinon derivatives and pharmaceutical compositions containing them as active components
JPH02256668A (ja) 1988-12-20 1990-10-17 Nissan Chem Ind Ltd ピリダジノン誘導体
GB9312210D0 (en) 1993-06-14 1993-07-28 Smithkline Beecham Plc Chemical compounds
AU686896B2 (en) 1994-11-16 1998-02-12 American Home Products Corporation Diaminocyclobutene-3,4-diones
AU6250298A (en) 1997-01-30 1998-08-25 American Home Products Corporation Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones
ATE224358T1 (de) 1998-10-02 2002-10-15 Neurosearch As Diaminocyclobuten-3,4-dionderivate, deren herstellung und deren verwendung
ES2234300T3 (es) 1998-10-08 2005-06-16 Smithkline Beecham Plc 3-(3-cloro-4-hidroxifenilamino)-4-(2-nitrofenil)-1h-pirrol-2,5-diona como inhibidor de glucogeno cinasa-3 (gsk-3)sintetasa.
JP2002532457A (ja) 1998-12-14 2002-10-02 アメリカン・ホーム・プロダクツ・コーポレイション Ｖｌａ−４により仲介される白血球接着を阻害する３，４−ジアミノ−３−シクロブテン−１，２−ジオン誘導体
NZ512339A (en) 1998-12-16 2003-03-28 Bayer Ag New biphenyl and biphenyl-analogous compounds as integrin antagonists
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
JP2003512355A (ja) 1999-10-15 2003-04-02 デュポン ファーマシューティカルズ カンパニー ケモカイン受容体活性のモジュレータとしての二環式および三環式アミン
WO2001064691A1 (en) 2000-03-01 2001-09-07 Smithkline Beecham Corporation Il-8 receptor antagonists
AR033803A1 (es) * 2000-03-01 2004-01-07 Smithkline Beecham Corp Compuestos de dianilino escuarano, composiciones farmaceuticas que los comprenden, y el uso de los mismos en la fabricacion de medicamentos para tratar enfermedades mediadas por quimioquinas
JP2003527360A (ja) 2000-03-14 2003-09-16 スミスクライン・ビーチャム・コーポレイション Ｉｌ−８受容体アンタゴニスト
AR035642A1 (es) * 2000-05-26 2004-06-23 Pharmacia Corp Uso de una composicion de celecoxib para el alivio rapido del dolor
MXPA02011868A (es) * 2000-05-30 2003-04-10 Smithkline Beecham Corp Antagonistas de receptor de interleucina 8.
WO2002067919A1 (en) * 2001-01-16 2002-09-06 Smithkline Beecham Corporation Il-8 receptor antagonists
ATE346043T1 (de) * 2001-01-16 2006-12-15 Smithkline Beecham Corp Il-8-rezeptorantagonisten
US20030204085A1 (en) * 2001-02-02 2003-10-30 Taveras Arthur G. 3, 4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor antagonists
US20030097004A1 (en) * 2001-02-02 2003-05-22 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC chemokine receptor antagonists
US7132445B2 (en) * 2001-04-16 2006-11-07 Schering Corporation 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
MXPA03009441A (es) * 2001-04-16 2004-02-12 Schering Corp Ciclobuteno-1,2-dionas 3,4-disustituidas como ligandos del receptor de quimocina cxc.
CN1599734A (zh) * 2001-10-12 2005-03-23 先灵公司 作为cxc趋化因子受体拮抗剂的3,4－二取代的马来酰亚胺化合物
US6878709B2 (en) * 2002-01-04 2005-04-12 Schering Corporation 3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists
JP4836388B2 (ja) 2002-03-22 2011-12-14 第一三共株式会社 ｅＮＯＳ発現に起因する疾患の予防または治療薬
PE20040570A1 (es) * 2002-10-09 2004-08-30 Pharmacopeia Drug Discovery Tiadiazoldioxidos y tiadiazoloxidos como ligandos del receptor de cxc- y cc-quimiocina

