WO2007083182A2 - Novel heterocycles - Google Patents

Novel heterocycles Download PDF

Info

Publication number
WO2007083182A2
WO2007083182A2 PCT/IB2006/003468 IB2006003468W WO2007083182A2 WO 2007083182 A2 WO2007083182 A2 WO 2007083182A2 IB 2006003468 W IB2006003468 W IB 2006003468W WO 2007083182 A2 WO2007083182 A2 WO 2007083182A2
Authority
WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
phenyl
pyrimidin
methylsulfonyl
fluorophenyl
Prior art date
Application number
PCT/IB2006/003468
Other languages
French (fr)
Other versions
WO2007083182A3 (en
Inventor
Visweswara Akella Staya Surya Srinivas
Ravikumar Tadiparthi
Ganapavarapu Veera Raghava Sharma
Sappanimuthu Thirunavukkarasu
Durairaj Peter Bhakiaraj
Virendra Kachhadia
Kilambi Narsimhan
Sathya Narayana Thara
Sriram Rajagopal
Gaddam Om Reedy
Sukunath Narayanan
Venkatesan Parameswaran
Venkatesan Janarthanam
Original Assignee
Orchid Research Laboratories Limited
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 Orchid Research Laboratories Limited filed Critical Orchid Research Laboratories Limited
Priority to ES06831640.5T priority Critical patent/ES2600804T3/en
Priority to BRPI0621226-3A priority patent/BRPI0621226A2/en
Priority to EP06831640.5A priority patent/EP1973884B1/en
Priority to CA2637631A priority patent/CA2637631C/en
Priority to JP2008550862A priority patent/JP5237115B2/en
Priority to CN200680051384.3A priority patent/CN101360717B/en
Priority to AU2006335967A priority patent/AU2006335967B2/en
Publication of WO2007083182A2 publication Critical patent/WO2007083182A2/en
Publication of WO2007083182A3 publication Critical patent/WO2007083182A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • A61P1/18—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
    • 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
    • A61P11/16—Central respiratory analeptics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel heterocyclic compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof.
  • the present invention more particularly provides novel hetereocycles of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel heterocyclic compounds of the general formula (I), their, derivatives, analogs, tautomeric forms, their stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof.
  • This invention also relates to intermediates useful in the preparation of such compounds.
  • novel heterocyclic compounds of the present invention are useful for the treatment of inflammation and immunological diseases.
  • the compounds of the present invention are useful for the treatment of cancer, inflammation and immunological diseases those mediated by cytokines such as TNF- ⁇ , IL-I, IL-6, IL-l ⁇ , IL-8 and cyclooxygenases such as COX-I, COX- 2 and COX-3.
  • the compounds of the present invention are also useful for the treatment of rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease, atherosclerosis, cancer, ischemic-induced cell damage, pancreatic ⁇ cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory ⁇ distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever and myalgias due to infection; and diseases mediated by HIV-I; HIV-2; HIV-3; cytomegalovirus (
  • the present invention is concerned with the treatment of immunological diseases or inflammation, notably such diseases are mediated by cytokines or cyclooxygenases.
  • the principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells.
  • the role of other immune cells such as NK cells, basophils, mast cells and dendritic cells are known, but their role in primary immunologic disorders is uncertain.
  • Macrophages are important mediators of both inflammation and provide the necessary "help" for T cell stimulation and proliferation.
  • macrophages make IL-I, IL- 12 and TNF- ⁇ , all of which are potent pro-inflammatory molecules and also provide help for T cells.
  • cyclooxygenase-2 (COX-2) and cyclooxygenase-3 (COX-3), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells.
  • enzymes such as cyclooxygenase-2 (COX-2) and cyclooxygenase-3 (COX-3)
  • iNOS inducible nitric oxide synthase
  • Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFN ⁇ ). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
  • PTKs phosphotyrosine kinases
  • other undefined cellular kinases are involved in the activation process.
  • Cytokines are molecules secreted by the immune cells, large number of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory responses. A large number of cytokines participate in this response, including IL-I, IL-6, IL-8 and TNF. It appears that the activity of these cytokines in the regulation of inflammation relies at least in part on the activation of an enzyme on the cell-signaling pathway, a member of the MAP known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-I and TNF.
  • Cytokines are molecules secreted by the immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality.
  • the cytokine tumor necrosis factor-alpha (TNF- ⁇ ) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory diseases. TNF- ⁇ is a polypeptide hormone released by activated macrophages and other cells.
  • TNF- ⁇ participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J Clin Invest, 83, 444-55,1989).
  • TNF- ⁇ can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21, 2575-79, 1991; Brennan et al, Lancet, 2, 244-7, 1989).
  • TNF- ⁇ also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S.
  • TNF- ⁇ mediates the cytokine cascade that leads to joint damage and destruction (Arend et al, Arthritis Rheum, 38, 151-60, 1995).
  • Inhibitors of TNF- ⁇ including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21, 75-87, 1999) and anti-TNF- ⁇ antibody (infliximab) (Luong et ah, Ann Pharmacother, 34, 743-60, 2000), are recently approved by the U. S. FD A as agents for the treatment of rheumatoid arthritis. Elevated levels of TNF-oc have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis etc.
  • IBD inflammatory bowel disease
  • Elevated levels of TNF- ⁇ and/or IL-I over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic ⁇ cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
  • TNF- ⁇ TNF- ⁇ IL-6
  • IL-6 has been found to be a growth factor for multiple myeloma cells; anti TL-6 antibodies were shown to block myeloma cell proliferation in leukemic patients (Lkein et al., Blood, 78, (5), pp 1198-1204,1991 and Lu et al., Err. J.
  • cytokine-induced acute phase response may be a primary component of cancer-related cachexia.
  • diminishing or blocking IL-6 activity in animal models attenuates cachexia, further demonstrating the essential role IL-6 plays in the development of this syndrome (For an excellent review see: Michael. J. Tisdale in "Biology of Cachexia", Journal of National Cancer Institute, Vol.89, No.23, Dec.3, 1997).
  • the cytokine IL-I ⁇ also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandins from synovial cells. Elevated or unregulated levels of the cytokine IL- l ⁇ have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome, allergy, Alzheimer's disease etc. Since overproduction of IL-I ⁇ is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL- 1 ⁇ .
  • IL-I is a more potent inducer of stromelysin than TNF- ⁇ . (Firestein, Am. J. Pathol. 140, 1309, 1992). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed.
  • IL-8 chemokines
  • adhesion molecules e.g., IL-8
  • IL-8 chemokines
  • adhesion molecules e.g., IL-8
  • both IL-I and TNF- ⁇ induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints.
  • IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated; chemotactic nature of IL-8, including, but is not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis.
  • IL-8 also has ability to activate neutrophils.
  • reduction in IL- 8 levels may lead to diminish neutrophil infiltration.
  • COX-I enzyme is essential and primarily responsible for the regulation of gastric fluids whereas COX-2 enzyme is present at the basal levels and is reported to have a major role in the prostaglandin synthesis for inflammatory response.
  • These prostaglandins are known to cause inflammation in the body. Hence, if the synthesis of these prostaglandins is stopped by way of inhibiting COX-2 enzyme, inflammation and its related disorders can be treated.
  • COX-3 possesses glycosylation- dependent cyclooxygenase activity.
  • X is O, S or NR 5 ;
  • R 1 and R 2 each independently represent ⁇ Y or --Z--Y, and R 3 and R 4 each independently --Z--Y or R 3 is a hydrogen radical; provided that R 4 is other than a substituted-aryl, (substituted-aryl)methyl or (substituted- aryl)ethyl radical; wherein each Z is independently optionally substituted alkyl, alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl; Y is independently a hydrogen; halo, cyano, nitro, etc., R 5 is independently a hydrogen, optionally substituted alkyl, alkenyl, alkynyl etc., R 11 and R 12 are each independently represent optionally substituted aryl or heteroaryl. An example of these compounds is shown in the formula (lib),
  • R 1 is hydrogen, CF 3 , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-S-(C 1 -C 6 )alkyl, (C 1 - C 6 )alkyl-SO-(C r C 6 )alkyL (CrC ⁇ alkyl-SOa- ⁇ rC ⁇ alkyl, hydroxy-(C r
  • R 2 and R 3 are independently selected from hydrogen, (C r C 6 )alkyl, phenyl and phenyl-
  • (Ci-C 4 )alkyl, or R 2 and R 3 form, together with the nitrogen to which they are attached, a cyclic group selected from azetidino, pyrrolidino, piperidino, piperazino and morpholino, wherein said cyclic group may optionally be substituted;
  • R 4 is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C r C 6 )alkyl, (C r C 6 )hydroxyalkyl, (C r C 6 )alkoxy, phenyl, naphthyl or furyl, wherein said phenyl, naphthyl and furyl may optionally be substituted;
  • R 5 is hydrogen, (C r C 6 )alkyl, (C r C 6 )alkoxy, trifluoromethyl, (C 1 - C 6 )hydroxyalkyl, -S-(C r C 6 )alkyl, -
  • R 1 and R 2 are each independently -Z-Y, preferably, R 2 is a radical of hydrogen, C 1 -C 4 alkyl, halo, hydroxy, amino, etc., Z is independently a bond, alkyl, alkenyl etc., Y is independently a hydrogen radical, halo, nitro radical;
  • R 20 is independently (1) alkyl, alkenyl, heterocyclyl radical, aryl, heteroaryl;
  • R 21 is independently hydrogen radical, R 20 ;
  • R 22 is independently hydrogen, heterocyclyl, aryl or heteroaryl.
  • R 1 , R 2 , R 3 and R 4 may be same or different and independently represent hydrogen, hydroxy, nitro, nitroso, formyl, azido, halo or substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heterocyclyl, acyl, acyloxy, cycloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives;
  • A represents pyrimidine derivative of the formula
  • R 5 , R 6 , R 7 may be same or different and represent, hydrogen, nitro, nitroso, formyl, azido, halo, or substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives; the pyrimidine group may be attached to the phenyl ring through carbon or nitrogen atom.
  • the derivatives may be useful in the treatment of inflammation, cancer and immunological diseases.
  • the compounds of the present invention are useful for the treatment of immunological diseases those mediated by cytokines such as TNF- ⁇ , IL-I, IL-6, IL-I ⁇ , IL-8, IL-12 and inflammation.
  • the compounds of the present invention are also useful in the treatment of rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; ischemic-induced cell damage; pancreatic ⁇ -cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
  • ARDS adult respiratory distress syndrome
  • psoriasis Crohn's disease
  • allergic rhinitis ulcerative co
  • the present invention relates to novel heterocyclic compounds of the general formula (I),
  • A represents substituted or unsubstituted groups selected from aryl
  • B represents substituted or unsubstituted groups selected from aryl or pyridyl.
  • R is selected from azido, halogens, substituted or unsubstituted groups selected from alkoxy, acyl, alkyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl;
  • R 1 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkyls
  • R represents substituted or unsubstituted groups selected from aryl, heteroaryl, aryloxy, -OSO 2 R' (wherein R' may be selected from substituted or unsubstituted: alkyl, aryl, alkyldialkylamino, haloalkyl, heterocyclyl, heteroaryl and the like), and heterocyclyl, the heterocyclyl group may be substituted with substitutents independently selected from substituted or unsubstitued aryl, alkylaryl (-CH 2 -Aryl), alkylheteroaryl (-CH 2 -Heteroaryl), substituted heteroarylcarbonyl (-CO- Heteroaryl), heteroaryl, cyanoalkyl, alkylsulfonyl, haloalkylsulfonyl, formyl and another substituted or unsubstituted heterocyclyl group; the attachment of the heterocyclyl group
  • R is selected from azido, halogens, substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl;
  • R 1 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO 2 NHNH 2j and -SO 2 Cl;
  • R 3 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO 2 NHNH 2; and -SO 2 Cl; provided that any one of R 1 or R 3 is always substituted
  • R 4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO 2 NHNH 2 , -SO 2 Cl, carboxylic acid and its derivatives.
  • the present invention relates to novel heterocyclic compounds of the formula (I),
  • A represents substituted or unsubstituted aryl group
  • B represents substituted or unsubstituted groups selected from aryl or pyridyl
  • X represents carbon or nitrogen atom
  • R is selected from azido, halogens such as fluorine, chlorine, bromine, iodine, substituted or unsubstituted groups selected from alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryl groups such as phenyl, naphthyl and the like, acyl groups such as acetyl, benzoyl and the like, substituted or unsubstituted linear or branched (C 1 -C 6 ) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.,
  • R 2 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO 2 NHNH 2
  • R represents substituted or unsubstituted groups selected from aryl, heteroaryl
  • the heteroaryl groups may be selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazine, benzofuranyl, benzimidazolyl, benzothiazolyl and the like, aryloxy, -OSO 2 R' (wherein R' may be selected from substituted or unsubstituted: alkyl, aryl, alkyldialkylamino, haloalkyl, heterocyclyl, heteroaryl and the like), and heterocyclyl groups such as morpholine, piperazine, piperidine, pyrrolidine, thiazolidine and the like; the heterocyclyl group may be substituted with substitutents
  • R is selected from azido, halogens, substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl;
  • R 1 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO 2 NHNH 2j and -SO 2 Cl;
  • R 3 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO 2 NHNH 2, and -SO 2 Cl; provided that any one of R 1 or R 3 is always substituted
  • R 4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO 2 NHNH 2 , -SO 2 Cl, carboxylic acid and its derivatives.
  • substituents may be selected from halogens, hydroxy, nitro, cyano, ureas, azido, amino, imino-1 -phenyl butanone, amide, thioamide, hydrazine, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryloxy, acyl groups such as acetyl, benzoyl and the like, haloacyl, acyloxyacyl, heterocyclyl, aryl, heteroaryl, monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl groups such as methoxy carbonyl, ethoxy carbonyl and the like, aryloxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, arylsul
  • substituents are further optionally substituted with substituents selected from hydroxy, alkoxy, halogens, acyl, haloalkyl, alkyl, aryl and the like, which in turn may be further substituted by groups such as halogens, alkyl etc.
  • analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms. Hence, a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
  • stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
  • tautomers include readily interconvertible isomeric forms of a compound in equilibrium.
  • the enol-keto tautomerism is an example.
  • polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
  • pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound.
  • derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like.
  • salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metals like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, choline hydroxyethylpiperidine, and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate, which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Particularly useful compounds according to the present invention include:
  • B represents pyridine and R represents a halogen atom and they may be prepared by converting the compound of formula (Ia), wherein all symbols are as defined earlier.
  • the conversion of the compound of formula (Ia) is carried out using reagents such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride and the like in the presence or absence of solvents such as toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, diphenyl ether and the like or a mixture thereof, in presence or absence of a catalytic amount of dimethylformamide or N,N-dimethylaniline or N,N-diethylaniline and the like.
  • the reaction is carried out at a temperature in the range of 2O 0 C to reflux temperatures for a period in the range of 2 to 12 hours.
  • the conversion of the compound of formula (Ib) may be carried out in the presence of one or more equivalents of a metal azide such as LiN 3 , NaN 3 , trialkyl silylazide and the like or hydrazine hydrate or substituted hydrazine.
  • a metal azide such as LiN 3 , NaN 3 , trialkyl silylazide and the like or hydrazine hydrate or substituted hydrazine.
  • the reaction may be carried out in the presence of a solvent such as toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ehtylacetate, acetonitrile, N 5 N- dimethylformamide, dimethylsulfoxide, ethanol, methanol, isopropylalcohol, tert-butylalcohol, diphenyl ether and the like or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably in the range of 0 0 C to 100°C.
  • the reaction time may range from 0.5 to 18 hours.
  • the conversion of the compound of the formula (Ib) is carried out with appropriate heterocyclyl or protected heterocyclyl groups such as morpholine, piperazine, benzylpiperazine, piperidine and the like and these heterocyclyl groups may be further substituted with heteroaryl, benzyl, alkyl heteroaryl, and other carboxylic acid heterocyclyl groups such as furoic acid, thiophene carboxylic acid, pyrazine carboxylic acid and the like in the presence or absence of appropriate solvents like toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, pyridine, diphenyl ether, ethanol, methanol, isopropylalcohol, tert-
  • the reaction may be carried out under acidic conditions using mineral or organic acids, or basic conditions viz. carbonates, bicarbonates, hydrides, hydroxides, alkyls and alkoxides of alkali metals and alkaline earth metals.
  • the reaction may be carried out in the presence of Pd 2 (dba)3, racemic- 2,2'-bis(di ⁇ henyl phosphino)-l,l'-dina ⁇ hthyl (BINAP) 5 EDCI, HOBT, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or by using phase transfer catalysts viz.
  • triethylbenzylammonium chloride tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) and the like.
  • the reaction is usually carried out under cooling to refluxing conditions.
  • the final product is purified by using chromatographic techniques or by recrystallization.
  • the reaction may be carried out for a time period in the range of 2 to 20 hours.
  • R represents -OSO 2 R' and all the other symbols are as defined above, and may be prepared by converting the compound of formula (Ia), wherein all the other symbols are as defined earlier.
  • the compound of the formula (Ia) is prepared according to the procedure described in our PCT/IB03/01289.
  • the conversion of compound of the formula (Ia) is carried out with appropriate heterocyclyl or aryl or alkyl sulfonyl chlorides or sulfonic acids such as naphthalene sulfonyl chloride, naphthalene sulfonic acid, phenyl sulfonic acid, phenyl sulfonyl chloride, thiophene sulfonyl chloride, thiophene sulfonic acid, propyl sulfonyl chloride, propyl sulfonic acid, chloropropyl sulfonyl chloride and the like in the presence or absence of appropriate solvents like toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitrile, N,N
  • the reaction may be carried out under acidic conditions using mineral or organic acids, or basic conditions viz. carbonates, bicarbonates, hydrides, hydroxides, alkyl and alkoxides of alkali metals and alkaline earth metals.
  • the reaction may be carried out in the presence of phase transfer catalysts viz. triethylbenzylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) and the like.
  • the reaction is usually carried out under cooling to refluxing conditions.
  • the final product is purified by using chromatographic techniques or by recrystallization.
  • the reaction may be carried out for a time period in the range of 2 to 20 hours.
  • the reaction of the compound of formula (Ic) with chlorosulfonic acid may be carried out in the presence of solvents such as dichloromethane, acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, and the like or a mixture thereof or in the absence of solvents.
  • the reaction may be carried out at a temperature in the range of 0°C to reflux temperature for period in the range of 2 to 24 hours.
  • reaction of compound of formula (Id) with alkylamine or the appropriate hydrazine may be carried out in the presence of solvents such as acetonitrile, dichloromethane, acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, water, an alcohol and the like or a mixture thereof or in absence of solvents.
  • solvents such as acetonitrile, dichloromethane, acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, water, an alcohol and the like or a mixture thereof or in absence of solvents.
  • the reaction may be carried out at a temperature in the range of O 0 C to reflux temperature for period in the range of 2 to 24 hours.
  • R represents substituted or unsubstituted heteroaryl groups and the other symbols are as defined earlier and they may be prepared by converting the compound of formula (Ie), wherein all the symbols are as defined earlier.
  • heterocyclic compounds thus obtained are further reacted with acyl or aroyl halides such as substituted or unsubstituted benzoyl chlorides in the presence of bases such as triethyl amine, diisopropylamine etc., in chlorinated solvents such as dichloromethane, dichloroethane, chloroform etc., at temperatures ranging from 0 to 100 0 C for 0.5 to 24 hours.
  • acyl or aroyl halides such as substituted or unsubstituted benzoyl chlorides in the presence of bases such as triethyl amine, diisopropylamine etc., in chlorinated solvents such as dichloromethane, dichloroethane, chloroform etc.
  • the pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 10 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used.
  • a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like
  • solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used.
  • Organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts.
  • Amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may be used for the preparation of amino acid salts.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, oxalic acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid
  • compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the hydrazine forms are intended to be inherently included in such name, description, display and/or claim.
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
  • Prodrugs of the compounds of formula (I) are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • Various polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations.
  • (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone: water, dioxane: water, N,N-dimethylformamide: water and the like, preferably water and recrystallization by using different crystallization techniques
  • the present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of inflammation, arthritis, pain, fever, psoriasis, allergic diseases, asthma, inflammatory bowel syndrome, gastro-intestinal ulcers, cardiovascular disorders including ischemic heart disease, atherosclerosis, cancer, ischemic- induced cell damage, particularly brain damage caused by stroke and other pathological disorders associated with free radicals.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • the compositions may be pepared by processes known in the art.
  • the amount of the active ingredient in the composition may be less than 70% by weight.
  • Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the pharmaceutical compositions of the invention are effective in lowering TNF- ⁇ , IL-I ⁇ , IL-6 levels, COX-I, and COX-2 activity without causing, ulcers.
  • the pharmaceutical compositions of the invention are thus effective for treating rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, bone resorption diseases, and osteoporosis.
  • compositions of the invention are also effective in the treatment of ischemic heart disease, ischemic-induced cell damage, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, sepsis, septic shock, toxic shock syndrome, fever, and myalgias due to infection.
  • the pharmaceutical compositions of the present invention are also effective in treating cancer, acute and chronic myelogenous leukemia, multiple myeloma, and pancreatic ⁇ cell destruction.
  • pharmaceutical compositions of the present invention are useful for the treatment of disorders, which includes adult respiratory distress syndrome (ARDS), anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, type I and type II diabetes.
  • ARDS adult respiratory distress syndrome
  • the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease.
  • a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results.
  • the daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose.
  • Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • terapéuticaally effective amount refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other therapies to a mammal in need of such treatment. More specifically, it is that amount that is sufficient to lower the cytokines such as TNF- ⁇ , IL-I ⁇ , IL-6, and to treat autoimmune diseases, inflammation, immunological diseases, and cancer.
  • cytokines such as TNF- ⁇ , IL-I ⁇ , IL-6
  • the term “animal” as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
  • treatment means any treatment of a disease in a mammal, including:
  • reaction mixture was treated with ethyl acetate: water (1:1, 100 ml) and extracted with ethyl acetate (50 ml x 3). The organic layer was washed with brine (100 ml) and dried over anhydrous sodium sulphate. The solid obtained upon evaporation was purified by column chromatography using methanol:dichloromethane (0.5:99.5) as an eluent to afford the title compound (0.1 Ig, yield 45.6 %).
  • the sulphonyl chloride group is converted into the sulphonamido group by treatment with ammonia gas under cold conditions (0-5 °C) by dissolving the substance in dichloromethane. Subsequently the reaction mixture was washed with water (10OmL) and then with brine solution; evaporation of the solvent furnished the titled compound.
  • Step 2 Synthesis of 5-amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]- 3-(methylthio)-N-phenyl-lH-pyrazoIe-4-carboxamide.
  • the compounds of this invention exhibited in vitro inhibition of COX- 2.
  • the COX-2 inhibition activities of the compounds illustrated in the examples were determined by the following method.
  • COX-I and COX-2 enzyme based assays were carried out to check the inhibitory potential of the test compounds on the production of prostaglandin by purified recombinant COX-l/COX-2 enzyme (Proc. Nat. Acad. Sci. USA, 88, 2692-2696, 1991; J. Clin. Immunoassay 15, 116-120, 1992)
  • this assay the potential of the test compound to inhibit the production of prostaglandin either by COX-I or COX-2 from arachidonic acid (substrate) was measured. This was an enzyme based in-vitro assay to evaluate selective COX inhibition with good reproducibility.
  • Arachidonic acid was converted to PGH 2 (Intermediate product) by COXl /COX-2 in the presence or absence of the test compound.
  • the reaction was carried out at 37 0 C and after 2 minutes it was stopped by adding IM HCl.
  • Intermediate product PGH 2 was converted to a stable prostanoid product PGF 2n by SnCl 2 reduction.
  • the amount of PGF 2 ⁇ produced in the reaction was inversely proportional to the COX inhibitory potential of the test compound.
  • the prostanoid product was quantified via enzyme immunoassay (EIA) using a broadly specific antibody that binds to all the major forms of prostaglandin, using Cayman ELISA kit as per the procedure outlined by the manufacturer (Cayman Chemicals, Ann Arbor, USA). Representative results of inhbition are shown in theTable II. Table II
  • TNF- ⁇ Tumor Necrosis Factor Alpha
  • PBMC Peripheral Blood Mononuclear Cells
  • This assay determines the effect of test compounds on the production of IL-6 in human PBMC (Physiol. Res. 52: 593-598, 2003). Compounds were tested for their ability to inhibit the activity of IL-6 in human PBMC.
  • PBMC were isolated from blood using BD Vacutainer CPTTM Cell preparation tube (BD Bio Science) and suspended in RPMI medium. The test compounds were pre-incubated with PBMC (0.5million/incubation well) for 15 minutes at 37° C and then stimulated with Lipopolysaccharide ⁇ Escherichia col ⁇ . B4; 1 ⁇ g/ml) for 18 hours at 37 0 C in 5% CO 2 .
  • the carrageenan paw edema test was performed as described by Winter et al (Proc.Soc.Exp.Biol.Med, 111, 544, 1962). Male wistar rats were selected with body weights equivalent within each group. The rats were fasted for 18 hours with free access to water. The rats were dosed orally with the test compound suspended in the vehicle containing 0.25% carboxymethylcellulose and 0.5% Tween 80. The control rats were administered with vehicle alone. After an hour, the rats were injected with 0.1 ml of 1% Carrageenan solution in 0.9% saline into the sub-plantar surface of the right hind paw. Paw volume was measured using digital plethysmograph before and after 3 hours of carrageenan injection.
  • Body weight, and paw volumes were measured at various days (0, 4, 14, 21) for all the groups.
  • the test compound or vehicle was administered orally, beginning post injection of adjuvant (O'day) and continued for 21 days (pre-treatment group).
  • pre-treatment group the test compound or vehicle was administered starting from day 14 1 to 21 st day.
  • body weight and paw volume of both right and left hind paws were taken.
  • Spleen, and thymus weights were determined.
  • the radiographs of both hind paws were taken to assess the tibio-tarsal joint integrity. Hind limb below the stifle joint was removed and fixed in 1% formalin saline for the histopathological assessment.
  • mice The LPS induced sepsis model in mice was performed as described by Les sekut et al (J Lab Clin Med 1994; 124:813-20).
  • Female Swiss albino mice were selected and the body weights were equivalent within each group. The mice were fasted for 20 hours with free access to water. The mice were dosed orally with the test compound suspended in vehicle containing 0.5% Tween 80 in 0.25% Carboxy-methylcellulose sodium salt. The control mice were administered the vehicle alone. After 30 minutes of oral dosing, mice were injected with 500 ⁇ g of Lipopolysaccharide (Escherichia coli, LPS: B4 from Siga) in phosphate buffer saline solution into the intraperitoneal cavity of the mice.
  • Lipopolysaccharide Escherichia coli, LPS: B4 from Siga
  • mice After 90 minutes of LPS administration mice were bled via retro-orbital sinus puncture. Blood samples were stored overnight at 4 0 C. Serum samples were collected by centrifuging the samples at 4000 rpm for 15 minutes at 4°C. Immediately the serum samples were analysed for TNF- ⁇ levels using commercially available mouse TNF- ⁇ ELISA kit (Amersham Biosciences) and assay was performed by the manufacturer instruction. Representative results of TNF- ⁇ inhibition are shown in the Table VII. Table VII
  • Experimental drugs are screened for anti-cancer activity in three cell lines for their GI 50 , TGI and LC 50 values (using 5 concentrations for each compound).
  • the cell lines are maintained in DMEM containing 10% fetal bovine serum.
  • 96 well microtiter plates are inoculated with cells in 100 ⁇ L for 24 hours at 37°C, 5% CO 2 , 95% air and 100% relative humidity.
  • 5000 HCTl 16 cells/well, 5000 NCIH460 cells/well, 10000 U251 cells/well and 5000 MDAMB231 cells/well are plated.
  • a separate plate with these cell lines is also inoculated to determine cell viability before the addition of the compounds (T 0 ).
  • mice are added to the 96 well plates.
  • Each plate contains one of the above cell lines and the following in triplicate: 5 different concentrations (0.01, 0.1, 1, 10 and 100 ⁇ M) of 4 different compounds, appropriate dilutions of a cytotoxic standard and control (untreated) wells.
  • Compounds are dissolved in dimethylsulfoxide (DMSO) to make 20 mM stock solutions on the day of drug addition and frozen at -20°C.
  • Serial dilutions of these 20 mM stock solutions are made in complete growth medium such that 100 ⁇ L of these drug solutions in medium, of final concentrations equaling 0.01, 0.1, 1, 10 and 100 ⁇ M can be added to the cells in triplicate.
  • Standard drugs whose anti-cancer activity has been well documented and which are regularly used are doxorubicin and SAHA.
  • Percent growth is calculated for each compound's concentration relative to the control and zero measurement wells (To; viability right before compound addition).
  • GI 50 is the concentration required to decrease % growth by 50%; TGI is the concentration required to decrease % growth by 100% and LC 50 is the concentration required to decrease % growth by 150%. Representative results of growth are shown in the Table VIII. Table VIII
  • NA indicates No activity and ND indicates Not Done.

Abstract

The present invention relates to novel heterocyclic compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. The present invention more particularly provides novel hetereocycles of the general formula (I). Also included is a method of treatment of immunological diseases, inflammation, pain disorder, rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic beta cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; muscle degeneration; cachexia; asthma; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection in a mammal comprising administering an effective amount of a compound of formula (I) as described above.

Description

NOVEL HETEROCYCLES Field of the Invention
The present invention relates to novel heterocyclic compounds of the general formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. The present invention more particularly provides novel hetereocycles of the general formula (I).
Figure imgf000003_0001
The present invention also provides a process for the preparation of the above said novel heterocyclic compounds of the general formula (I), their, derivatives, analogs, tautomeric forms, their stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof. This invention also relates to intermediates useful in the preparation of such compounds.
The novel heterocyclic compounds of the present invention are useful for the treatment of inflammation and immunological diseases. Particularly the compounds of the present invention are useful for the treatment of cancer, inflammation and immunological diseases those mediated by cytokines such as TNF-α, IL-I, IL-6, IL-lβ, IL-8 and cyclooxygenases such as COX-I, COX- 2 and COX-3. The compounds of the present invention are also useful for the treatment of rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease, atherosclerosis, cancer, ischemic-induced cell damage, pancreatic β cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory ■ distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever and myalgias due to infection; and diseases mediated by HIV-I; HIV-2; HIV-3; cytomegalovirus (CMV); influenza; adenovirus; the herpes viruses (including HSV-I, HSV-2) and herpes zoster viruses.
Background of the Invention
The present invention is concerned with the treatment of immunological diseases or inflammation, notably such diseases are mediated by cytokines or cyclooxygenases. The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells are known, but their role in primary immunologic disorders is uncertain. Macrophages are important mediators of both inflammation and provide the necessary "help" for T cell stimulation and proliferation. Most importantly macrophages make IL-I, IL- 12 and TNF-α, all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages results in the induction of enzymes, such as cyclooxygenase-2 (COX-2) and cyclooxygenase-3 (COX-3), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFN γ). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
Cytokines are molecules secreted by the immune cells, large number of chronic and acute conditions have been recognized to be associated with perturbation of the inflammatory responses. A large number of cytokines participate in this response, including IL-I, IL-6, IL-8 and TNF. It appears that the activity of these cytokines in the regulation of inflammation relies at least in part on the activation of an enzyme on the cell-signaling pathway, a member of the MAP known as CSBP and RK. This kinase is activated by dual phosphorylation after stimulation by physiochemical stress, treatment with lipopolysaccharides or with proinflammatory cytokines such as IL-I and TNF. Therefore, inhibitors of the kinase activity of p38 are useful anti-inflammatory agents. Cytokines are molecules secreted by the immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor-alpha (TNF-α) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory diseases. TNF-α is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-α participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J Clin Invest, 83, 444-55,1989). At higher concentrations, TNF-α can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21, 2575-79, 1991; Brennan et al, Lancet, 2, 244-7, 1989). TNF-α also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-α mediates the cytokine cascade that leads to joint damage and destruction (Arend et al, Arthritis Rheum, 38, 151-60, 1995). Inhibitors of TNF-α, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21, 75-87, 1999) and anti-TNF-α antibody (infliximab) (Luong et ah, Ann Pharmacother, 34, 743-60, 2000), are recently approved by the U. S. FD A as agents for the treatment of rheumatoid arthritis. Elevated levels of TNF-oc have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis etc.
Elevated levels of TNF-α and/or IL-I over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic β cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-I, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-I, HSV-2), and herpes zoster are also exacerbated by TNF-α.
It can be seen that inhibitors of TNF-α are potentially useful in the treatment of a wide variety of diseases. Compounds that inhibit TNF-α have been described in several patents. Cytokines play an important role in the communication between cells of multicellular organisms. Early studies indicate that B cells lineage tend to secrete IL-6 in response to host immune defense mechanisms, but in recent decades studies have indicated elevated levels of IL-6 in various cancer phenotypes. IL-6 has been found to be a growth factor for multiple myeloma cells; anti TL-6 antibodies were shown to block myeloma cell proliferation in leukemic patients (Lkein et al., Blood, 78, (5), pp 1198-1204,1991 and Lu et al., Err. J. Immunol, 22. 2819 -24,1992). Elevation of inflammatory cytokine levels, particularly IL-6 and TNF-α also appears to be associated with the Cancer-related Cachexia, a syndrome involving loss of adipose and skeletal muscle tissue, and one that is not responsive to increased caloric intake. Cachexia may also be related to the role of acute phase proteins. The acute phase response and production of acute phase proteins (e.g., C-reactive protein [CRP]) are mediated by IL-6. Studies correlate elevated levels of IL-6 elevate acute phase proteins, which, interestingly, are also associated with increased weight loss and decreased survival. Thus, with elevated IL-6 levels, amino acid metabolism is directed away from peripheral tissues to the liver for production of acute phase proteins. This in turn leads to muscle wasting, which is a component of cachexia. Accordingly, the cytokine-induced acute phase response may be a primary component of cancer-related cachexia. Moreover, diminishing or blocking IL-6 activity in animal models attenuates cachexia, further demonstrating the essential role IL-6 plays in the development of this syndrome (For an excellent review see: Michael. J. Tisdale in "Biology of Cachexia", Journal of National Cancer Institute, Vol.89, No.23, Dec.3, 1997).
Thus having an IL-6 inhibitory activity, compound may be useful for various inflammatory diseases, sepsis, multiple myeloma, plasmacytoid leukemia, osteoporosis, cachexia, psoriasis, Nephritis, Kaposi's sarcoma, rheumatoid arthritis autoimmune disease, endometriosis and solid cancer (PCT: WO02/074298 Al). Compounds that inhibit IL-6 have been described in U.S. Patents: 6,004,813; 5,527,546 and 5,166,137.
The cytokine IL-I β also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandins from synovial cells. Elevated or unregulated levels of the cytokine IL- lβ have been associated with a number of inflammatory diseases and other disease states, including but not limited to adult respiratory distress syndrome, allergy, Alzheimer's disease etc. Since overproduction of IL-I β is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL- 1 β .
In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-I have led to an acute and destructive form of arthritis (Chandrasekhar et al, Clinical Immunol Immunopathol. 55, 382, 1990). In studies using cultured rheumatoid synovial cells, IL-I is a more potent inducer of stromelysin than TNF-α. (Firestein, Am. J. Pathol. 140, 1309, 1992). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531, 1994). In rheumatoid arthritis, both IL-I and TNF-α induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In a model of arthritis (collagen- induced arthritis, CIA in rats and mice) intra-articular administration of TNF- α either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11, 253, 1992; and Cooper, Clin. Exp.Imrnunol. 898, 244, 1992).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated; chemotactic nature of IL-8, including, but is not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has ability to activate neutrophils. Thus, reduction in IL- 8 levels may lead to diminish neutrophil infiltration.
It has been reported that the cyclooxygenase enzyme exists in three isoforms, namely, COX-I, COX-2 and COX-3. COX-I enzyme is essential and primarily responsible for the regulation of gastric fluids whereas COX-2 enzyme is present at the basal levels and is reported to have a major role in the prostaglandin synthesis for inflammatory response. These prostaglandins are known to cause inflammation in the body. Hence, if the synthesis of these prostaglandins is stopped by way of inhibiting COX-2 enzyme, inflammation and its related disorders can be treated. COX-3 possesses glycosylation- dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-I and COX-2 demonstrated that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal anti- inflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever. Earlier reports prior to Coxib's development show that inhibitors of COX-I enzyme causes gastric ulcers, where as selective COX-2 and COX-3 enzyme inhibitors are devoid of this function and hence are found to be safe. But, recent reports show that the selective COX-2 inhibitors (COXIBs) are associated with cardiovascular risks. So, inhibition of COX-2 without causing cardiovascular risks and gastric ulcers due to inhibition of COX-I are shown to be safe. Few prior art references, which disclose the closest compounds, are given here: i) US 6,420,385 discloses novel compounds of the formula (Ha),
(Ha)
Figure imgf000009_0001
wherein:
Figure imgf000010_0001
X is O, S or NR5; R1 and R2 each independently represent ~Y or --Z--Y, and R3 and R4 each independently --Z--Y or R3 is a hydrogen radical; provided that R4 is other than a substituted-aryl, (substituted-aryl)methyl or (substituted- aryl)ethyl radical; wherein each Z is independently optionally substituted alkyl, alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl; Y is independently a hydrogen; halo, cyano, nitro, etc., R5 is independently a hydrogen, optionally substituted alkyl, alkenyl, alkynyl etc., R11 and R12 are each independently represent optionally substituted aryl or heteroaryl. An example of these compounds is shown in the formula (lib),
Figure imgf000010_0002
ii) US 5,728,704 discloses novel pyrimidines of the formula (I),
Figure imgf000010_0003
wherein R1 is hydrogen, CF3, (C1 -C6)alkyl, (C1-C6)alkyl-S-(C1-C6)alkyl, (C1 - C6)alkyl-SO-(CrC6)alkyL (CrC^alkyl-SOa-^rC^alkyl, hydroxy-(Cr
C6)alkyl, dihydroxy-(CrC6)alkyl, Q-C^alkoxy, (CrC6)alkoxycarbonyl-(Cr
C6)alkyl, aryl selected from phenyl and naphthyl, aryl-(C1-C6)alkyl; R2 and R3 are independently selected from hydrogen, (CrC6)alkyl, phenyl and phenyl-
(Ci-C4)alkyl, or R2 and R3 form, together with the nitrogen to which they are attached, a cyclic group selected from azetidino, pyrrolidino, piperidino, piperazino and morpholino, wherein said cyclic group may optionally be substituted; R4 is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (CrC6)alkyl, (CrC6)hydroxyalkyl, (CrC6)alkoxy, phenyl, naphthyl or furyl, wherein said phenyl, naphthyl and furyl may optionally be substituted; R5 is hydrogen, (CrC6)alkyl, (CrC6)alkoxy, trifluoromethyl, (C1- C6)hydroxyalkyl, -S-(CrC6)alkyl, -SO-(CrC6)alkyl, -SO2-(CrC6)alkyl, phenyl or furyl. iii) US 6,420,385 and 6,410,729 discloses novel compounds of the formula (He),
Figure imgf000011_0001
wherein R1 and R2 are each independently -Z-Y, preferably, R2 is a radical of hydrogen, C1-C4 alkyl, halo, hydroxy, amino, etc., Z is independently a bond, alkyl, alkenyl etc., Y is independently a hydrogen radical, halo, nitro radical;
R20 is independently (1) alkyl, alkenyl, heterocyclyl radical, aryl, heteroaryl;
R21 is independently hydrogen radical, R20; R22 is independently hydrogen, heterocyclyl, aryl or heteroaryl. iv) US 2005/0107413 discloses novel compounds of the formula (I),
Figure imgf000011_0002
wherein R1, R2, R3 and R4 may be same or different and independently represent hydrogen, hydroxy, nitro, nitroso, formyl, azido, halo or substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heteroaryl, heterocyclyl, acyl, acyloxy, cycloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives; A represents pyrimidine derivative of the formula
Figure imgf000012_0001
wherein R5, R6, R7, may be same or different and represent, hydrogen, nitro, nitroso, formyl, azido, halo, or substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl, carboxylic acid or its derivatives; the pyrimidine group may be attached to the phenyl ring through carbon or nitrogen atom.
Objective of the Invention
We have focused our research to identify cytokine inhibitors predominantly acting through the inhibition of the tumor necrosis factor-α (TNF-α), which are devoid of any side effects normally associated with TNF- α inhibitors, and to identify novel small molecule anticancer agents. Our sustained efforts have resulted in novel heterocyclic compounds of the formula (I). The derivatives may be useful in the treatment of inflammation, cancer and immunological diseases. Particularly the compounds of the present invention are useful for the treatment of immunological diseases those mediated by cytokines such as TNF-α, IL-I, IL-6, IL-I β, IL-8, IL-12 and inflammation. The compounds of the present invention are also useful in the treatment of rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; ischemic-induced cell damage; pancreatic β-cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
Summary of the Invention
The present invention relates to novel heterocyclic compounds of the general formula (I),
Figure imgf000013_0001
their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, pharmaceutically acceptable salts, compositions, metabolites and prodrugs therof, wherein A represents substituted or unsubstituted groups selected from aryl; wherein B represents substituted or unsubstituted groups selected from aryl or pyridyl.
When B is pyridyl then R is selected from azido, halogens, substituted or unsubstituted groups selected from alkoxy, acyl, alkyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl; R1 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R2 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfϊnyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R3 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfmyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R4 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives, and X represents carbon or nitrogen atom. When B is aryl or pyridyl then R represents substituted or unsubstituted groups selected from aryl, heteroaryl, aryloxy, -OSO2R' (wherein R' may be selected from substituted or unsubstituted: alkyl, aryl, alkyldialkylamino, haloalkyl, heterocyclyl, heteroaryl and the like), and heterocyclyl, the heterocyclyl group may be substituted with substitutents independently selected from substituted or unsubstitued aryl, alkylaryl (-CH2-Aryl), alkylheteroaryl (-CH2-Heteroaryl), substituted heteroarylcarbonyl (-CO- Heteroaryl), heteroaryl, cyanoalkyl, alkylsulfonyl, haloalkylsulfonyl, formyl and another substituted or unsubstituted heterocyclyl group; the attachment of the heterocyclyl group to the pyrimidine ring may be through carbon or nitrogen; R1 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R2 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R3 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; and X represents carbon or nitrogen atom. When A and B are both aryl then R is selected from azido, halogens, substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl; R1 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO2NHNH2j and -SO2Cl; R3 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO2NHNH2; and -SO2Cl; provided that any one of R1 or R3 is always substituted sulfamoyl, or substituted or unsubstituted -SO2NHNH2, or - SO2Cl and the like; R2 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives. R4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives.
Detailed Description of the Invention
The present invention relates to novel heterocyclic compounds of the formula (I),
Figure imgf000016_0001
their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, pharmaceutically acceptable salts, compositions, metabolites and prodrugs therof, wherein A represents substituted or unsubstituted aryl group; wherein B represents substituted or unsubstituted groups selected from aryl or pyridyl, and X represents carbon or nitrogen atom.
When B is pyridyl then R is selected from azido, halogens such as fluorine, chlorine, bromine, iodine, substituted or unsubstituted groups selected from alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; aryl groups such as phenyl, naphthyl and the like, acyl groups such as acetyl, benzoyl and the like, substituted or unsubstituted linear or branched (C1-C6) alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like, cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., haloalkyl groups such as chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl, dichloroethyl and the like; amino, hydrazine groups such as hydrazine and methylhydrazine, monoalkylamino groups such as -NHCH3, - NHC2H5, -NHC3H7, -NHC6H13; dialkylamino groups such as -N(CH3)2, - NCH3(C2H5), -N(C2H5)2 and the like; acylamino groups such as - NHC(=O)CH3, -NHC(=O)C2H5, -NHC(=O)C3H7, -NHC(^O)C6H13 and the like, alkylsufonyl groups such as methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, iso-propylsulfonyl and the like, alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl and the like, arylsulfonyl, arylsulfinyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and the like; aryloxycarbonyl groups such as phenoxycarbonyl, napthoxycarbonyl and the like, sulfamoyl; R1 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl groups such as phenyl, naphthyl and the like, aryloxy groups such as phenoxy, napthoxy and the like; acyloxy groups such as MeCOO-, EtCOO-,
PhCOO- and the like; amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxy, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R2 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R3 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R4 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; and X represents nitrogen.
When B is aryl or pyridyl then R represents substituted or unsubstituted groups selected from aryl, heteroaryl, the heteroaryl groups may be selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazine, benzofuranyl, benzimidazolyl, benzothiazolyl and the like, aryloxy, -OSO2R' (wherein R' may be selected from substituted or unsubstituted: alkyl, aryl, alkyldialkylamino, haloalkyl, heterocyclyl, heteroaryl and the like), and heterocyclyl groups such as morpholine, piperazine, piperidine, pyrrolidine, thiazolidine and the like; the heterocyclyl group may be substituted with substitutents independently selected from substituted or unsubstitued aryl, heteroaryl, alkylaryl (-CH2- Aryl), alkylheteroaryl (-CH2-Heteroaryl), substituted heteroarylcarbonyl (— CO-Heteroaryl), cyanoalkyl, alkylsulfonyl, haloalkylsulfonyl, formyl and another substituted or unsubstituted heterocyclyl group; the attachment of the heterocyclyl group to the pyrimidine ring may be through carbon or nitrogen; R1 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R2 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R3 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; and X represents carbon or nitrogen atom.
When A and B are both aryl then R is selected from azido, halogens, substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl, sulfamoyl; R1 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO2NHNH2j and -SO2Cl; R3 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO2NHNH2, and -SO2Cl; provided that any one of R1 or R3 is always substituted sulfamoyl, or substituted or unsubstituted -SO2NHNH2j or - SO2Cl and the like; R2 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives. R4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives.
When the groups R, R1, R2, R3, R4 and R' are substituted by one or more substituents these substituents may be selected from halogens, hydroxy, nitro, cyano, ureas, azido, amino, imino-1 -phenyl butanone, amide, thioamide, hydrazine, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryloxy, acyl groups such as acetyl, benzoyl and the like, haloacyl, acyloxyacyl, heterocyclyl, aryl, heteroaryl, monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl groups such as methoxy carbonyl, ethoxy carbonyl and the like, aryloxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, thioalkyl, thioaryl, sulfamoyl, alkoxyalkyl groups, carboxylic acids and its derivatives such as hydroxamic acid, hydroxamates, esters, amides and acid halides. These substituents are further optionally substituted with substituents selected from hydroxy, alkoxy, halogens, acyl, haloalkyl, alkyl, aryl and the like, which in turn may be further substituted by groups such as halogens, alkyl etc.
The term analog includes a compound, which differs from the parent structure by one or more C, N, O or S atoms. Hence, a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former. The term stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical. Stereoisomers include enantiomers and diastereoisomers.
The term tautomers include readily interconvertible isomeric forms of a compound in equilibrium. The enol-keto tautomerism is an example.
The term polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
The term pharmaceutically acceptable solvates includes combinations of solvent molecules with molecules or ions of the solute compound. The term derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like. Pharmaceutically acceptable salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metals like Ca and Mg, salts of organic bases such as diethanolamine, α-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, choline hydroxyethylpiperidine, and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate, which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols. A term once described, the same meaning applies for it, throught the patent
Particularly useful compounds according to the present invention include:
1. N-({4-[4-Amino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin -5-yl]phenyl} sulfonyl)acetamide;
2. 4-{4-Amino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin- 5-yl}-N-methylbenzenesulfonamide;
3. 4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin- 5-yl }benzenesulfonyl chloride; 4. 4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin- 5-yl}-N-methylbenzenesulfonamide;
5. 4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}-iV-methylbenzenesulfonamide;
6. N-[(4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}phenyl)sulfonyl]acetamide; 7. 4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin -5 -y 1 } benzenesulfonohydrazide;
8. 4-[4-(4-Fluorophenyl)-6-hydrazino-2-(trifluoromethyl)pyrimidin-5-yl] benzenesulfonohydrazide; 9. N-[(4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}phenyl)sulfonyl]acetaniide;
10. 4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimdin-5-yl}-N-methylbenzenesulfonamide;
11. 4-Hydrazino-5-phenyl-6-pyridin-3-yl-2-(trifluoromethyl)pyrimidine; 12. 4-Hydrazino-5-phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;
13. 5-(4-Fluorophenyl)-4-hydrazino-6-pyridin-4-yl-2-(trifluoromethyl) pyrimidine;
14. 252,2-Trifluoro-iV-[5-(4-fluorophenyl)-6-pyridin-4-yl-2-(trifluoromethyl) pyrimidin-4-yl]acetohydrazide; 15. Nl-[5-Phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]aceto hydrazide;
16. 2,2,2-Trifluoro-iV-[5-phenyl-6-pyridin-4-yl-2-(trifluoroniethyl)pyrimidin-4 -yl]acetohydrazide;
17. N-[(4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}phenyl)sulfonyl] acetamide;
18. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin- 4-ylnapthalenesulfonate;
19. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- 3 -chloropropane- 1 -sulfonate; 20. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- 3-(trifluoromethyl)benzenesulfonate;
21. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- 2-(trifluoromethyl)benzenesulfonate;
22. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- 4-methylbenzenesulfonate; 23. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- 4-nitrobenzenesulfonate;
24. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- 4-trifluoromethoxybenzenesulfonate; 25. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl thioρhene-2-sulfonate;
26. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluorometliyl)pyrimidin-4-yl- 4-fluorobenzenesulfonate;
27. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- 2-fluorobenzenesulfonate;
28. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl- (dimethylamino)propanesulfonate;
29. 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl-piperazin-l-yl)-2- (trifluoromethyl)pyrimidine; 30. 4-[4-(4-Fluorophenyl)-6-piperazin-l -yl-2-(trifluoromethyl)pyrimidin-5-yl] benzenesulfonamide ;
31. 4-[5-(4-Fluorophenyl)-6-piperazin-l-yl-2-(trifluoromethyl)pyrimidin-4-yl] benzenesulfonamide;
32. N-Methyl-4-[4-(methylsulfonyl)phenyl]-6-piperazin-l -yl-2- (trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;
33. 4-[4-(Methylsulfonyl)phenyl]-6-piperazin- 1 -yl-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
34. 4-{4-(Morpholin-4yl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl} -N-methylbenzenesulfonamide; 35. 5-{4-[4-(Methylsulfonyl)phenyl]-6-piperidin-l-yl-2-(trifluoromethyl) pyrimidin-5-yl} -iV-methylbenzenesulfonamide;
36. 4-[4-(Methylsulfonyl)phenyl]-6-{4-[(5-methylpyrazin-2-yl)carbonyl] piperazin-l-yl}-5-phenyl-2-(trifluoromethyl)pyrimidine;
37. 6-[4-(Methylsulfonyl)ρhenyl]-5-ρhenyl-4-{4-[(l-methyl-lH"-pyrrol-2-yl) carbonyl]piperazin-l-yl}-2-(trifluoromethyl)pyrimidine; 38. 6-[4-(Methylsulfonyl)phenyl]-4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-5- phenyl-2-(trifluoromethyl)pyrimidine;
39. N-Methyl-4-{4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-6-[4-(methylsulfonyl) phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide; 40. 4-{5-[4-Fluorophenyl]-4-[4-(5-nitro-2-jEuroyl)piperazin-l-yl]-2-(trifluoro methyl)pyrimidin-6-yl}benzenesulfonamide;
41. 4-{6-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-2-(trifluoro methyl)pyrimidin-5-yl}benzenesulfonamide;
42. 6-[4-(Methylsulfonyl)phenyl]-4-{4-[(5-nitro-lH-pyrazol-3-yl)carbonyl] piperazin- 1 -yl} -5-phenyl-2-(trifluoromethyl)pyrimidine;
43. 5,6-Diphenyl-4-[4-(5-nitro-2-furoyl)piperazin- 1 -yl]-2-(trifluoromethyl) pyrimidine;
44. 5-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-6-pyridin-4-yl- 2-(trifluoromethyl)pyrimidine; 45. 6-[4-(Methylsulfonyl)phenyl]-5-ρhenyl-4-[4-(l,3-thiazol-2-ylmethyl) piperazin- 1 -yl]-2-(trifluoromethyl)pyrimidine;
46. 4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-[4-(pyridin-4-ylmethyl) piperazin- 1 -y 1] -2-(trifluoromethyl)pyrimidine ;
47. 6-[4-(Methylsulfonyl)phenyl]-4-{4-[(5-nitro-2-thienyl)methyl]piperazin-l- yl} -5-phenyl-2-(trifluoromethyl)pyrimidine;
48. 4,5-Diphenyl-6-(4-pyridin-2-yl-piperazin- 1 -yl)-2-(trifluoromethyl) pyrimidine;
49. 4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-(4-pyridin-2-yl-piperazin- 1 -yl)- 2-(trifluoromethyl)pyrimidine; 50. 3-[4-(4-Fluorophenyl)-6-piperazin-l-yl-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
51. 3-[5-Phenyl-6-piperazin-l-yl-2-(trifluoromethyl)pyrimidin-4-yl] benzenesulfonamide;
52. 3 - [5-(3 - Aminosulfonylphenyl)] -6-piperazin- 1 -yl-2-(trifluoromethy 1) pyrimidin-4-yl]benzenesulfonamide; 53. 3-[4-(4-Fluoroρhenyl)-6-(4-pyridin-2-ylpiperazin- 1 -yl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
54. 3-[4-(4-Fluorophenyl)-6-(4-pyrimidin-2-ylpiperazin-l -yl)- 2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide; 55. 3-[5-Phenyl-6-(l,3-thiazolidin-3-yl)-2-(trifluoromethyl)pyrimidin-4-yl] benzenesulfonamide;
56. 3-[6-[(4-Hydroxycyclohexyl)amino]-5-(3-aminosulfonylphenyl)-2- (trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;
57. 3-[6-(4-Pyrimidin-2-ylpiperazin-l-yl)]-5-phenyl-2-(trifluoromethyl) pyrimidin-4-yl]benzenesulfonamide;
58. 3-[6-(4-Pyridin-2-ylpiperazin-l-yl)]-5-phenyl-2-(trifluoroniethyl) pyrimidin-4-yl]benzenesulfonamide;
59. Ethyl-l-[5-(3-aminosulfonylphenyl)-6-(4-fluorophenyl)-2 -(trifluoromethyl)pyrimidin-4-yl]piperidine-4-carboxylate; 60. 3-[4-[(4-Hydroxycyclohexyl)amino]-6-(4-fluorophenyl)-2-(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide;
61. Ethyl 1 -[5-phenyl-6-(3-aminosulfonylphenyl)l-2-(trifluoromethyl) pyrimidin-4-yl]piperidine-4-carboxylate;
62. 4- [5-Phenyl-6-(3 -moφholinosulfonylphenyl)-2-(trifluoromethyl) pyrimidin-4-yl]morpholine;
63. 3-[4-(4-Fluorophenyl)-6-morpholin-4-yl-2-(trifluoromethyl)pyrimidin-5- yljbenzenesulfonamide;
64. (3i?)-l-[6-(4zFluorophenyl)-5-(3-aminosulfonylphenyl)-2-(trifluoro methyl)pyrimidin-4-yl]pyrrolidin-3-ol; 65. Ethyl (25',4i?)-4-hydroxy-l-[6-(4-fluorophenyl)-5-(3-aminosulfonyl phenyl)-2-(trifluoromethyl)pyrimidin-4-yl]pyrrolidine-2-carboxylate;
66. 4-[4-(2,6-Dimethoxypyrimidin-4-yl)piperazin-l-yl]-5-(3-aminosulfonyl phenyl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidine;
67. 5-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin-l-yl)-6-[4-(methylsulfonyl) phenyl]-2-(trifluoromethyl)pyrimidine; 68. 4-(4-Methylsulfonylphenyl)-5-(4-fluorophenyl)-6-(4-pyrimidin-2-yl piperazin-l-yl)-2-(trifluoromethyl)pyrimidine;
69. 4-[5-(4-Fluoroρhenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-4-yl]piperazine- 1 -carbaldehyde; 70. 1 '-[5-(4-Flurophenyl)-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl) pyrimidin-4-yl]-l,4'-bipiperidine;
71. 3-[4-(4-Fluoroρhenyl)-6-(l ,4'-bipiρeridin-l '-yl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
72. 3-[4-(2-Furoyl)piperazin-l-yl)-6-(4-fluorophenyl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
73. 5-(3-Aminosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)- 6- { 4- [3 -(trifluoromethy l)phenyl]piperazin- 1 -yl } pyrimidine;
74. 5-(4-Fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(trifluoromethyl)- 6- { 4 - [3 -(trifluoromethy l)pheny ljpiperazin- 1 -y 1 } pyrimidine ; 75. 3-[4-(4-Fluorophenyl)-6-(l ,3-thiazolidin-3-yl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
76. l-[5-[3-(Aminosulfonyl)phenyl]-6-(4-fluoropb.enyl)-2-(trifluoromethyl) pyrimidin-4-yl]pyrrolidine-2-carboxamide;
77. 5-(3-Aminosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)- 6- {4-[(trifluoromethyl)sulfonyl]piperazin- 1 -yl}pyrimidine;
78. 3-[4-[4-(Methylsulfonyl)piperazin-l-yl]-6-(4-fluorophenyl)-2-(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide;
79. 3 - [4- [4-(Cyanomethyl)piperazin- 1 -y 1] -6-(4-fluoropheny l)-2-(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide; 80. 3-[4-(4-Fluorophenyl)-6-(lH-imidazol-l -yl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
81. 5-(4-Fluorophenyl)-4-(lH-imidazol-l-yl)-6-[4-(methylsulfonyl)ρhenyl]- 2-(trifluoromethyl)pyrimidine;
82. 3-[6-(4-Pyridin-5-trifluoromethyl-2-ylpiperazin-l-yl)]-5-phenyl-2- (trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide; 83. 3-[6-{4-[2,6-Dimethoxypyrimidin-4-yl]piperazin-l-yl}-5-phenyl- 2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;
84. 3-[6-{4-[5-(Nitro)pyridin-2-yl]piperazin-l-yl}-5-phenyl- 2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide; 85. 3 - [6- { 4- [5-(Amino)pyridin-2-y l]piperazin- 1 -yl } -4- [4-fluoropheny 1] - 2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;
86. 4-[5-(Acetylamino)pyridin-2-yl]piperazin- 1 -yl-5-(4-fluorophenyl)- 6-[4-(meth.ylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine;
87. N-({3-[4-pyridin-2-yl]piperazin-l-yl)-6-(4-fluorophenyl)- 2-(trifluoromethyl) pyrimidin-5-yl]phenyl}sulfonyl) acetamide;
88. 4-Fluorophenyl-5-(3-propionylaminosulfonylphenyl)-6-([4-pyridin-2-yl] piperazin- 1 -yl)-2-(trifluoromethyl)pyrimidine;
89. 1 -{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)- 2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylic acid; 90. 4-[4-(Methoxyaminocarbonyl)piperidin-l-yl}-5-(4-fluorophenyl)- 6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidine;
91. Methyl-3-methoxy-4-({6-[4-(methylsulfonyl)phenyl]- 5-(4-fluoroρhenyl)-2-(trifluoromethyl)pyrimidin-4-yl}oxy)benzoate;
92. 3-Methoxy-4-({6-(4-fluorophenyl)-5-[3-(aminosulfonyl)phenyl]- 2-(trifluoromethyl)pyrimidin-4-yl} oxy)-N-methoxybenzamide;
93. 4- { [5-(4-Fluorophenyl)-6(4-methylsufonylphenyl)-2-(trifluoromethyl) pyrimidin-4-yl]oxy}-N,3-dimethoxybenzamide;
94. 5- Amino- 1 - [5 , 6-diphenyl-2-(trifluoromethy l)pyrimidin-4-yl] -3 -methyl- 1 H -pyrazole-4-carbonitrile; 95. Ethyl-5-amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]- 3-(methylthio)-lH-pyrazole-4-carboxylate;
96. 5-Amino- 1 -[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]- lH-pyrazole- 4-carbonitrile;
97. 3-t-Butyl-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-l/f-pyrazol- 5-amine; 98. 4-(3,5-Dimethyl-lH-pyrazol-l-yl)-5,6-diphenyl-2-(trifluoromethyl) pyrimidine;
99. 3-[4-(5-Amino-4-cyano-3-methyl-lH"-pyrazol-l-yl)-6-(4-fluorophenyl) -2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide; 100. Ethyl-5-amino-l-[5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2- (trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-lH-pyrazole-4-carboxylate;
101. 4-[4-(Methylsulfonyl)ρhenyl]-5-phenyl-2-(trifluoromethyl)- 6- [5-(trifluoro methyl)- 1 H-pyrazol- 1 -yljpyrimidine;
102. 5-Amino- 1 -[556-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]- lH-pyrazole-4-carbothioamide;
103. (3Z)-434,4-Trifluoro-l-phenylbutane-l,3-dione-3-{[5-phenyl- 6-(4-niethylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]hydrazone}
104. N-{l-[5,6-Diρhenyl-2-(trifluoromethyl)ρyrimidin-4-yl]-3-t-butyl-lH- pyrazol-5-yl} -4-methoxybenzamide; 105. N-{l-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-lH- pyrazol-5-yl} -3-fluorobenzamide;
106. N-{l-[5,6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-lH'- pyrazol-5-yl} -4-(trifluoromethyl)benzamide;
107. Ethyl-5-amino-l-[5-phenyl-6-[4-(methylsulfonyl)phenyl]- 2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-l/f-pyrazole-4-carboxylate;
108. 5-Amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methyl thio)-N-phenyl- 1 H-pyrazole-4-carboxamide;
109. 5-Amino-N-(4,5-dimethylphenyl)-l-[5-(4-fluorophenyl)-6-pyridin-4-yl -2-(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-lH-pyrazole-4- carboxamide;
110. l-(2,6-Dichloroρhenyl)-3-{l-[5,6-diρhenyl-2- (trifluoromethy l)pyrimidin-4-y 1] -3 -t-butyl- 1 Η-pyrazol-5 -y 1} urea;
111. 4-[4-(Methylthio) phenyl]-5,6-diphenyl-2-(trifluoromethyl)pyrimidine; and 112. 5-Phenyl-4-[4-(methylsulfonyl)phenyl]-6-[4-(methylthio)phenyl]-2- (trifluoromethyl)pyrimidine.
According to another embodiment of the present invention, there is provided a process for the preparation of novel heterocyclic compounds of the formula (I),
Figure imgf000029_0001
wherein B represents pyridine and R represents a halogen atom and they may be prepared by converting the compound of formula (Ia), wherein all symbols are as defined earlier.
Figure imgf000029_0002
The compound of formula (Ia) is prepared according to the procedure described in our PCT/IB03/01289.
The conversion of the compound of formula (Ia) is carried out using reagents such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride and the like in the presence or absence of solvents such as toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, diphenyl ether and the like or a mixture thereof, in presence or absence of a catalytic amount of dimethylformamide or N,N-dimethylaniline or N,N-diethylaniline and the like. The reaction is carried out at a temperature in the range of 2O0C to reflux temperatures for a period in the range of 2 to 12 hours.
In yet another embodiment of the present invention, there is provided a process for the preparation of novel heterocyclic compounds of the formula (I)
Figure imgf000030_0001
wherein B represents pyridine and R represents azido or hydrazine or substituted hydrazine and they may be prepared by converting the compound of the formula (Ib), wherein all the symbols are as defined earlier.
Figure imgf000030_0002
The conversion of the compound of formula (Ib) may be carried out in the presence of one or more equivalents of a metal azide such as LiN3, NaN3, trialkyl silylazide and the like or hydrazine hydrate or substituted hydrazine. The reaction may be carried out in the presence of a solvent such as toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ehtylacetate, acetonitrile, N5N- dimethylformamide, dimethylsulfoxide, ethanol, methanol, isopropylalcohol, tert-butylalcohol, diphenyl ether and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of ambient temperature to reflux temperature of the solvent, preferably in the range of 00C to 100°C. The reaction time may range from 0.5 to 18 hours.
In yet another embodiment of the present invention, there is provided a process for the preparation of novel heterocyclic compounds of the formula (I),
Figure imgf000031_0001
wherein R represents substituted or unsubstituted heterocyclyl groups, and the other symbols are as defined earlier and they may be prepared by converting the compound of formula (Ib), wherein all the symbols are as defined earlier.
Figure imgf000031_0002
The compound of formula (Ib) is prepared according to the procedure described in our PCT/IB03/02879
The conversion of the compound of the formula (Ib) is carried out with appropriate heterocyclyl or protected heterocyclyl groups such as morpholine, piperazine, benzylpiperazine, piperidine and the like and these heterocyclyl groups may be further substituted with heteroaryl, benzyl, alkyl heteroaryl, and other carboxylic acid heterocyclyl groups such as furoic acid, thiophene carboxylic acid, pyrazine carboxylic acid and the like in the presence or absence of appropriate solvents like toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, pyridine, diphenyl ether, ethanol, methanol, isopropylalcohol, tert-butylalchol, acetic acid, propionic acid etc or the like, or a mixture thereof or by neat reactions. The reaction may be carried out under acidic conditions using mineral or organic acids, or basic conditions viz. carbonates, bicarbonates, hydrides, hydroxides, alkyls and alkoxides of alkali metals and alkaline earth metals. The reaction may be carried out in the presence of Pd2(dba)3, racemic- 2,2'-bis(diρhenyl phosphino)-l,l'-dinaρhthyl (BINAP)5 EDCI, HOBT, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine or by using phase transfer catalysts viz. triethylbenzylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) and the like. The reaction is usually carried out under cooling to refluxing conditions. The final product is purified by using chromatographic techniques or by recrystallization. The reaction may be carried out for a time period in the range of 2 to 20 hours.
In yet another embodiment of the present invention, there is provided a process for the preparation of novel heterocyclic compounds of the formula (I)
Figure imgf000032_0001
wherein R represents -OSO2R' and all the other symbols are as defined above, and may be prepared by converting the compound of formula (Ia), wherein all the other symbols are as defined earlier.
Figure imgf000032_0002
The compound of the formula (Ia) is prepared according to the procedure described in our PCT/IB03/01289.
The conversion of compound of the formula (Ia) is carried out with appropriate heterocyclyl or aryl or alkyl sulfonyl chlorides or sulfonic acids such as naphthalene sulfonyl chloride, naphthalene sulfonic acid, phenyl sulfonic acid, phenyl sulfonyl chloride, thiophene sulfonyl chloride, thiophene sulfonic acid, propyl sulfonyl chloride, propyl sulfonic acid, chloropropyl sulfonyl chloride and the like in the presence or absence of appropriate solvents like toluene, xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, dichloroethane, o-dichlorobenzene, acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, pyridine, diphenyl ether, ethanol, methanol, isopropylalcohol, t-butylalchol, acetic acid, propionic acid etc, or the like, or a mixture thereof, or by neat reactions. The reaction may be carried out under acidic conditions using mineral or organic acids, or basic conditions viz. carbonates, bicarbonates, hydrides, hydroxides, alkyl and alkoxides of alkali metals and alkaline earth metals. The reaction may be carried out in the presence of phase transfer catalysts viz. triethylbenzylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tricaprylylmethylammonium chloride (aliquat 336) and the like. The reaction is usually carried out under cooling to refluxing conditions. The final product is purified by using chromatographic techniques or by recrystallization. The reaction may be carried out for a time period in the range of 2 to 20 hours.
In yet another embodiment of the present invention, there is provided a process for the preparation of novel heterocyclic compounds of the formula (I) wherein R1, R2, R3 and R4 represent SO2Cl, and all other symbols are as defined earlier, and which comprises reacting compound of formula (Ic) wherein all symbols. are as defined earlier. Wherein any Of R1, R2, R3, and R4 which represents hydrogen on treatment with chlorosulfonic acid, is replaced by — SO2Cl; this may result in both possibilities mono/disubstitution.
Figure imgf000033_0001
The reaction of the compound of formula (Ic) with chlorosulfonic acid may be carried out in the presence of solvents such as dichloromethane, acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, and the like or a mixture thereof or in the absence of solvents. The reaction may be carried out at a temperature in the range of 0°C to reflux temperature for period in the range of 2 to 24 hours. In yet another embodiment of the present invention, there is provided a process for the preparation of novel heterocyclic compounds of the formula (I), wherein R1, R2, R3 or R4 represent -SO2NHCH3, -SO2NHNH2 and all the other symbols are as defined earlier, which comprises reacting the compound of formula (Id), wherein R1, R2, R3 or R4 represents -SO2Cl and all the other symbols are as defined earlier; with methylamine or appropriate alkylamine or hydrazine hydrate or substituted hydrazine.
Figure imgf000034_0001
The reaction of compound of formula (Id) with alkylamine or the appropriate hydrazine may be carried out in the presence of solvents such as acetonitrile, dichloromethane, acetone, tetrahydrofuran, dioxane, ethyl acetate, chloroform, water, an alcohol and the like or a mixture thereof or in absence of solvents. The reaction may be carried out at a temperature in the range of O0C to reflux temperature for period in the range of 2 to 24 hours.
In yet another embodiment of the present invention, there is provided a process for the preparation of novel heterocyclic compounds of the formula (I)
ω
Figure imgf000034_0002
wherein R represents substituted or unsubstituted heteroaryl groups and the other symbols are as defined earlier and they may be prepared by converting the compound of formula (Ie), wherein all the symbols are as defined earlier.
Figure imgf000035_0001
The reaction of (Ie) with reagents such as 1-methoxyethylidene malononitrile, ethyl-2-cyano-3,3-δw(methylthio)acrylate, ethoxymethylene malononitrile, pivaloyl nitrile, acetyl acetone, 1-ethoxyethylidene malononitrile etc., in alcoholic solvents such as ethanol, methanol, isopropanol, butanol etc., or in chlorinated solvents such as dichloromethane, dichloroethane, chloroform etc., or hydrocarbon solvents such as toluene etc., at temperatures ranging from 0 to 200°C for 0.5 to 24 hours. Some of the heterocyclic compounds thus obtained are further reacted with acyl or aroyl halides such as substituted or unsubstituted benzoyl chlorides in the presence of bases such as triethyl amine, diisopropylamine etc., in chlorinated solvents such as dichloromethane, dichloroethane, chloroform etc., at temperatures ranging from 0 to 1000C for 0.5 to 24 hours.
The reactions of (Ie) with 1,3-diketones such as acetylacetone, phenyltrifluoroacetyl acetone etc., was carriedout in alcoholic solvents such as ethanol, methanol etc., at temperatures ranging from 0 to 150°C for 0.5 to 24 hours.
The pharmaceutically acceptable salts are prepared by reacting the compound of formula (I) with 1 to 10 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, tetrahydrofuran, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may also be used. Organic bases such as diethanolamine, α-phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline, guanidine and the like, ammonium or substituted ammonium salts, aluminum salts. Amino acids such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine etc may be used for the preparation of amino acid salts. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, oxalic acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, tetrahydrofuran, dioxane etc. Mixture of solvents may also be used.
It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, and though one form is named, described, displayed and/or claimed herein, all the hydrazine forms are intended to be inherently included in such name, description, display and/or claim.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
Prodrugs of the compounds of formula (I) are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. Various polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques. Pharmaceutically acceptable solvates of the compounds of the formula
(I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone: water, dioxane: water, N,N-dimethylformamide: water and the like, preferably water and recrystallization by using different crystallization techniques
The present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of inflammation, arthritis, pain, fever, psoriasis, allergic diseases, asthma, inflammatory bowel syndrome, gastro-intestinal ulcers, cardiovascular disorders including ischemic heart disease, atherosclerosis, cancer, ischemic- induced cell damage, particularly brain damage caused by stroke and other pathological disorders associated with free radicals.
The pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. The compositions may be pepared by processes known in the art.
The amount of the active ingredient in the composition may be less than 70% by weight. Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds. The injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
The pharmaceutical compositions of the invention are effective in lowering TNF-α, IL-I β, IL-6 levels, COX-I, and COX-2 activity without causing, ulcers. The pharmaceutical compositions of the invention are thus effective for treating rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, bone resorption diseases, and osteoporosis. The pharmaceutical compositions of the invention are also effective in the treatment of ischemic heart disease, ischemic-induced cell damage, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, sepsis, septic shock, toxic shock syndrome, fever, and myalgias due to infection. The pharmaceutical compositions of the present invention are also effective in treating cancer, acute and chronic myelogenous leukemia, multiple myeloma, and pancreatic β cell destruction. Furthermore, pharmaceutical compositions of the present invention are useful for the treatment of disorders, which includes adult respiratory distress syndrome (ARDS), anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, type I and type II diabetes. Generally, the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease. Generally, a daily dose of active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results. The daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose. Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound or mixture of compounds of Formula I that is sufficient to effect treatment, as defined below, when administered alone or in combination with other therapies to a mammal in need of such treatment. More specifically, it is that amount that is sufficient to lower the cytokines such as TNF-α, IL-I β, IL-6, and to treat autoimmune diseases, inflammation, immunological diseases, and cancer. The term "animal" as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula I chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
The term "treatment" or "treating" means any treatment of a disease in a mammal, including:
a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or
c) Relieving the disease, that is, causing the regression of clinical symptoms.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, make various changes and modifications of the invention to adapt it to various usages and conditions.
The present invention is provided by the examples given below, which are provided by the way of illustration only, and should not be considered to limit the scope of the invention. Variation and changes, which are obvious to one skilled in the art, are intended to be within the scope and nature of the invention, which are defined in the appended claims. , Preparation 1
Synthesis of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl) pyrimidin-4-amine
Figure imgf000041_0001
Ammonia gas was purged through a solution of 4-chloro-6-[4- (methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine (5.5g, 13.33 mmol, prepared according to the procedure described in PCT/IB03/02879) in THF (500 ml), continuously for 30 hours under stirring at 0-100C. Then after completion of the reaction the THF was distilled completely in-vacuo, water (100 ml) was added, and extracted with ethyl acetate (200 ml x 3). The combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 6-[4- (methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidm-4-amine (3.6g, yield 87.79%).
The following compounds were prepared according to the above procedure
Figure imgf000042_0002
Example 3
Synthesis of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}benzenesulfonyl chloride
Figure imgf000042_0001
To a solution of chlorosulphonic acid (605mmol, 40.4ml) was added 4- chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidine (5.Og, 12.1mmol, prepared according to the procedure described in PCT7IB03/02879) slowly under continuous stirring at O0C until the completion of the addition. Then the reaction mixture was stirred at 32°C until TLC confirmed the completion of the reaction. The resulting reaction mass was poured slowly under vigorous stirring onto crushed ice and the solid obtained was filtered, washed thoroughly with water (100 ml) and extracted with ethyl acetate (200 ml x 3). The combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2- (trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl chloride (2.75g, yield 65.59%, purity by HPLC 98.17%). M.p: 207 - 210°C. 1H-NMR (400 MHz, CDCl3) δ: 3.01 (s, 3H), 7.511 - 7.515 (d, 2H), 7.53 - 7.67 (m, IH), 7.72 - 7.76 (t, IH), 7.86 - 7.89 (m, 3H), 8.11 - 8.13 (d, IH). IR (KBr) cm'1: 1557, 1524.
Figure imgf000043_0001
Example 4 Synthesis of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyriinidin-5-yl}-iV-methylbenzenesulfonamide
Figure imgf000043_0002
To a solution of 4-{4-chloro-6-[4-(methylsulfonyl)phenyi]-2- (trifluoromethyl)pyrimidin-5-yl}benzenesulfonyl chloride (0.5g, 0.98mmol, prepared according to the procedure described for Example 3) in dichloromethane (5ml) was added methylamine solution (0.08ml, 0.98mmol, 40% aqueous solution) under stirring at 0-100C. After 15 minutes of the stirring, TLC confirmed the completion of the reaction. The solvent was distilled off under reduced pressure and the solid thus obtained was filtered, washed thoroughly with cold water to yield the title compound (0.446g, yield 90.1%, purity by HPLC 98.1%). M.p: 226 - 230°C. 1H-NMR (400 MHz, DMSO-d6) δ: 2.09 - 2.10 (d, 3H), 3.1 (s, 3H), 7.43 - 7.44 (m, IH, D2O exchangeable), 7.54 - 7.56 (d, 2H), 7.69 - 7.81 (m, 4H), 7.86 - 7.88 (d, 2H). IR (KBr) cm"1: 3335, 1562, and 1530. MS m/z: 506.1(M+H-I). The following compounds were prepared according to the procedure described for example 4
Figure imgf000044_0001
Example 7
Synthesis of 4-{4-hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoro methy l)py rimidin-5-yl} b enzenesulf onohy drazide
Figure imgf000045_0001
To a suspension of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2- (trifluoroniethyl)pyrimidin-5-yl}benzenesulfonyl chloride (Ig, 1.9 mmol, prepared according to the procedure described for Example 3) in ethanol (10ml) was added hydrazine hydrate (0.195g, 3.9rnmol), at 0-100C under stirring. The stirring was continued at the same temperature for 3 hours until TLC using ethyl acetate and hexane as solvent system confirmed the completion of the reaction. The solid that reappeared was filtered and washed with ethanol (5ml) and finally with hexane (10ml) to afford the desired compound (0.9g, yield 91.56%, purity by HPLC 94.49%). M.p. 203-206°C. 1H-NMR (DMSO-d6) δ: 3.17 (s, 3H), 4.0 (s, 2H, D2O exchangeable), 7.44 - 7.46 (d, 3H), 7.59 - 7.64 (m, IH), 7.76 - 7.77 (d, 3H), 8.33s, IH), 8.44 (s, IH, D2O exchangeable). IR (KBr) cm"1: 3353, 1581,1567. MS m/z: 503.1 (M++l). The following compounds were prepared according to the procedure described for example 7
Figure imgf000045_0002
Figure imgf000046_0001
Figure imgf000047_0002
Example 14
Synthesis of 2,2,2-trifluoro-iV^-[5-(4-fluorophenyl)-6-pyridm-4-yl-2-
(trifluoromethyl)pyrimidin-4-yl]acetohydrazide
Figure imgf000047_0001
To a solution of 5-(4-fluorophenyl)-4-hydrazino-6-pyridin-4-yl-2- (trifluoromethyl)pyrimidine (0.5g, 1.43mmol, example 13, prepared according to the procedure described for example 7) in dichloromethane (10ml) was added trifluoroacetic anhydride (0.22ml, 1.57mmol) under stirring at -40°C. The stirring was continued at the same temperature for 30 minutes, until TLC using ethyl acetate and hexane (3:7) as solvent system confirmed the completion of the reaction. Subsequently the reaction mixture was poured onto ice and extracted with ethyl acetate (50ml), dried over anhydrous sodium sulphate and evaporated to afford the desired compound (0.34g, yield 53.3%, purity by HPLC 97%). M.p. 240-242 0C. 1H-NMR (DMSO-d6) δ: 7.17 - 7.35 (m, 6H), 8.49 - 8.50 (d, 2H)5 9.3 (s, IH)5 11.7 (s, IH5 D2O exchangeable). IR (KBr) cm"1: 3678, 3395, 3208, and 1742. MS m/z: 446.1 (M++l). Following compounds were prepared according to the procedure described for example 14
Figure imgf000048_0002
Example 17
Synthesis of iV-[(4-{4-chloro-6-[4-(methylsuIfonyl)phenyl]-2~
(trifluoromethyl)pyrimidin-5-yl}phenyl)sulfonyl]acetamide
Figure imgf000048_0001
A solution of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2- (trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide (0.5g, 1.Olmmol, prepared according to the procedure described in PCT/IB03/02879), DMAP (O.Olg) and acetyl chloride (0.5g, 6.36mmol) were stirred at 3O0C. TLC confirmed the completion of the reaction after 4 hours of stirring under the same conditions. Subsequently the resulting mass was poured onto the ice, and the procedure described for example 14 was followed to afford the title compound (0.252g5 46.41%, purity by HPLC 98.82%). M.p.: 230 - 235°C. 1H- NMR (DMSO-d6) δ: 1.87 (s, 3H)5 3.17 (s, 3H), 7.51 - 7.53 (m, 2H), 7.66 - 7.67 (m, 2H), 7.8 - 7.82 (d, 2H), 7.9 (s, IH), 7.99 (s, IH), 12.14 (s, IH, D2O exchangeable). IR (KBr) cm"1: 3150, 1720, and 1525. MS m/z: 533.7(M+). Example 18
Synthesis of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl) pyrimidin-4-yl napthalenesulfonate
Figure imgf000049_0001
To a solution of 6-[4-(methylsulfonyl) phenyl]-5-phenyl-2- (trifluoromethyl)pyrimidin-4-ol (O.lg, 0.25 mmol, prepared according to the procedure described in PCT/IB03/01289) in dichloromethane (10 ml) was added naphthalene- 1-sulfonyl chloride (0.086 g, 0.37 mmol) in dichloromethane (4ml) at 0°C and the mixture was stirred for 10 minutes. Subsequently pyridine (0.04 ml, 0.5 mmol) was added under stirring and the stirring was continued further for 6 hours at 37°C. Dichloromethane was removed under vacuo and the resultant mixture was diluted with wateπethyl acetate (1:1, 100 ml) and then extracted with ethyl acetate (25 ml x 3). The organic layer was washed with brine (100ml), dried over anhydrous sodium sulphate, and evaporated to afford the title compound (0.096 g, yield 67%), m.p. 204-206°C. 1H-NMR (CDCl3) δ: 2.99 (s, 3H), 7.12 - 7.14 (d, 2H), 7.26 - 7.29 (dd, 3H), 7.37 - 7.39 (m, 2H), 7.48 - 7.50 (m, 2H), 7.61 - 7.64 (m, 3H), 7.77 - 7.79(d, 2H), 7.84 - 7.86 (d, 2H), 7.94 - 7.96 (d, 2H). MS m/z: 585.1 (M++l).
The following compounds were prepared according to the procedure described for Example 18 -
Figure imgf000050_0001
Figure imgf000051_0001
Example 29
Synthesis of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl- piperazin-l-yI)-2-(trifluoromethyl)pyrimidine
Figure imgf000052_0001
To a suspension of Pd2(dba)3(0.443 g, 0.484 mmol) in toluene (50ml) was added racemic-2,2'-Zuχdiphenyl phosphino)-l,r-dinaphthyl (0.151 g, 0.242 mmol) at 370C under stirring. After 10 minutes of stirring the resulting solution was added to a suspension of N-benzyl piperazine (2.51 ml, 14.55 mmol), 4-chloro-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl) pyrimidine (5 g, 12.12 mmol, prepared according to the procedure described in PCT/IB03/02879) and cesium carbonate (5.53 g, 16.9 mmol) in toluene (80 ml) under stirring. Subsequently the reaction mixture was refluxed for 6 hours and filtered. The solid obtained was washed thoroughly with ethyl acetate and the resultant organic layer was washed successively with water (100 ml x 3), brine (200 ml) then dried over anhydrous sodium sulphate and evaporated to afford the title compound (5.5 g, yield 82.21%). Preparation 2 Method A:
Synthesis of 6-[4-(methyIsulfonyl)phenyl]-5-phenyl-4-piperazin-l-yl-2- (trifluoromethyl)pyrimidine
Figure imgf000052_0002
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl- piperazin-l-yl)-2-(trifluoromethyl)pyrimidine (5g, 9mmol) in dry dichloromethane (20 ml) was added diisopropyl ethylamine (2.5 ml, 18 mmol) under stirring at O0C. 1-chloro-ethyl chloroformate (1.35 ml, 13.5 mmol) was later added to the above, under stirring, and the stirring was further continued at 370C for 5 hours. Subsequently dichloromethane was evaporated upto dryness and methanol (20 ml) was added dropwise to the resulting mass, which was refluxed for 3 hours at 6O0C. The reaction mixture was poured onto ice and filtered; the solid obtained was washed with hexane (100 ml) and diisopropyl ether (50ml) to give the title compound (4 g, yield 95.9 %). Method B:
Figure imgf000053_0001
Piperazine (4.12g, 47.8mmol) was added to a solution of 4-chloro-5,6- diphenyl-2-trifluoromethylpyrimidine (4.Og, 11.95 mmol, prepared according to the procedure described in the PCT/IB03/02879) in acetonitrile (30ml) under stirring at 37°C. TLC confirmed the completion of the reaction after 2 hours, and then the reaction mixture was poured onto ice and extracted with ethyl acetate (250 ml). The organic layer was dried over anhydrous sodium sulphate and evaporated to afford the title compound (3.5g, yield 76.25%, purity by HPLC 100%). M.p: 160-1620C. 1H-NMR (DMSO-d6) δ: 2.5 (s, 4H),
3.16 (t, 4H), 7.07 - 7.08 (m, 2H), 7.17 - 7.31 (m, 9H, IH, D2O exchangeable).
IR cm'1 (KBr): 3304, 3058, and 1559. MS m/z: 385.2 (M++l).
The . following compounds were prepared according to the procedure described for the preparation 2
Figure imgf000054_0001
Figure imgf000055_0002
Preparation 3
Prep aration of 6- [4-(methy lsulf onyl)pheny 1] -5-pheny 1-4- [4-(2-thienyl carbonyl)piperazin-l-yl]-2-(trifluoromethyl)pyrimidine
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piρerazin-l- yl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.43 mmol, prepared according to the procedure described in preparation 2) in dimethylformamide (20 ml) was added thiophene-2-carboxylic acid (0.149 g, 0.78 mmol) under stirring at 37°C, and then after 10 minutes EDCI (0.149 g, 0.78 mmol), and HOBt (0.023 g, 0.173 mmol) were added. Further TEA (0.179 ml, 2.9 mmol) was added to the resultant clear solution and it was stirred for 18 hours. Subsequently the reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed successively with water, 10% sodium bi carbonate solution (100 ml), and brine (100 ml) respectively and dried over anhydrous sodium sulphate. Evaporation of the solvent and purification by column chromatography (0.4 % MeOH:DCM) gave the title compound (0.12g, yield 48.6 %), m.p. 189-194°C. 1H- NMR (CDCl3) δ: 2.98 (s, 3H), 3.4 - 3.41 (t, 4H), 3.66 - 3.68 (t, 4H), 7.02 - 7.77 (m, 12H). MS m/z: 573.2 (M++l). The following compounds were prepared according to the procedure described for the preparation 3
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0002
Example 45
Synthesis of 6- [4-(methy lsulf ony I)pheny 1] -5-pheny 1-4- [4-(l ,3-thiazol-2-yl methyl)piperazin-l-yl]-2-(trifluoromethyl)pyrimidine
Figure imgf000058_0001
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-l- yl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.43 mmol, prepared according to the procedure described in preparation 2) in dichloroethane (25 ml) was added thiazole-2-carboxaldehyde (0.144 g, 1.3 mmol) under stirring at 37°C. After five minutes, sodium triacetoxy borohydride (0.364 g, 1.72 mmol) was added to reaction mixture and then after 10 minutes, acetic acid (0.1 ml) was added to it. The reaction mixture was stirred for 36 hours under the same conditions. Subsequently the reaction mixture was treated with ethyl acetate: water (1:1, 100 ml) and extracted with ethyl acetate (50 ml x 3). The organic layer was washed with brine (100 ml) and dried over anhydrous sodium sulphate. The solid obtained upon evaporation was purified by column chromatography using methanol:dichloromethane (0.5:99.5) as an eluent to afford the title compound (0.1 Ig, yield 45.6 %). 1H-NMR (CDCl3) δ: 0.88 - 0.89 (m, 2H), 1.25 - 1.28 (t, 2H), 1.33 - 1.38 (t, 2H), 2.85 (s, 6H), 2.97 (s, 3H), 7.04 - 7.74 (m, 9H). MS m/z: 544.59 (M++l).
The following compounds were prepared according to the procedure described for example 45
Figure imgf000059_0001
Example 48
Synthesis of 4,5-diphenyl-6-(4-pyridin~2-yl-piperazin-l-yl)-2-(trifluoro methyl)pyrimidine.
Figure imgf000060_0001
To a solution of 4-chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine
(0.5g, 1.49mmol, prepared according to the procedure described in PCT/IB03/02879) in dimethylformamide (5 ml) was added l-pyridin-2-yl piperazine (0.107g, 0.66mmol) and anhydrous potassium carbonate (0.2g) under stirring at 28°C. The reaction mixture was stirred for 4 hours, and when TLC confirmed the completion, it was poured onto ice. The solid thus obtained was filtered and washed with water (20ml). The above solid was then dissolved in dichloromethane (50ml) and dried over anhydrous sodium sulphate, evaporation of the solvent afforded the title compound (0.48g, yield 69.66%, purity by HPLC 99.8%). M.p. 165-1670C. 1H-NMR (CDCl3) δ: 3.43 (s, 8H), 6.58 - 6.64 (m, 2H), 7.14 - 7.21 (m, 7H), 7.26 - 7.29 (m, 3H), 7.45 - 7.49 (t, IH), 8.14 - 8.15 (d, IH). IR cm"1 (KBr): 3436, 2839, 1591, and 1557. MS m/z: 462.1 (M++l). Similar to the above the following compound was prepared
Figure imgf000060_0002
Preparation 4
Preparation of 3-[4-(4-fluorophenyI)-6-piperazin-l-yl-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide hydrochloride (Hydrochloride of the example-50) and 4-[4-(4-fluorophenyl)-6-piperazin-l-yl-2- (trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide hydrochloride
(example-30). Stepl:
Preparation of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonyl chloride and 4-[4-chIoro-6-(4- fluorophenyl)-2-(trifluoromethyl)py rimidin-5-yl]benzenesulfonyl chloride
Figure imgf000061_0001
4-Chloro-6-(4-fluorophenyl)-5-phenyl-2-(trifluoromethyl)pyrimidine . (3Og, 0.085mol) was added to cold chlorosulfonic acid (20OmL, 3.0mol) and the reaction mixture was stirred for 48 hours at room temperature. Subsequently it was poured into crushed ice (~3 kg) and was extracted with dichloromethane (lOOOmL). The organic layer was washed with sodium bicarbonate (7%, 100OmL), and with brine solution (50OmL). The crude material obtained after evaporation was recrystallised from hexane-EtOAc to obtain the pure para and meta substituted sulphonyl chlorides. However, the crude product containing mixture of meta and para isomers was used as such in the examples mentioned below unless otherwise mentioned. '
3-[4-Chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5- yl]benzenesulfonyl chloride: 1H-NMR (CDCl3) δ : 6.97 - 7.01 (m, 2H), 7.32 - 7.36 (m, 2H), 7.63 - 7.65 (d, IH), 7.71 - 7.74 (t, IH)5 7.90 - 7.91 (s, IH), 8.10 - 8.12 (d, IH). 4-[4-ChIoro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5- yl]benzenesulfonyl chloride: 1H-NMR (CDCl3) δ : 6.97 - 7.01 (m, 2H)5 7.34 -
7.38 (m, 2H)5 7.50 - 7.53 (d, 2H)5 8.11 - 8.13 (d, 2H).
Step 2a:
Synthesis of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl) pyrimidin-
5-yl] b enzenesulf onamide.
Figure imgf000062_0001
The sulphonyl chloride group is converted into the sulphonamido group by treatment with ammonia gas under cold conditions (0-5 °C) by dissolving the substance in dichloromethane. Subsequently the reaction mixture was washed with water (10OmL) and then with brine solution; evaporation of the solvent furnished the titled compound. 1H-NMR (DMSOd6) δ: 7.14 - 7.18 (m, 2H)5 7.38 - 7.42 (m, 2H), 7.48 (brs, 2H5 D2O exchangeable), 7.56 (d, IH), 7.62 - 7.66 (t, IH)5 7.86 (s, IH)5 7.88 (d, IH); MS m/z: 433 (M++l). Step 2b:
Preparation of 4-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide.
Figure imgf000062_0002
Similarly 4-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4- yl]benzenesulfonamide was prepared from 4-chloro-5,6-diphenyl-2- (trifluoromethyl)pyrimidine which in turn was prepared according to the procedure described in PCT/IB03/02879). 1H-NMR (DMSO-d6) δ: 7.16 - 7.21 (m, 2H)5 7.38 - 7.41 (m, 2H)5 7.48 (brs, 2H5 D2O exchangeable), 7.57 (d, 2H), 7.86 (d, 2H). MS m/z: 432 (M+). Example 50
Synthesis of 3-[4-(4-fluorophenyl)-6-piperazin-l-yl-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide.
Figure imgf000063_0001
The solution of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide (O.lg, 0.24mmol, prepared according to the procedure described above in preparation 4, Step 2a), in acetonitrile (2mL) was treated with piperazine (0.104g, 1.203mmol) and the reaction mixture was stirred overnight at room temperature. Subsequently the reaction mixture was poured into ice-cold water and was extracted with ethylacetate (25mL). The organic layer was washed with water, brine solution, and then evaporated to obtain the title compound. 1H-NMR (DMSO-d6) δ: 2.58 (s, 4H), 3.19 (s, 4H), 7.03 - 7.14 (m, 4H), 7.32 (d, IH), 7.41 (brs, D2O exchangeable, 2H), 7.46 - 7.50 (t, IH)5 7.72 (s, IH), 7.73 (d, IH). MS m/z: 482.1 (M++l). The following compounds were prepared according to the above procedure.
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
003468
65
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0002
Example 82
Synthesis of 3-[6-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}-5- phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide.
Figure imgf000070_0001
Step 1:
Preparation of l-[5-(trifluoromethyl)pyridin-2-yl]piperazine
Figure imgf000071_0001
Piperazine (1.2g, 13.77mM) was heated with 2-chloro-5- (trifluoromethyl)pyridine (0.5g, 2.75mmol) in THF (2mL) for 2 hours. Subsequently the reaction mixture was poured onto crushed ice and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and evaporated to furnish the required product. Step 2:
Synthesis of 3-[6-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl}-5- phenyI-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide.
Figure imgf000071_0002
The solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4- yl]benzenesulfonamide (O.lg, 0.242mM) in pyridine (2mL) was treated with l-[5-(trifluoromethyl)pyridin-2-yl]piperazine (0.3g, 0.68mmol) and the reaction mixture was stirred for 1 hour at room temperature. Subsequently the reaction mixture was poured onto crushed ice containing two drops of concentrated hydrochloric acid, extracted with ethyl acetate (25mL), and the organic layer was washed with brine and evaporated. The title compound was obtained by column chromatographic purification of the crude material with 30% ethyl acetate in hexane. 1H-NMR (DMSO-d6) δ: 3.33 - 3.37 (m, 4H), 3.56 (m, 4H), 6.86 - 6.88 (d, IH), 7.10 - 7.12 (d, 2H), 7.22 - 7.29 (m, 3H), 7.35 - 7.37 (m, IH), 7.44 - 7.48 (m, IH), 7.74 - 7.79 (m, 3H)5 8.38 (s, IH). MS m/z: 608.8 (M+). Example 83
Synthesis of 3-[6-{4-[2,6-dimethoxypyrimidin-4-yl]piperazin-l-yl}-5- phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide.
Figure imgf000072_0001
Step 1:
Preparation of 2,4-dimethoxy-6-piperazin-l-ylpyrimidine.
Figure imgf000072_0002
Piperazine (1.23g, 14.32mmol) was treated with 6-chloro-2,4- dimethoxy pyrimidine (0.5g, 2.86mmol) in acetonitrile (5mL) and stirred at room temperature for 6 hours. Subsequently the reaction mixture was poured onto ice-cold water (25mL) and extracted with ethyl acetate (25mL). The organic layer was washed with aqueous sodium bicarbonate solution and evaporated to furnish the required compound. Step 2:
Synthesis of 3-[6-{4-[2,6-dimethoxypyrimidin-4-yl]piperazin-l-yl}-5- phenyl-2-(trifluoromethyl)pyrimidin-4-yI]benzenesulfonamide.
Figure imgf000073_0001
The solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4- yl]benzenesulfonamide (O.lg, 0.242mmol) in pyridine (1.5mL) was treated with 2,4-dimethoxy-6-piperazin-l-ylpyrimidine (0.081g, 0.363mmol) and the reaction mixture was stirred for 8 hours. Subsequently the reaction mixture was poured onto ice-cold water and extracted with ethyl acetate (25mL). The organic layer was washed with brine and evaporated to furnish the title compound. 1H-NMR (CDCl3) δ: 3.39 - 3.41 (m, 4H), 3.51 - 3.52 (m, 4H), 3.87
- 3.88 (s, 6H), 7.07 - 7.09 (d, 2H), 7.20 - 7.26 (m, 3H), 7.30 - 7.32 (m, IH), 7.47 - 7.61 (t, IH), 7.64 (s, IH), 7.82 - 7.87 (m, 2H). MS m/z: 601.8 (M+).
Example 84
Synthesis of 3-[6-{4-[5-(nitro)pyridin-2-yl]piperazin-l-yl}-5-phenyl-2- (trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide.
Figure imgf000073_0002
Step 1;
Preparation of l-(5-nitropyridin-2-yl) piperazine. HN NH + Br-^ ^"NO2 *- HN^ N — ( j~N0 2
2-Bromo-5-nitropyridine (0.3g, 1.48mmol) was treated with piperazine (0.64g, 7.89mmol) in tetrahydrofuran (4mL) and the reaction mixture was stirred for 30 minutes. Subsequently the reaction mixture was poured onto ice- cold water (25mL) and extracted with ethyl acetate (25mL). The organic layer was washed with brine and evaporated to furnish the product. Step2:
Synthesis of 3-[6-{4-[5-(nitro) pyridin-2-yl]piperazin-l-yl}-5-phenyl-2- (trifluoromethyl) pyrimidin-4-yl] benzenesulfonamide.
Figure imgf000074_0001
The solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4- yl]benzenesulfonamide (O.lg, 0.242mmol) in pyridine (2mL) was treated with l-(5-nitropyridin-2-yl)piperazine (0.075g, 0.363mmol) and stirred for 11 hours. Subsequently the reaction mixture was poured onto ice-cold water and extracted with ethyl acetate (25mL). The organic layer was washed with brine and evaporated to give the crude material. Purification by column chromatography (elution with 70% ethyl acetate in hexane) yielded the title compound. 1H-NMR (CDCl3) δ: 3.45 - 3.46 (m, 4H)5 3.72 (m, 4H)5 6.52 - 6.54 (d, IH)5 7.08 - 7.11 (d, 2H), 7.21 - 7.26 (m, 2H)5 7.32 - 7.34 (d, IH), 7.40 - 7.42 (d, IH)5 7.50 (m, IH), 7.68 (s, IH)5 7.84 - 7.89 (m, IH)5 8.21 - 8.23 (d, IH)5 8.99 (S5 IH). MS m/z: 585.8 (M+). Example 85
Synthesis of 3- [6- {4- [5-(amino)py ridin-2-yl] piperazin-1 -yl}-4- [4- fluorophenyl]-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide.
Figure imgf000075_0001
3-[6-{4-[5-(Nitro)pyridin-2-yl]piperazin-l-yl}-4-[4-fluorophenyl]-2-
(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide (0.13g, 0.22mmol) was taken in concentrated hydrochloric acid (1.5 niL) and to this tin (II) chloride dihydrate (0.145g, 0.65mmol) was added and the reaction mixture was stirred for 24 hours at room temperature. Subsequently the reaction mixture was poured onto crushed ice, neutralized with sodium bicarbonate, and extracted with ethyl acetate. Evaporation of the solvent yielded the required product. 1H- NMR (DMSO-d6) «5: 3.13 (m, 4H), 3.30 (m, 4H), 4.58 (br, 2H, D2O exchangeable), 6.57 - 6.59 (m, IH), 6.88 (d, IH), 7.04 - 7.09 (m, 2H), 7.12 - 7.14 (m, 2H), 7.39 (br, 2H, D2O exchangeable), 7.41 (d, IH), 7.50 - 7.55 (m, 2H), 7.73 - 7.77 (m, 2H). MS m/z: 574.1 (M++l). Example 86
Synthesis of 4-[5-(acetylamino)pyridin-2-yl]piperazin-l-yl-5-(4~ fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine
Figure imgf000075_0002
4-Chloro-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoro methyl)pyrimidine (0.15g, 0.35mmol) was treated with l-(5-nitropyridin-2- yl)ρiperazine (0.087g, 0.418mmol) and diisopropylethylamine (0.06mL, 0.35mmol), acetonitrile (2.5mL) and heated at 60-650C for 2 hours. Subsequently the reaction mixture was precipitated by the addition of diisopropyl ether (2mL). The above-obtained solid (0.1 Ig, 0.182mmol) was taken up in acetic acid (2mL) and tin (II) chloride dihydrate (0.123g, 0.182mmol) was added to it. Stirring was continued further for 11 hours, and then the reaction mixture was poured onto ice-cold water, and extracted with ethyl acetate (25mL x 2). After neutralization with sodium bicarbonate, the organic layer was evaporated to obtain the crude material, which was purified by column chromatography (2% MeOH in dichloromethane) to yield the title compound. 1H-NMR (DMSOd6) δ: 1.99 (s, 3H), 3.19 (s, 3H), 3.29 - 3.40 (m, 8H), 6.77 (d, IH), 7.19 - 7.23 (m, 2H), 7.31 - 7.34 (m, 2H), 7.36 (d, 2H), 7.74 (d, IH)5 7.80 (d, 2H), 8.24 (d, IH), 9.77 (s, IH, D2O exchangeable). MS m/z: 615.1 (M++l). Example 87
Synthesis of N-({3-[4-pyridin-2-yl]piperazin-l-yl)-6-(4-fluorophenyl) -2- (trifluoromethyl) pyrimidin-5-yl] phenyl} sulfonyl) acetamide.
Figure imgf000076_0001
3-[4-{4-(5-Pyridin-2-yl)piperazin-l-yl)}-6-(4-fluorophenyl)-2-(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide (O.lg, 0.178mmol) was treated with acetyl chloride (0.35mL) and the reaction mixture was stirred for 40 hours. Subsequently it was poured onto crushed ice, extracted with dichloromethane (25mL), and washed with brine. The organic layer was evaporated to furnish the required compound. 1H-NMR (DMSOd6) δ: 1.81 (s, 3H), 3.32 - 3.37 (m, 8H)5 6.62 (t, IH), 6.75 (d, IH), 7.02 - 7.07 (m, 2H), 7.11 - 7.14 (m, 2H), 7.50 - 7.59 (m, 3H), 7.80 (s, IH), 7.84 (d, IH), 8.06 (d, IH), 12.09 (bra, IH, D2O exchangeable). MS m/z: 601.1 (M++!). The following compound was prepared according to the procedure described above.
88 1H-NMR (CDCl 3) δ: 1 .02 - 1.05 (t, 3H),
2.18 - 2 .24 (q, 2H), 3 45 - 3.49 (m, 8H),
6.60 - 6. 65 (m, 2H), 6 85 - 6.89 (m, 2H),
7.08 - 7 10 (m, 2H), 7 .37 (d, IH), 7 .47 -
7.50 (m, 2H), 7 •94 (s, IH), 8.02 (d, IH),
Figure imgf000077_0001
8.12(d, IH). MS m/z: 615.1 (M++l).
Example 89
Synthesis of l-{5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2- (trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylic acid.
Figure imgf000077_0002
A solution of ethyl l-{5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)- 2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylate (0.4g, 0.725mmol) in tetrahydrofuran (4mL) was treated with lithium hydoxide monohydrate (0.036g, 0.87mmol) in water (0.2mL) and was stirred for 17 hours. Subsequently the reaction mixture was poured onto ice-cold water, acidified with dilute hydrochloric acid and extracted with dichloromethane (25mL). Evaporation of organic layer furnished the required product. 1H-NMR (DMSO-d6) δ: 1.39 (m, 2H), 1.64 (m, 2H), 2.09 (m, IH), 2.84 - 2.89 (m, 2H), 3.66 (m, 2H)5 7.02 - 7.07 (m, 2H), 7.07 - 7.13 (m, 2H), 7.37 - 7.39 (m, 2H), 7.49 - 7.53 (m, IH), 7.69 (s, IH), 7.72 - 7.74 (d, IH), 12.25 (br, IH, D2O exchangeable). MS m/z: 525.0 (M++!). Example 90
Synthesis of 4-[4-(methoxyaminocarbonyl)piperidin-l-yl}-5-(4-fluoro phenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidine.
Figure imgf000078_0001
A solution of l-{5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2- (trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylic acid (0.15g, 0.30mmol) in dichloromethane (5mL) was treated with O-methyl hydroxylamine hydrochloride (0.028g, 0.30mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.127g,
0.663mmol), 1-hydroxybenzotriazole (O.OOδg, 0.066mmol) and diisopropylethylamine (0.042, 0.33mmol). After 2 hours of stirring the reaction mixture was poured onto ice-cold water, extracted with dichloromethane, and washed with brine. Evaporation of the organic layer furnished the required compound. 1H-NMR (DMSO-d6) δ: 1.46 (m, 4H), 2.14 (m, IH), 2.73 - 2.78 (m, 2H), 3.18 (s, 3H), 3.53 (s, 3H), 3.81 - 3.84 (m, 2H), 7.24 (d, 2H), 7.31 - 7.36 (m, 5H), 7.75 (d, 2H), 11.01 (br, IH, D2O exchangeable). MS m/z: 535.1 (M++l). Example 91
Synthesis of methyl 3-methoxy-4-({6-[4-(methylsulfonyl)phenyl]-5-(4- fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}oxy)benzoate.
Figure imgf000079_0001
4-Chloro-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoro methyl)pyrimidine (0.5g, 1.63mmol), methyl vanillate (0.423g, 2.33mmol), potassium carbonate (0.24g, 1.74mmol) and acetonitrile (7mL) were stirred at room temperature for 2 hours, and subsequently the reaction mixture was refluxed for 6 hours. Further, potassium carbonate (0.08g, 0.58mmol) and vanillic ester (0.12g, 0.66mmol) were added to the reaction mixture and the refluxing was continued for another 4 hours. Subsequently the reaction mixture was poured onto ice-cold water, extracted with ethyl acetate (25mL), and washed with brine solution. Evaporation of the organic layer yielded the required product. 1H-NMR (DMSO-dβ) δ: 3.24 (s, 3H), 3.81 (s, 3H), 3.88 (s, 3H), 7.26 - 7.30 (m, 2H)5 7.44 (d, IH), 7.49 - 7.53 (m, 2H)5 7.61 - 7.69 (m, 4H), 7.91 (d, 2H). MS m/z: 576.8 (M++l). Example 92 Synthesis of 3-methoxy-4-({6-(4-fluorophenyl)-5-[3-(aminosulfonyl) phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}oxy)-N-methoxybenzamide.
Figure imgf000079_0002
Step 1:
Preparation of 4-hydroxy-N-3-dimethoxybenzamide. Vanillic acid (1.Og, 5.93mmol), O-methylhydroxylamine (0.5g,
5.99mmol), 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.37g, 7.12mmol), and 1-hydroxybenzotriazole (0.095g, 0.713mmol), diisopropylethylamine (0.76g, 5.93mmol) in dichloromethane (8mL) were stirred for 2 hours. Subsequently the reaction mixture was poured onto cold water and extracted with dichloromethane (5OmL). The crude material obtained on evaporation of the organic layer was purified by column chromatography; elution with 1.5% MeOH in dichloromethane yielded the pure compound. Step 2:
Synthesis of 3-methoxy-4-({6-(4-fluorophenyl)-5-[3-
(aminosulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}oxy)-N- methoxy b enzamide.
Figure imgf000080_0001
A suspension of 3-[4-chloro-6-(4-fluoroρhenyl)-2-
(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.15g, 0.35mmol), 4- hydroxy-N,3-dimethoxybenzamide (0.102g, 0.52mmol) and potassium carbonate (0.52mmol) in acetonitrle (3mL) were heated to relfux (650C) for 2 hours. Subsequently the reaction mixture was poured onto ice-cold water, extracted with dichloromethane (5OmL), and washed with brine. Evaporation of the organic layer furnished a crude material, which was purified by column chromatography; elution with 2% MeOH in dichloromethane furnished the required compound. 1H-NMR (DMSO-d6) δ: 3.73 (s, 3H), 3.79 (s, 3H), 7.16 - 7.20 (m, 2H), 7.37 (d, IH), 7.41 - 7.45 (m, 5H), 7.53 (s, IH), 7.62 - 7.63 (d, 2H), 7.85 (d, IH)5 7.89 (s, IH). 11.9 (s, IH); MS m/z: 593 (M++l). Similarly the following compound was made
Figure imgf000081_0002
Example 94
Synthesis of 5-amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]- 3-methyl-lH-pyrazole-4-carbonitrile.
Figure imgf000081_0001
1-Methoxyethylidene malononitrile (0.17g, 1.36mmol) (prepared from malononitrile and triethyl orthoacetate by heating with acetic anhydride) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15g, 0.45mmol) in methanol (6mL), overnight at 60-650C. The solid that separated out from the reaction mixture was filtered and washed with methanol (5mL)5 to yield the title compound. 1H-NMR (DMSO-d6) δ: 1.97 (s, 3H), 6.97 (br, 2H5 D2O exchangeable), 7.07 (d, 2H), 7.26 - 7.38 (m, 7H), 7.40 - 7.41 (m, IH); MS m/z: 421.1 (M++l). Example 95
Synthesis of ethyl 5-amino-l-[5,6-diphenyl-2-(trifluoromethyl) pyrimidin-4-yl]-3-(methylthio)-lH-pyrazole-4-carboxylate.
Figure imgf000082_0001
Ethyl 2-cyano-3,3-bis(methylthio)acrylate (Q.3 g, 1.36mmol) was heated with 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.15g, 0.45mmol) in methanol (6mL) overnight at 60-65°C. The solid that separated out from the reaction mixture was filtered and washed with isopropylalcohol (5mL), to furnish the required compound. 1H-NMR (DMSOd6) δ: 1.22 - 1.25 (t, 3H), 3.16 (s, 3H), 4.11 - 4.17 (q, 2H), 4.36 (br, 2H, D2O exchangeable), 7.12 (d, 2H), 7.25 - 7.35 (m, 7H), 7.69 (d, IH). MS m/z: 500.1 (M++l). The following compounds were prepared according to the procedure described above.
Figure imgf000082_0002
Figure imgf000083_0001
Figure imgf000084_0001
Example 108
Synthesis of 5-amino-l-[5,6-diphenyl-2-(trifluoromethyI) pyrimidin-4-yl]-
3-(methylthio)-N-phenyl-lH-pyrazoIe-4-carboxamide.
Figure imgf000085_0001
Step 1;
Preparation of 2-cyano-3,3-bis(methyIthio)-N-phenylacryIamide.
2-Cyano-N-phenylacetamide (l.Ogm, 6.25mmol) was treated with sodium hydride 60% (1.13g, 28.13mmol) in tetrahydrofuran under ice-cold conditions and stirring for 15 minutes. Carbon disulfide (0.9mL, 15.65mmol) was added to the above mixture and the stirring was continued at ice-cold condition for a further 15 minutes. Methyliodide (2.22g, 15.65mmol) was added to the above under the same ice-cold conditions and the stirring was continued at room temperature overnight. Subsequently the reaction mixture was acidified with dilute hydrochloric acid (5mL) and extracted with ethyl acetate (5OmL). Evaporation of the organic layer yielded an oily crude material. Step 2: Synthesis of 5-amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]- 3-(methylthio)-N-phenyl-lH-pyrazoIe-4-carboxamide.
A solution of 4-hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.2gm, 0.63mmol) in methanol (6mL) was heated with 2-cyano-3,3- bis(methylthio)-N-phenylacrylamide (0.5g, 1.89mmol) in at 60-65°C overnight. The solid that separated out was filtered and washed with isopropyl alcohol (3mL) to yield the required product. 1H-NMR (CDCl3) δ: 1.98 (s, 3H), 6.96 - 7.57 (m, 15H), 7.25-7.30 (2H, D2O exchangeable), 8.86 (br, IH, D2O exchangeable). MS m/z: 547.1 (M++l). The following compound was made by the procedure mentioned above
Figure imgf000086_0001
Example 110
Synthesis of l-(2,6-dichlorophenyI)-3-{l-[5,6-diphenyl-2-
(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-lH-pyrazol-5-yl}urea.
Figure imgf000086_0002
The solution of 3-t-butyl-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin- 4-yl]-lH-pyrazol-5-amine (0.23mmol) in dichloromethane (3mL) was treated with 2,6-dichlorophenyl isocyanate (0.056g, 0.3mmol) in the presence of triethylamine (0.05mL), and the reaction was mixture was stirred at room temperature, overnight. Subsequently water (15mL) was added to above and it was extracted with ethyl acetate (25mL). The organic layer was evaporated and the crude material purfied by column chromatography; elution with 1.5% of ethyl acetate in hexane yielded the title compound.1H-NMR (CDCl3) δ: 0.86 (s, 9H), 6.58 (s, IH)5 7.02 - 7.05 (m, 3H)5 7.14 (d, 2H), 7.24 - 7.33 (m, 8H)5 8.43 - 8.44 (br, IH, D2O exchangeable), 10.52 (br, IH5 D2O exchangeable). MS m/z: 625 (M+). Example 111
Synthesis of 4-[4-(methylthio)phenyI]-5,6-diphenyI-2-(trifluoro methyl)pyrimidine.
Figure imgf000087_0001
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.2g, O.βmmol, prepared according to the procedure described in PCT/IB03/02879) was heated to reflux with tetra-kis triphenyl palladium (0) (0.068g, 0.058mmol), aqueous solution of potassium carbonate (0.16g in 0.6mL water), 4- (methylthio)benzene boronic acid (0.168g, lmmol) and toluene (2OmL) under a nitrogen atmosphere overnight. The reaction mixture was acidified with dilute hydrochloric acid 1OmL and extracted with ethyl acetate. The organic layer was concentrated; the crude obtained was triturated with ether and filtered to yield the title compound.1H-NMR (DMSOd6) δ: 2.45 (s, 3H), 7.13 - 7.15 (m, 4H)3 7.23 - 7.34 (m, 8H), 7.61 (d, 2H). MS m/z: 423.1 (M++l). Similarly the following compound was prepared.
Figure imgf000087_0002
Described below are the examples of pharmacological assays used for finding out the efficacy of the compounds of the present invention wherein their protocols and results are provided. In vitro evaluation of cyclooxygenase-2 (COX-2) inhibition activity
The compounds of this invention exhibited in vitro inhibition of COX- 2. The COX-2 inhibition activities of the compounds illustrated in the examples were determined by the following method.
Human Whole Blood Assay
Human whole blood provides a protein and cell rich milieu appropriate for the study of the biochemical efficacy of anti-inflammatory compounds such as selective COX-2 inhibitors. Studies have shown that normal human blood does not contain the COX-2 enzyme. This correlates with the observation that COX-2 inhibitors have no effect on prostaglandin E2 (PGE2) production in normal blood. These inhibitors were active only after incubation of human blood with lipopolysaccharide (LPS), which induces COX-2 production in the blood. Fresh blood was collected in tubes containing sodium heparin by vein puncture from healthy male volunteers. The subjects should have no apparent inflammatory conditions and should have not taken NSAIDs for at least 7 days prior to blood collection. Blood was preincubated with aspirin in vitro (12μg/ml, at time zero) to inactivate COX-I for 6 hours. Then test compounds (at various concentrations) or vehicle were added to blood, the blood was stimulated with LPS B:4 (10 μg/ml) and incubated for another 18 hours at 37°C water bath. After which the blood was centrifuged, plasma was separated and stored at -80°C (J. Pharmacol. Exp.Ther, 271, 1705, 1994; Proc. Natl. Acad. Sci. USA, 96, 7563, 1999). The plasma was assayed for PGE2 using Cayman ELISA kit as per the procedure outlined by the manufacturer (Cayman Chemicals, Ann Arbor, USA). Representative results of PGE-2 inhibition are shown in the Table I. Table I
Figure imgf000089_0001
COX-I and COX-2 enzyme based assay.
COX-I and COX-2 enzyme based assays were carried out to check the inhibitory potential of the test compounds on the production of prostaglandin by purified recombinant COX-l/COX-2 enzyme (Proc. Nat. Acad. Sci. USA, 88, 2692-2696, 1991; J. Clin. Immunoassay 15, 116-120, 1992) In this assay, the potential of the test compound to inhibit the production of prostaglandin either by COX-I or COX-2 from arachidonic acid (substrate) was measured. This was an enzyme based in-vitro assay to evaluate selective COX inhibition with good reproducibility.
Arachidonic acid was converted to PGH2 (Intermediate product) by COXl /COX-2 in the presence or absence of the test compound. The reaction was carried out at 370C and after 2 minutes it was stopped by adding IM HCl. Intermediate product PGH2 was converted to a stable prostanoid product PGF2n by SnCl2 reduction. The amount of PGF2α produced in the reaction was inversely proportional to the COX inhibitory potential of the test compound. The prostanoid product was quantified via enzyme immunoassay (EIA) using a broadly specific antibody that binds to all the major forms of prostaglandin, using Cayman ELISA kit as per the procedure outlined by the manufacturer (Cayman Chemicals, Ann Arbor, USA). Representative results of inhbition are shown in theTable II. Table II
Figure imgf000090_0001
In vitro measurement of Tumor Necrosis Factor Alpha (TNF- α).
This assay determines the effect of test compounds on the production of TNF α in human Peripheral Blood Mononuclear Cells (PBMC). Compounds were tested for their ability to inhibit the activity of TNF α in human PBMC. PBMC were isolated from blood (of healthy volunteers) using BD Vacutainer CPT™ (Cell preparation tube, BD Bio Science) and suspended in PvPMI medium (Physiol. Res. 52: 593-598, 2003). The test compounds were pre- incubated with PBMC (0.5million/incubation well) for 15 minutes at 370C and then stimulated with Lipopolysaccharide {Escherichia colϊ. B4; 1 μg/ml) for 18 hours at 370C in 5% CO2. The levels of TNF-α in the cell culture medium were estimated using enzyme-linked immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer (Cayman Chemical, Ann Arbor, USA). Representative results of TNF-α inhibition are shown in the Table III. Table III
Figure imgf000091_0001
In vitro measurement of Interleukin-6 (IL-6)
This assay determines the effect of test compounds on the production of IL-6 in human PBMC (Physiol. Res. 52: 593-598, 2003). Compounds were tested for their ability to inhibit the activity of IL-6 in human PBMC. PBMC were isolated from blood using BD Vacutainer CPT™ Cell preparation tube (BD Bio Science) and suspended in RPMI medium. The test compounds were pre-incubated with PBMC (0.5million/incubation well) for 15 minutes at 37° C and then stimulated with Lipopolysaccharide {Escherichia colϊ. B4; 1 μg/ml) for 18 hours at 370C in 5% CO2. The levels of IL-6 in cell culture medium were estimated using enzyme-linked immunosorbent assay performed in a 96 well format as per the procedure of the manufacturer (Cayman Chemical, Ann Arbor, USA). Representative results of IL-6 inhibition are shown in the Table IV. Table IV
Figure imgf000092_0001
Carrageenan induced Paw Edema test in Rat
The carrageenan paw edema test was performed as described by Winter et al (Proc.Soc.Exp.Biol.Med, 111, 544, 1962). Male wistar rats were selected with body weights equivalent within each group. The rats were fasted for 18 hours with free access to water. The rats were dosed orally with the test compound suspended in the vehicle containing 0.25% carboxymethylcellulose and 0.5% Tween 80. The control rats were administered with vehicle alone. After an hour, the rats were injected with 0.1 ml of 1% Carrageenan solution in 0.9% saline into the sub-plantar surface of the right hind paw. Paw volume was measured using digital plethysmograph before and after 3 hours of carrageenan injection. The average of foot swelling in drug treated animals was compared with that of the control animals. Anti-inflammatory activity was expressed as the percentage inhibition of edema compared with control group [Arzneim-Forsch/Drug Res., 43 (I), 1,44-50,1993; Otterness and Bliven, Laboratory Models for Testing NSAIDs, In Non-Steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed.1985)]. Representative results of edema inhibition are shown in the Table V. Table V
Figure imgf000093_0001
Ulcerogenic potential
In order to evaluate the compound's role on the ulcer formation, the animals were sacrificed and the stomach was taken out and flushed with 1% formalin. Animals (male wistar 20Og) were fasted for 18 hours with free access to water and the test compounds were suspended in 0.5% Tween 80 and 0.25% CMC (carboxymethylcellulose) solution to make a uniform suspension. After 4 hours of oral administration of test compounds, all the animals were sacrificed by cervical dislocation. The stomach was dissected carefully and filled up with a sterile saline solution and embedded in 6% formalin solution. Finally the stomach was cut longnitudinaly and ulcer lesions were observed with computerized stereomicroscope. The test compound treated groups were compared with the vehicle treated groups. Doses selected: 50, 100, 200mg/kg (Marco Romano et al, Journal of clinical Investigation, 1992; 2409-2421.) Representative results of ulcer incidence are shown in the Table VI. Table VI
Figure imgf000093_0002
Inhibitory Action on Adjuvant Arthritis in rats
Compounds were assayed for their activity on rat adjuvant induced arthritis model according to Theisen-Popp et al, (Agents Actions, 42, 50-55,1994). 6 to 7 weeks old, wistar rats were weighed, marked and assigned to groups [a negative control group in which arthritis was not induced (non-adjuvant control), a vehicle- treated arthritis control group, test substance treated arthritis group]. Adjuvant induced arthritis was induced by an injection of 0.1ml of Mycobacterium butyricum (Difco) suspended in mineral oil (5mg/ml) into the sub-plantar region of the right hind paw (J.Pharmacol.Exp.Ther., 284, 714, 1998). Body weight, and paw volumes were measured at various days (0, 4, 14, 21) for all the groups. The test compound or vehicle was administered orally, beginning post injection of adjuvant (O'day) and continued for 21 days (pre-treatment group). In the post-treatment group, the test compound or vehicle was administered starting from day 141 to 21st day. On day 21, body weight and paw volume of both right and left hind paws were taken. Spleen, and thymus weights were determined. In addition, the radiographs of both hind paws were taken to assess the tibio-tarsal joint integrity. Hind limb below the stifle joint was removed and fixed in 1% formalin saline for the histopathological assessment. At the end of the experiment, serum samples were analysed for inflammatory mediators. The presence or absence of lesions in the stomach was also observed. Two-factor (" treatment" and 'time') analysis of variance with repeated measures on "time" was applied to the percentage (%) changes for body weight and foot volumes. A post hoc Dunnett's test was conducted to compare the effect of treatments to vehicle control. A one-way analysis of variance was applied to the thymus and spleen weights followed by the Dunnett's test to compare the effect of treatments to vehicle. Dose-response curves for percentage inhibition in foot volumes on days 4, 14 and 21 were fitted by a 4-parameter logistic function using a nonlinear least Squares' regression. IC50 was defined as the dose corresponding to a 50% reduction compared to the vehicle control and was derived by interpolation from the fitted 4-parameter equation. LPS induced sepsis for measurement of TNF-α inhibition in mice
The LPS induced sepsis model in mice was performed as described by Les sekut et al (J Lab Clin Med 1994; 124:813-20). Female Swiss albino mice were selected and the body weights were equivalent within each group. The mice were fasted for 20 hours with free access to water. The mice were dosed orally with the test compound suspended in vehicle containing 0.5% Tween 80 in 0.25% Carboxy-methylcellulose sodium salt. The control mice were administered the vehicle alone. After 30 minutes of oral dosing, mice were injected with 500μg of Lipopolysaccharide (Escherichia coli, LPS: B4 from Siga) in phosphate buffer saline solution into the intraperitoneal cavity of the mice. After 90 minutes of LPS administration mice were bled via retro-orbital sinus puncture. Blood samples were stored overnight at 40C. Serum samples were collected by centrifuging the samples at 4000 rpm for 15 minutes at 4°C. Immediately the serum samples were analysed for TNF-α levels using commercially available mouse TNF-α ELISA kit (Amersham Biosciences) and assay was performed by the manufacturer instruction. Representative results of TNF-α inhibition are shown in the Table VII. Table VII
Figure imgf000095_0001
Anti-cancer screen
Experimental drugs are screened for anti-cancer activity in three cell lines for their GI50, TGI and LC50 values (using 5 concentrations for each compound). The cell lines are maintained in DMEM containing 10% fetal bovine serum. 96 well microtiter plates are inoculated with cells in 100 μL for 24 hours at 37°C, 5% CO2, 95% air and 100% relative humidity. 5000 HCTl 16 cells/well, 5000 NCIH460 cells/well, 10000 U251 cells/well and 5000 MDAMB231 cells/well are plated. A separate plate with these cell lines is also inoculated to determine cell viability before the addition of the compounds (T0).
Addition of experimental drugs Following 24-hour incubation, experimental drugs are added to the 96 well plates. Each plate contains one of the above cell lines and the following in triplicate: 5 different concentrations (0.01, 0.1, 1, 10 and 100 μM) of 4 different compounds, appropriate dilutions of a cytotoxic standard and control (untreated) wells. Compounds are dissolved in dimethylsulfoxide (DMSO) to make 20 mM stock solutions on the day of drug addition and frozen at -20°C. Serial dilutions of these 20 mM stock solutions are made in complete growth medium such that 100 μL of these drug solutions in medium, of final concentrations equaling 0.01, 0.1, 1, 10 and 100 μM can be added to the cells in triplicate. Standard drugs whose anti-cancer activity has been well documented and which are regularly used are doxorubicin and SAHA.
End-point measurement
Cells are incubated with compounds for 48 hours followed by the addition of 10 μL 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) solution per well and a subsequent incubation at 370C, 5% CO2, 95% air and 100% relative humidity, protected from light. After 4 hours, well contents are aspirated carefully followed by addition of 150 μL DMSO per well. Plates are agitated to ensure solution of the formazan crystals in DMSO and absorbance read at 570 nm. Calculation of GIgn, TGI and LCgn
Percent growth is calculated for each compound's concentration relative to the control and zero measurement wells (To; viability right before compound addition).
If a test well's O.D. value is greater than the T0 measurement for that cell line % Growth = (test - zero) / (control - zero) X 100
If a test well's O.D. value is lower than the T0 measurement for that cell line, then
% Growth = (test - zero) / zero X 100
Plotting % growth versus experimental drug concentration, GI50 is the concentration required to decrease % growth by 50%; TGI is the concentration required to decrease % growth by 100% and LC50 is the concentration required to decrease % growth by 150%. Representative results of growth are shown in the Table VIII. Table VIII
Figure imgf000097_0001
Wherein, NA indicates No activity and ND indicates Not Done.

Claims

We Claim:
1. A compound of the general formula (I),
Figure imgf000098_0001
derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof, wherein A represents substituted or unsubstituted aryl group; wherein B represents substituted or unsubstituted groups selected from aryl or pyridyl; and X represents carbon or nitrogen atom; when B is pyridyl then R is selected from azido, halogens comprising fluorine, chlorine, bromine, iodine, substituted or unsubstituted groups selected from alkoxy groups comprising methoxy, ethoxy, n-propoxy and isopropoxy, aryl groups comprising phenyl and naphthyl, acyl groups comprising acetyl and benzoyl, substituted or unsubstituted linear or branched (C]-C6) alkyl groups, comprising methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl and hexyl, cycloalkyl groups comprising cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, haloalkyl groups comprising chloromethyl, chloroethyl, trifluoromethyl, trifluoroethyl, dichloromethyl and dichloroethyl, amino, hydrazine groups comprising hydrazine and methylhydrazine, monoalkylamino groups comprising -NHCH3, -NHC2H5, -NHC3H7 and -NHC6H13, dialkylamino groups comprising - N(CH3)2, -NCH3(C2H5) and -N(C2Hs)2, acylamino groups comprising - NHC(=O)CH3, -NHC(=O)C2H5, -NHC(=O)C3H7 and -NHC(=O)C6H13, alkylsufonyl groups comprising methylsulfonyl, ethylsulfonyl, n- propylsulfonyl and iso-propylsulfonyl, alkylsulfinyl groups comprising methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and iso-propylsulfϊnyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl groups comprising methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl and isopropoxycarbonyl, aryloxycarbonyl groups comprising phenoxycarbonyl and napthoxycarbonyl, sulfamoyl; R1 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl groups comprising phenyl, naphthyl; aryloxy groups comprising phenoxy and napthoxy, acyloxy groups comprising MeCOO-, EtCOO- and PhCOO-, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxy, sulfamoyl, -SO2NHNH2 > -SO2Cl, carboxylic acid and its derivatives; R2 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH, -SO2Cl, carboxylic acid and its derivatives; R3 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R4 represents hydrogen, hydroxy, nitro, formyl, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; and X represents nitrogen; when B is aryl or pyridyl then R represents substituted or unsubstituted groups selected from aryl, heteroaryl, the heteroaryl groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazine, benzofuranyl, benzimidazolyl and benzothiazolyl; aryloxy, -OSO2R' (wherein R' is selected from substituted or unsubstituted: alkyl, aryl, alkyldialkylamino, haloalkyl, heterocyclyl and heteroaryl) and heterocyclyl groups comprising morpholine, piperazine, piperidine, pyrrolidine and thiazolidine; the heterocyclyl group is optionally substituted with substitutents independently selected from substituted or unsubstitued heteroaryl, alkylaryl (-CH2-Aryl), alkylheteroaryl (-CH2- Heteroaryl), substituted heteroarylcarbonyl (-CO-Heteroaryl), cyanoalkyl, alkylsulfonyl, haloalkylsulfonyl, formyl and another substituted or unsubstituted heterocyclyl group; the attachment of the heterocyclyl group to the pyrimidine ring is through carbon or nitrogen; R1 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups are selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2 -SO2Cl, carboxylic acid and its derivatives; R2 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2 d -SO2Cl, carboxylic acid and its derivatives; R3 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, aryl, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; and X represents carbon or nitrogen atom; when A and B are both aryl then R is selected from azido, halogens, substituted or unsubstituted groups selected from alkyl, alkoxy, acyl, cycloalkyl, haloalkyl, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsufonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, alkoxycarbonyl, aryloxycarbonyl, alkoxyalkyl and sulfamoyl; R1 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO2NHNH2 and -SO2Cl; R3 represents hydrogen, substituted sulfamoyl, substituted or unsubstituted -SO2NHNH2 and -SO2Cl; provided that any one of R1 or R3 is always substituted sulfamoyl, or substituted or unsubstituted -SO2NHNH2> or - SO2Cl; R2 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2, -SO2Cl, carboxylic acid and its derivatives; R4 represents hydrogen, hydroxy, nitro, azido, halogens, substituted or unsubstituted groups selected from alkyl, aryl, haloalkyl, alkoxy, aryloxy, acyloxy, amino, hydrazine, monoalkylamino, dialkylamino, acylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxycarbonyl, alkoxyalkyl, sulfamoyl, -SO2NHNH2; -SO2Cl, carboxylic acid and its derivatives; when the groups R, R1, R2, R3, R4 and R' are substituted by one or more substituents these substituents are selected from halogens, hydroxy, nitro, cyano, ureas, azido, amino, imino-1 -phenyl butanone, amide, thioamide, hydrazine, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryloxy, acyl groups comprising acetyl and benzoyl, haloacyl, acyloxyacyl, heterocyclyl, aryl, heteroaryl, monoalkylamino, dialkylamino, acylamino, alkoxycarbonyl groups comprising methoxycarbonyl and ethoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, thioalkyl, thioaryl, sulfamoyl, alkoxyalkyl groups, carboxylic acids and its derivatives comprising hydroxamic acid, hydroxamates, esters, amides and acid halides. These substituents are further optionally substituted with substituents selected from hydroxy, alkoxy, halogens, haloalkyl, alkyl and aryl which in turn is optionally further substituted by groups comprising halogens and alkyl.
2. The heterocyclic compound of claim 1, selected from a group consisting of: JV-( { 4- [4- Amino-6- [4-(methylsulfony l)ρheny 1] -2-(trifluoromethy l)pyrimidin -
5-yl]phenyl} sulfonyl)acetamide;
4-{4-Amino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-
5-yl}-N-methylbenzenesulfonamide;
4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin- 5-yl }benzenesulfonyl chloride;
4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-
5-yl}-N-methylbenzenesulfonamide;
4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}-N-methylbenzenesulfonamide; N-[(4-{4-(Methylamino)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidm-5-yl}phenyl)sulfonyl]acetamide;
4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin
-5-yl}benzenesulfonohydrazide;
4-[4-(4-Fluorophenyl)-6-hydrazino-2-(trifluoromethyl)pyrimidin-5-yl] benzenesulfonohydrazide;
N-[(4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}phenyl)sulfonyl]acetamide;
4-{4-Hydrazino-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimdin-5-yl}-N-methylbenzenesulfonamide; 4-Hydrazino-5-phenyl-6-pyridin-3-yl-2-(trifluoromethyl)pyrimidήie;
4-Hydrazino-5-phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidine;
5-(4-Fluorophenyl)-4-hydrazino-6-pyridin-4-yl-2-(trifluoromethyl) pyrimidine;
2,2,2-Trifluoro-N'-[5-(4-fluorophenyl)-6-pyridin-4-yl-2-(trifluoromethyl) pyrimidin-4-yl]acetohydrazide; iV-[5-Phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4-yl]aceto hydrazide;
2,2,2-Trifluoro-NI-[5-phenyl-6-pyridin-4-yl-2-(trifluoromethyl)pyrimidin-4 - yl]acetohydrazide; N-[(4-{4-Chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl}phenyl)sulfonyl] acetamide;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-
4-ylnapthalenesulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-3- chloropropane-1 -sulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-3-
(trifluoromethyl)benzenesulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-2-
(trifluoromethyl)benzenesulfonate; 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)ρyrimidin-4-yl-4- methylbenzenesulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4- nitrobenzenesulfonate;
6- [4-(Methylsulfony l)pheny 1] -5 -pheny l-2-(trifluoromethyl)pyrimidin-4-y 1-4- trifluoromethoxybenzenesulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl thiophene-2-sulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-4- fluorobenzenesulfonate ; 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-2- fluorobenzenesulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl-
(dimethylamino)propanesulfonate;
6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-(N-benzyl-piperazin-l-yl)-2- (trifluoromethyl)pyrimidine; 4-[4-(4-Fluorophenyl)-6-piperazin-l-yl-2-(trifluoromethyl)pyrimidin-5-yl] benzenesulfonamide ;
4-[5-(4-Fluorophenyl)-6-piperazin-l-yl-2-(trifluoromethyl)pyrimidin-4-yl] benzenesulfonamide; N-Methyl-4-[4-(methylsulfonyl)phenyl]-6-piperazin- 1 -yl-2-
(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;
4-[4-(Methylsulfonyl)phenyl]-6-ρiperazin-l-yl-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
4-{4-(Morpholin-4yl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-5-yl} -iV-methylbenzenesulfonamide;
5-{4-[4-(Methylsulfonyl)phenyl]-6-piperidin-l-yl-2-(trifluoromethyl) pyrimidin-5-yl}-iV-methylbenzenesulfonamide;
4-[4-(Methylsulfonyl)phenyl]-6-{4-[(5-methylpyrazin-2-yl)carbonyl] piperazin-l-yl}-5-phenyl-2-(trifluoromethyl)pyrimidine; 6-[4-(Methylsulfonyl)ρhenyl]-5-ρhenyl-4-{4-[(l-methyl-lH"-ρyrrol-2-yl) carbonyl]piperazin-l-yl}-2-(trifluoromethyl)pyrimidine;
6-[4-(Methylsulfonyl)phenyl]-4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-5- phenyl-2-(trifluoromethyl)pyrimidine; iV-Methyl-4-{4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-6-[4-(methylsulfonyl) phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide;
4- { 5 - [4-Fluoropheny 1] -4- [4-(5 -nitro-2-furoyl)piperazin- 1 -yl] -2-(trifluoro methyl)pyrimidin-6-yl}benzenesulfonamide;
4- { 6- [4-Fluorophenyl] -4- [4-(5 -nitro-2-furoyl)piperazin- 1 -y 1] -2-(trifluoro methyl)pyrimidin-5-yl}benzenesulfonamide; 6-[4-(Methylsulfonyl)phenyl]-4- {4-[(5-nitro- 1 H-pyrazol-3 -y l)carbonyl] piperazin- 1 -yl} -5-phenyl-2-(trifluoromethyl)pyrimidine;
5,6-Diphenyl-4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-2-(trifluoromethyl) pyrimidine;
5-[4-Fluorophenyl]-4-[4-(5-nitro-2-furoyl)piperazin-l-yl]-6-pyridin-4-yl- 2-(trifluoromethyl)pyrimidine; 6-[4-(Methylsulfonyl)phenyl]-5-phenyl-4-[4-(l,3-thiazol-2-ylmethyl) piperazin-l-yl]-2-(trifluoromethyl)pyrimidine;
4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-[4-(pyridin-4-ylmethyl) piperazin-l-yl]-2-(trifluoromethyl)ρyrimidine; 6-[4-(Methylsulfonyl)phenyl]-4-{4-[(5-nitro-2-thienyl)methyl]piperazin-l-yl}-
5-phenyl-2-(trifluoromethyl)pyrimidine;
4,5-Diphenyl-6-(4-pyridin-2-yl-piperazin-l-yl)-2-(trifluoromethyl) pyrimidine;
4-[4-(Methylsulfonyl)phenyl]-5-phenyl-6-(4-pyridin-2-yl-piperazin-l-yl)- 2-(trifluoromethyl)pyrimidine;
3-[4-(4-Fluorophenyl)-6-piperazin- 1 -yl-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
3 - [5 -Pheny 1-6-piperazin- 1 -yl-2-(trifluoromethy l)pyrimidin-4-y 1] benzenesulfonamide; 3-[5-(3-Aminosulfonylphenyl)]-6-piperazin-l-yl-2-(trifluoromethyl) pyrimidin-4-yl]benzenesulfonamide;
3-[4-(4-Fluorophenyl)-6-(4-pyridin-2-ylpiperazin-l-yl)-2-(trifluoromethyl) ρyrimidin-5-yl]benzenesulfonamide;
3-[4-(4-Fluorophenyl)-6-(4-pyrimidin-2-ylpiperazin-l-yl)- 2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;
3-[5-Phenyl-6-(l,3-thiazolidin-3-yl)-2-(trifluoromethyl)ρyrimidin-4-yl] benzenesulfonamide;
3-[6-[(4-Hydroxycyclohexyl)amino]-5-(3-aminosulfonylphenyl)-2-
(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide; 3-[6-(4-Pyrimidin-2-ylpiperazin-l-yl)]-5-phenyl-2-(trifluoromethyl) pyrimidin-4-yl]benzenesulfonamide;
3-[6-(4-Pyridin-2-ylpiperazin-l-yl)]-5-phenyl-2-(trifluoromethyl) pyrimidin-4-yl]benzenesulfonamide;
Ethyl-l-[5-(3-aminosulfonylphenyl)-6-(4-fluorophenyl)-2 -(trifluoromethy l)pyrimidin-4-y l]piperidine-4-carboxy late ; 3 - [4- [(4-Hy droxycy clohexyl)amino] -6-(4-fluoropheny l)-2-(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide;
Ethyl l-[5-phenyl-6-(3-aminosulfonylphenyl)l-2-(trifluoromethyl) pyrimidin-4-yl]piperidine-4-carboxylate; 4-[5-Phenyl-6-(3-morpholinosulfonylphenyl)-2-(trifluoromethyl) pyrimidin-4-yl]morpholine;
3-[4-(4-Fluorophenyl)-6-morpholin-4-yl-2-(trifluoromethyl)pyrimidin-5- yl]benzenesulfonamide ;
(3i?)-l-[6-(4rFluorophenyl)-5-(3-aminosulfonylphenyl)-2-(trifluoro methyl)pyrimidin-4-yl]pyrrolidin-3 -ol;
Ethyl (2S',4i?)-4-hydroxy-l-[6-(4-fluorophenyl)-5-(3-aminosulfonyl phenyl)-2-(trifluoromethyl)pyrimidin-4-yl]ρyrrolidine-2-carboxylate;
4-[4-(2,6-Dimethoxypyrimidin-4-yl)piperazin-l-yl]-5-(3-aminosulfonyl phenyl)-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidine; 5-(4-Fluorophenyl)-4-(4-pyridin-2-ylpiperazin- 1 -yl)-6-[4-(methylsulfonyl) phenyl]-2-(trifluoromethyl)pyrimidine;
4-(4-Methylsulfonylphenyl)-5-(4-fluorophenyl)-6-(4-pyrimidin-2-yl piperazin- 1 -y l)-2-(trifluoromethyl)pyrimidine ;
4-[5-(4-Fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl) pyrimidin-4-y l]piperazine- 1 -carbaldehy de ; r-[5-(4-Flurophenyl)-6-(4-methylsulfonylphenyl)-2-(trifluoromethyl) pyrimidin-4-yl]-l,4'-bipiperidine;
3 -[4-(4-Fluorophenyl)-6-( 1 ,4 ' -bipiperidin- 1 ' -yl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide; 3-[4-(2-Furoyl)piperazin- 1 -yl)-6-(4-fluorophenyl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
5-(3-Atninosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)-
6-{4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}pyrimidine;
5-(4-Fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(trifluoromethyl)- 6-{4-[3-(trifluoromethyl)phenyl]piperazin-l-yl}pyrimidine; ' 3-[4-(4-Fluoroρhenyl)-6-(l53-thiazolidin-3-yl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfbnamide; l-[5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl) pyrimidin-4-yl]pyrrolidine-2-carboxamide; 5-(3-Aminosulfonylphenyl)-4-(4-fluorophenyl)-2-(trifluoromethyl)-
6- {4- [(trifluoromethy 1) sulfony l]piperazin- 1 -y 1} pyrimidine ;
3-[4-[4-(Methylsulfonyl)piperazin-l-yl]-6-(4-fluorophenyl)-2-(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide;
3-[4-[4-(Cyanomethyl)piperazin-l-yl]-6-(4-fluorophenyl)-2-(trifluoro methyl)pyrimidin-5-yl]benzenesulfonamide;
3-[4-(4-Fluorophenyl)-6-(lH-imidazol-l-yl)-2-(trifluoromethyl) pyrimidin-5-yl]benzenesulfonamide;
5-(4-Fluorophenyl)-4-(lH-imidazol-l-yl)-6-[4-(methylsulfonyl)phenyl]-
2-(trifluoromethy l)pyrimidine ; 3-[6-(4-Pyridin-5-trifluoromethyl-2-ylpiperazin-l-yl)]-5-phenyl-2-
(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;
3-[6-{4-[2,6-Dimethoxypyrimidin-4-yl]piperazin-l-yl}-5-phenyl-
2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;
3-[6-{4-[5-(Nitro)pyridin-2-yl]piperazin-l-yl}-5-phenyl- 2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide;
3 - [6- { 4- [5-( Amino)pyridin-2-y l]piperazin- 1 -y 1} -4- [4-fluorophenyl] -
2-(trifluoromethyl)ρyrimidin-5-yl]benzenesulfonamide;
4-[5-(Acetylamino)pyridin-2-yl]piperazin-l-yl-5-(4-fluorophenyl)-
6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidine; N-({3-[4-pyridin-2-yl]piperazin-l-yl)-6-(4-fluorophenyl)-
2-(trifluoromethyl) pyrimidin-5-yl]phenyl} sulfony 1) acetamide;
4-Fluorophenyl-5-(3-propionylaminosulfonylphenyl)-6-([4-pyridin-2-yl] piperazin- 1 -y l)-2-(trifluoromethyl)pyrimidine ; l-{5-[3-(Aminosulfonyl)phenyl]-6-(4-fluorophenyl)- 2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylic acid; 4-[4-(Methoxyaminocarbonyl)piperidin-l-yl}-5-(4-fluorophenyl)-
6- [4-(methy lsulfony l)phenyl] -2-(trifluoromethy 1) pyrimidine ;
Methy 1-3 -methoxy-4-( {6- [4-(methy lsulfony l)pheny 1] -
5-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}oxy)benzoate; 3 -Methoxy-4-( { 6-(4-fluorophenyl)-5 - [3 -(aminosulfony l)pheny 1] -
2-(trifluoromethyl)pyrimidin-4-yl}oxy)-N-methoxybenzamide;
4-{[5-(4-Fluorophenyl)-6(4-methylsufonylphenyl)-2-(trifluoromethyl) pyrimidin-4-yl]oxy}-iV33-dimethoxybenzamide;
5-Amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-methyl-l/f -pyrazole-4-carbonitrile;
Ethyl-5-amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-
3-(methylthio)-lH-pyrazole-4-carboxylate;
5-Amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-lH-pyrazole-4- carbonitrile; 3 -t-Butyl- 1 - [5 ,6-dipheny l-2-(trifluoromethy l)pyrimidin-4-y 1] - 1 H-pyrazol-
5 -amine;
4-(3,5-Dimethyl-lif-pyrazol-l-yl)-5,6-diphenyl-2-(trifluoromethyl) pyrimidine;
3 - [4-(5 - Amino-4-cy ano-3 -methyl- 1 H-pyrazol- 1 -yl)-6-(4-fluoropheny 1) -2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide;
Ethyl-5-amino-l-[5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-
(trifluoromethyl)pyrimidin-4-yl]-3-(methylthio)-lH-pyrazole-4-carboxylate;
4-[4-(Methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-
6-[5-(trifluoro methyl)-lH-pyrazol-l-yl]pyrimidine; 5-Amino- 1 -[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]- lH-pyrazole-4-carbothioamide;
(3Z)-4,4,4-Trifluoro-l-phenylbutane-l,3-dione-3-{[5-phenyl-
6-(4-methylsulfonylphenyl)-2-(trifluoromethyl)pyrimidin-4-yl]hydrazone}
N-{l-[5s6-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-lH- pyrazol-5-yl} -4-methoxybenzamide; N-{l-[5,6-Diphenyl-2-(trifluoromethyl)ρyrimidin-4-yl]-3-t-butyl-lH- pyrazol-5-yl} -3 -fluorobenzamide;
N- { 1 -[556-Diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3 -t-butyl- 1 H- pyrazol-5-yl}-4-(trifluoromethyl)benzamide; Ethyl-5-amino-l -[5-phenyl-6-[4-(methylsulfonyl)phenyl]-
2-(trifluoromethy l)pyrimidin-4-y 1] -3 -(methy lthio)- 1.H-pyrazole-4-carboxy late ;
5-Amino-l-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-3-(methyl thio)-iV-phenyl- 1 H-pyrazole-4-carboxamide;
5-Aniino-iV-(4,5-dimethylphenyl)-l-[5-(4-fluoropb.enyl)-6-pyridin-4-yl -2-(trifluoromethyl)pyriniidin-4-yl]-3-(methylthio)-lH-pyrazole-4- carboxamide;
1 -(2,6-Dichlorophenyl)-3- { 1 -[5,6-diρhenyl-2-
(trifluoromethyl)pyrimidin-4-yl]-3-t-butyl-lΗ-pyrazol-5-yl}urea;
4-[4-(Methylthio) phenyl]-5,6-diphenyl-2-(trifluoromethyl)pyrimidine; and 5-Phenyl-4-[4-(methylsulfonyl)ρhenyl]-6-[4-(methylthio)ρhenyl]-2-
(trifluoromethy l)py r imidine .
3. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1, as an active ingredient along with a pharmaceutically acceptable carrier, diluent, excipient or solvate.
4. A pharmaceutical composition as claimed in claim 3, wherein the pharmaceutical composition is in a tablet, capsule, powder, syrup, solution, aerosol or suspension.
5. A pharmaceutical composition as claimed in claim 3, wherein the amount of the compound in the composition is less than 70 % by weight.
6. A method of treatment of a pain disorder, inflammation, and immunological diseases in a mammal comprising administering an effective amount of, a compound according to claim 1, to the mammal in need thereof.
7. A method of treatment of rheumatoid arthritis; osteoporosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; ischemic heart disease; atherosclerosis; cancer; ischemic-induced cell damage; pancreatic beta cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; muscle degeneration; cachexia; asthma; bone resorption diseases; ischemia reperfusion injury; brain trauma; multiple sclerosis; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection in a mammal comprising administering an effective amount of, a compound according to claim 1, to the mammal in need thereof.
8. A method of lowering plasma concentrations of anyone or a combination or all of TNF-α, IL- lβ, and IL-6 comprising administering an effective amount of a compound according to claim 1, to the mammal in need thereof.
9. A method for inhibiting production of cytokines as selected from TNF-α, IL-I β, and IL-6, by the method comprising of administering the compound of the formula (I) as claimed in claim 1.
10. A method of treating immunological diseases, those mediated by cytokines such as TNF-α, IL-I β, and IL-6 comprising administering an effective amount of a compound according to claim 1 , to the mammal in need thereof.
PCT/IB2006/003468 2006-01-19 2006-12-01 Novel heterocycles WO2007083182A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
ES06831640.5T ES2600804T3 (en) 2006-01-19 2006-12-01 New heterocycles
BRPI0621226-3A BRPI0621226A2 (en) 2006-01-19 2006-12-01 heterocycle compounds
EP06831640.5A EP1973884B1 (en) 2006-01-19 2006-12-01 Novel heterocycles
CA2637631A CA2637631C (en) 2006-01-19 2006-12-01 Pyrimidine compounds and uses thereof
JP2008550862A JP5237115B2 (en) 2006-01-19 2006-12-01 New heterocycles
CN200680051384.3A CN101360717B (en) 2006-01-19 2006-12-01 Compound including pyrimidine
AU2006335967A AU2006335967B2 (en) 2006-01-19 2006-12-01 Novel heterocycles

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN86CH2006 2006-01-19
IN0086/CHE/2006 2006-01-19

Publications (2)

Publication Number Publication Date
WO2007083182A2 true WO2007083182A2 (en) 2007-07-26
WO2007083182A3 WO2007083182A3 (en) 2007-11-15

Family

ID=38263980

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/003468 WO2007083182A2 (en) 2006-01-19 2006-12-01 Novel heterocycles

Country Status (10)

Country Link
US (1) US20070167413A1 (en)
EP (1) EP1973884B1 (en)
JP (1) JP5237115B2 (en)
CN (1) CN101360717B (en)
AU (1) AU2006335967B2 (en)
BR (1) BRPI0621226A2 (en)
CA (1) CA2637631C (en)
ES (1) ES2600804T3 (en)
PL (1) PL1973884T3 (en)
WO (1) WO2007083182A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095773A3 (en) * 2008-02-01 2010-04-22 Orchid Research Laboratories Limited Novel heterocycles
US7863446B2 (en) 2006-01-19 2011-01-04 Orchid Research Laboratories Limited Heterocycles

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1599468T3 (en) 2003-01-14 2008-02-04 Arena Pharm Inc 1,2,3-Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prevention and treatment of disorders associated therewith such as diabetes and hyperglycemia
AR045047A1 (en) * 2003-07-11 2005-10-12 Arena Pharm Inc ARILO AND HETEROARILO DERIVATIVES TRISUSTITUIDOS AS MODULATORS OF METABOLISM AND PROFILAXIS AND TREATMENT OF DISORDERS RELATED TO THEMSELVES
EP2287166A3 (en) 2003-07-14 2011-06-22 Arena Pharmaceuticals, Inc. Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
MY148521A (en) * 2005-01-10 2013-04-30 Arena Pharm Inc Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto
GB0818241D0 (en) * 2008-10-06 2008-11-12 Cancer Res Technology Compounds and their use
ES2937386T3 (en) 2010-01-27 2023-03-28 Arena Pharm Inc Processes for the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts of same
SG188548A1 (en) 2010-09-22 2013-04-30 Arena Pharm Inc Modulators of the gpr119 receptor and the treatment of disorders related thereto
SI3255043T1 (en) * 2011-07-12 2021-04-30 Astrazeneca Ab N-(6-((2r,3s)-3,4-dihydroxybutan-2-yloxy)-2-(4-fluorobenzylthio)pyrimidin-4-yl)-3- methylazetidine-1-sulfonamide as chemokine receptor modulator
AR101198A1 (en) * 2014-07-16 2016-11-30 Gruenenthal Gmbh PYRIMIDINES 2,5-REPLACED AS PDE4B INHIBITORS
EP3242666A1 (en) 2015-01-06 2017-11-15 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the s1p1 receptor
JP6838744B2 (en) 2015-06-22 2021-03-03 アリーナ ファーマシューティカルズ， インコーポレイテッド (R) -2- (7- (4-cyclopentyl-3- (trifluoromethyl) benzyloxy) -1,2,3,4-tetrahydrocyclopenta [b] indole-for use in S1P1 receptor-related disorders Crystalline L-arginine salt of 3-yl) acetic acid (Compound 1)
KR20190116416A (en) 2017-02-16 2019-10-14 아레나 파마슈티칼스, 인크. Compounds and Methods for Treating Primary Bile Cholangitis
CN108707096B (en) * 2018-05-07 2021-03-19 上海科技大学 Process for preparing aminoalcohol derivatives
CN115043828B (en) * 2022-07-27 2024-01-30 黑龙江中医药大学 Medicament for treating nasosinusitis and preparation method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5486534A (en) 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
WO1996024585A1 (en) 1995-02-10 1996-08-15 G.D. Searle & Co. 3,4-diaryl substituted pyridines for the treatment of inflammation
WO2003084935A2 (en) 2002-04-10 2003-10-16 Orchid Chemicals & Pharmaceuticals Ltd Diaryl pyrimidinone derivatives useful for the treatment of inflammation and immunogolical diseases
WO2004009560A1 (en) 2002-07-22 2004-01-29 Orchid Chemicals & Pharmaceuticals Ltd Novel bio-active molecules

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5166137A (en) * 1991-03-27 1992-11-24 Nobipols Forskningsstiftelse Guluronic acid polymers and use of same for inhibition of cytokine production
WO1994007867A1 (en) * 1992-09-28 1994-04-14 Pfizer Inc. Substituted pyrimidines for control of diabetic complications
US5527546A (en) * 1994-08-10 1996-06-18 Bayer Corporation Human interleukin 6 inhibitor
WO1996035782A1 (en) * 1995-05-11 1996-11-14 Applied Research Systems Il-6 activity inhibitor
US6410729B1 (en) * 1996-12-05 2002-06-25 Amgen Inc. Substituted pyrimidine compounds and methods of use
US6096753A (en) * 1996-12-05 2000-08-01 Amgen Inc. Substituted pyrimidinone and pyridone compounds and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5486534A (en) 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
US6028072A (en) 1994-07-21 2000-02-22 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
WO1996024585A1 (en) 1995-02-10 1996-08-15 G.D. Searle & Co. 3,4-diaryl substituted pyridines for the treatment of inflammation
WO2003084935A2 (en) 2002-04-10 2003-10-16 Orchid Chemicals & Pharmaceuticals Ltd Diaryl pyrimidinone derivatives useful for the treatment of inflammation and immunogolical diseases
WO2004009560A1 (en) 2002-07-22 2004-01-29 Orchid Chemicals & Pharmaceuticals Ltd Novel bio-active molecules

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ARZNEIM-FORSCH/DRUG RES., vol. 43, no. I, 1993, pages 1,44 - 50
J. CLIN. IMMUNOASSAY, vol. 15, 1992, pages 116 - 120
JAQUES ET AL.: "Enantiomers, Racemates and Resolution", 1981, WILEY INTERSCIENCE
LES SEKUT ET AL., J LAB CLIN MED, vol. 124, 1994, pages 813 - 20
MARCO ROMANO ET AL., JOURNAL OF CLINICAL INVESTIGATION, 1992, pages 2409 - 2421
OTTERNESS; BLIVEN: "Non-Steroidal Anti-Inflammatory Drugs", 1985, article "Laboratory Models for Testing NSAIDs"
PHYSIOL. RES., vol. 52, 2003, pages 593 - 598
PROC. NAT. ACAD. SCI. USA, vol. 88, 1991, pages 2692 - 2696
See also references of EP1973884A4
WINTER ET AL., PROC.SOC.EXP.BIOL.MED, vol. 111, 1962, pages 544

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7863446B2 (en) 2006-01-19 2011-01-04 Orchid Research Laboratories Limited Heterocycles
WO2009095773A3 (en) * 2008-02-01 2010-04-22 Orchid Research Laboratories Limited Novel heterocycles
KR20100131443A (en) * 2008-02-01 2010-12-15 오키드 리서치 레버라토리즈 리미티드 Novel heterocycles
US20100329998A1 (en) * 2008-02-01 2010-12-30 Visweswara Akella Satya Surya Srinivas Novel heterocycles
JP2011510967A (en) * 2008-02-01 2011-04-07 オーキッド リサーチ ラボラトリーズ リミティド New heterocyclic compounds
AU2009208712B2 (en) * 2008-02-01 2013-03-14 Orchid Chemicals & Pharmaceuticals Limited Novel heterocycles
US8420653B2 (en) 2008-02-01 2013-04-16 Orchid Chemicals & Pharmaceuticals Limited Pyrimidine compounds and their uses
US8828999B2 (en) 2008-02-01 2014-09-09 Orchid Chemicals & Pharmaceuticals Limited Pyrimidine compounds and their uses
CN101965338B (en) * 2008-02-01 2014-09-17 幽兰化学医药有限公司 Novel heterocycles
KR101595506B1 (en) * 2008-02-01 2016-02-18 오키드 리서치 레버라토리즈 리미티드 Novel heterocycles

Also Published As

Publication number Publication date
CA2637631A1 (en) 2007-07-26
EP1973884B1 (en) 2016-08-03
US20070167413A1 (en) 2007-07-19
PL1973884T3 (en) 2017-05-31
CA2637631C (en) 2014-04-29
EP1973884A4 (en) 2010-03-17
AU2006335967B2 (en) 2012-01-19
CN101360717B (en) 2014-04-16
CN101360717A (en) 2009-02-04
AU2006335967A1 (en) 2007-07-26
JP2009523779A (en) 2009-06-25
JP5237115B2 (en) 2013-07-17
BRPI0621226A2 (en) 2012-07-10
EP1973884A2 (en) 2008-10-01
ES2600804T3 (en) 2017-02-10
WO2007083182A3 (en) 2007-11-15

Similar Documents

Publication Publication Date Title
AU2006335967B2 (en) Novel heterocycles
US7759350B2 (en) Pyrimidine carboxamides
US20080221103A1 (en) New heterocyclic compounds
JP2005535570A (en) New pyrimidone derivatives
CA2492342C (en) Novel bio-active pyrimidine derivatives
US7863446B2 (en) Heterocycles
US8828999B2 (en) Pyrimidine compounds and their uses
JP2023527698A (en) Novel malonitrile derivative
WO2006129181A2 (en) Preparation of 4-pyrimidone derivatives for treating inflammatory diseases

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
REEP Request for entry into the european phase

Ref document number: 2006831640

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2006831640

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2637631

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 200680051384.3

Country of ref document: CN

Ref document number: 2008550862

Country of ref document: JP

Ref document number: 2006335967

Country of ref document: AU

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2006335967

Country of ref document: AU

Date of ref document: 20061201

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2006335967

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2006831640

Country of ref document: EP

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
ENP Entry into the national phase

Ref document number: PI0621226

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20080714