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4170588A (en) * 1976-08-28 1979-10-09 Chemische Werke Huls Aktiengesellschaft Synthetic resin stabilizers based on quadratic acid amides
US4639523A (en) * 1984-06-01 1987-01-27 Ikeda Mohando Co., Ltd. Aminoalkylphenoxy derivatives
US5206252A (en) * 1992-05-08 1993-04-27 American Home Products Corporation Thiadiazolyl-amino derivatives of benzopyrans and indanes
US5403853A (en) * 1993-11-17 1995-04-04 American Home Products Corporation Substituted N-aryl-1,2-diaminocyclobutene-3,4-diones
US5397790A (en) * 1993-11-17 1995-03-14 American Home Products Corporation Substituted isoquinolinyl-1-2-diaminocyclobutene-3,4,-diones
US5401753A (en) * 1993-11-17 1995-03-28 American Home Products Corporation Substituted n-heteroaryl-1, 2-diaminocyclobutene-3, 3-diones
US5354763A (en) * 1993-11-17 1994-10-11 American Home Products Corporation Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones
US5506252A (en) * 1993-11-17 1996-04-09 American Home Products Corporation Substituted N-heteroaryl and N-aryl-1,2-diaminocyclobutene-3,4-diones
US5466712A (en) * 1994-11-04 1995-11-14 American Home Products Corporation Substituted n-aryl-1,2-diaminocyclobutene-3,4-diones
US5532245A (en) * 1994-11-04 1996-07-02 American Home Products Corporation Substituted N-heteroaryl-1,2-diaminocyclobutene-3,4-dione compounds
US6300325B1 (en) * 1997-01-23 2001-10-09 Smithkline Beecham Corporation IL-8 receptor antagonists
US5840764A (en) * 1997-01-30 1998-11-24 American Home Products Corporation Substituted hydroxy-anilino derivatives of cyclobutene-3,4-diones
US20010018447A1 (en) * 1997-09-05 2001-08-30 Widdowson Katherine L. Il-8 receptor antagonists
US6376555B1 (en) * 1998-12-04 2002-04-23 American Home Products Corporation 4-substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones and analogs thereof as novel potassium channel openers
US6420396B1 (en) * 1998-12-16 2002-07-16 Beiersdorf Ag Biphenyl and biphenyl-analogous compounds as integrin antagonists

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070021494A1 (en) * 2001-04-16 2007-01-25 Schering Corporation And Pharmacopeia, Inc. 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
US7964646B2 (en) * 2001-04-16 2011-06-21 Schering Corporation 3,4-DI-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
US7947720B2 (en) * 2001-04-16 2011-05-24 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
US20090306079A1 (en) * 2001-04-16 2009-12-10 Schering Corporation 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
US7691856B2 (en) 2002-10-09 2010-04-06 Schering Corporation Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands
US20070264230A1 (en) * 2002-10-09 2007-11-15 Schering Corporation Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands
US7645476B2 (en) 2002-11-07 2010-01-12 Abbott Laboratories Method of loading beneficial agent to a prosthesis by fluid-jet application
US20040185081A1 (en) * 2002-11-07 2004-09-23 Donald Verlee Prosthesis with multiple drugs applied separately by fluid jet application in discrete unmixed droplets
US8524148B2 (en) 2002-11-07 2013-09-03 Abbott Laboratories Method of integrating therapeutic agent into a bioerodible medical device
US20070189915A1 (en) * 2002-11-07 2007-08-16 Sanjay Shrivastava Method of integrating therapeutic agent into a bioerodible medical device
US20070191943A1 (en) * 2002-11-07 2007-08-16 Sanjay Shrivastava Integration Of Therapeutic Agent Into A Bioerodible Medical Device
US20040254634A1 (en) * 2002-11-07 2004-12-16 Donald Verlee Prosthesis having varied concentration of beneficial agent
US20080020129A1 (en) * 2002-11-07 2008-01-24 Abbott Laboratories Method of Loading Beneficial Agent to a Prosthesis by Fluid-Jet Application
US20060223864A1 (en) * 2003-12-19 2006-10-05 Schering Corporation And Pharmacopeia Drug Discovery, Inc. Thiadiazoles AS CXC- and CC- chemokine receptor ligands
US7786149B2 (en) 2003-12-19 2010-08-31 Schering Corp. Thiadiazoles as CXC- and CC- chemokine receptor ligands
US7338968B2 (en) 2003-12-19 2008-03-04 Schering Corporation Thiadiazoles AS CXC- and CC- chemokine receptor ligands
US20080090823A1 (en) * 2003-12-19 2008-04-17 Biju Purakkattle J Thiadiazoles as cxc- and cc- chemokine receptor ligands
US20060025453A1 (en) * 2003-12-22 2006-02-02 Schering Corporation And Pharmacopeia Drug Discovery, Inc. Isothiazole dioxides as CXC- and CC-chemokine receptor ligands
US7671212B2 (en) 2003-12-22 2010-03-02 Schering Corporation Isothiazole dioxides as CXC- and CC-chemokine receptor ligands
US20060030579A1 (en) * 2004-03-30 2006-02-09 Boehringer Ingelheim International Gmbh Compounds for the treatment of proliverative processes
US20110076238A1 (en) * 2004-03-30 2011-03-31 Boehringer Ingelheim International Gmbh Compounds for the treatment of proliferative processes
US20060099662A1 (en) * 2004-04-16 2006-05-11 Genentech, Inc. Assay for antibodies
US20070248594A1 (en) * 2004-05-12 2007-10-25 Schering Corporation Cxcr1 and cxcr2 chemokine antagonists
US20080132526A1 (en) * 2004-05-24 2008-06-05 Glaxo Group Limited Purine Derivative
US7737126B2 (en) 2004-05-24 2010-06-15 Glaxo Group Limited Purine derivative
US7897606B2 (en) 2005-06-29 2011-03-01 Schering Corporation 5,6-di-substituted oxadiazolopyrazines and thiadiazolopyrazines as CXC-chemokine receptor ligands
US7718678B2 (en) 2005-06-29 2010-05-18 Schering Corporation Di-substituted oxadiazoles as CXC-chemokine receptor ligands
US20070004682A1 (en) * 2005-06-29 2007-01-04 Schering Corporation Di-substituted oxadiazoles as CXC-chemokine receptor ligands
US20070015731A1 (en) * 2005-06-29 2007-01-18 Biju Purakkattle J 5,6-Di-substituted oxadiazolopyrazines and thiadiazolopyrazines as CXC-chemokine receptor ligands
US7985740B2 (en) 2005-07-19 2011-07-26 Glaxo Group Limited Purine derivatives as agonists of the adenosine A2A receptor
US20080045489A1 (en) * 2006-07-07 2008-02-21 Jianhua Chao 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine receptor ligands
US20080200523A1 (en) * 2007-02-21 2008-08-21 Murthi Krishna K Derivatives of squaric acid with anti-proliferative activity
US8450348B2 (en) * 2007-02-21 2013-05-28 Forma Tm, Llc Derivatives of squaric acid with anti-proliferative activity
WO2010131146A1 (en) * 2009-05-12 2010-11-18 Pfizer Limited Cyclobutenedione derivatives
WO2010131147A1 (en) * 2009-05-12 2010-11-18 Pfizer Limited Cyclobutenedione derivatives
WO2010131145A1 (en) * 2009-05-12 2010-11-18 Pfizer Limited Cyclobutenedione derivatives
WO2012125413A2 (en) * 2011-03-12 2012-09-20 Vicus Therapeutics, Llc Compositions for ameliorating systemic inflammation and methods for making and using them
WO2012125413A3 (en) * 2011-03-12 2012-12-27 Vicus Therapeutics, Llc Compositions for ameliorating systemic inflammation and methods for making and using them
US8865723B2 (en) 2012-10-25 2014-10-21 Tetra Discovery Partners Llc Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury
US9763992B2 (en) 2014-02-13 2017-09-19 Father Flanagan's Boys' Home Treatment of noise induced hearing loss

Also Published As

Publication number Publication date
WO2003080053A1 (en) 2003-10-02
AR040400A1 (es) 2005-04-06
CA2479126A1 (en) 2003-10-02
NZ535314A (en) 2007-08-31
AU2003220384A1 (en) 2003-10-08
TW200808314A (en) 2008-02-16
CA2479126C (en) 2011-11-15
EP1485089B1 (en) 2013-04-17
CN1652779A (zh) 2005-08-10
ZA200407339B (en) 2005-10-06
EP1485089A1 (en) 2004-12-15
US20070155756A1 (en) 2007-07-05
JP2005533005A (ja) 2005-11-04
US7960433B2 (en) 2011-06-14
TW200304811A (en) 2003-10-16
JP4733350B2 (ja) 2011-07-27
BR0308739A (pt) 2005-01-11
AU2003220384B2 (en) 2007-05-10
NO20044402L (no) 2004-12-17
CN100444839C (zh) 2008-12-24
MXPA04009127A (es) 2005-01-25

Similar Documents

Publication Publication Date Title
US20040053953A1 (en) Treatment of chemokine mediated diseases
JP5813734B2 (ja) ５員複素環アミドおよび関連化合物
KR20070011475A (ko) Ｃｘｃｒ1 및 ｃｘｃｒ2 케모카인 길항제
JP2009542700A (ja) Ｃｘｃケモカイン受容体リガンドとしての３，４−ジ置換シクロブテン−１，２−ジオン
WO2014167530A1 (en) Cannabinoid compounds
JP6486002B2 (ja) Ｃｘｃｒ２モジュレーターとしてのアミノピリジンカルボキサミドおよびアミノピリミジンカルボキサミド
JP2005534684A (ja) Ｃｘｃケモカインレセプタ配位子としての３，４−二置換シクロブテン−１，２−ジオン
JP2005532251A (ja) 抗炎症剤としてのイミダゾール誘導体
KR20030081520A (ko) Ｅｐ１ 안타고니스트를 유효 성분으로서 함유하는 울병의치료제
TW200911817A (en) Polycyclic guanine derivatives and methods of use thereof
BR112020018444A2 (pt) Compostos de (2-azabiciclo[3,1,0]hexan-2-il)pirazolo[1,5-a]pirimidina substituída e imidazo[1,2-b]piridazina como inibidores de trk cinases
ES2230171T3 (es) Compuestos 3,4-dihidro-(1h)quinazolin-2-ona como inhibidores de csbp/p38 quinasa.
JP5726301B2 (ja) 新規抗ヒスタミン剤
AU2016381152B2 (en) Indolizine derivatives, composition and methods of use
JPH06505724A (ja) チアゾール誘導体
WO2024009120A1 (en) Triazine derivatives and methods of use thereof
US20240182448A1 (en) Triazine derivatives and methods of use thereof
TW200930714A (en) Novel compounds as cannabinoid receptor ligands and uses thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: SCHERING CORPORATION, NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:TAVERAS, ARTHUR G.;BILLAH, MOTASIM;LUNDELL, DANIEL;AND OTHERS;REEL/FRAME:014732/0522;SIGNING DATES FROM 20030314 TO 20030319

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE