WO1997025047A1 - Nouveaux imidazoles cycloalkyle-substitues - Google Patents

Nouveaux imidazoles cycloalkyle-substitues Download PDF

Info

Publication number
WO1997025047A1
WO1997025047A1 PCT/US1997/000614 US9700614W WO9725047A1 WO 1997025047 A1 WO1997025047 A1 WO 1997025047A1 US 9700614 W US9700614 W US 9700614W WO 9725047 A1 WO9725047 A1 WO 9725047A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
compound
substituted
optionally substituted
Prior art date
Application number
PCT/US1997/000614
Other languages
English (en)
Inventor
Jerry L. Adams
Ravi S. Garigipati
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EP97904766A priority Critical patent/EP0883402A4/fr
Priority to US09/101,525 priority patent/US5929076A/en
Priority to JP52546597A priority patent/JP2001508395A/ja
Publication of WO1997025047A1 publication Critical patent/WO1997025047A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a novel group of imidazole compounds, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for use in such therapy.
  • Interleukin- 1 and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages.
  • IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease. 6, 51 (1984)].
  • the myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
  • EL- 1 production is implicated in exacerbating and/or causing the disease.
  • diseases states include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic ⁇ cells.
  • TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs.
  • allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.
  • AIDS cachexia secondary to infection or malignancy
  • cachexia secondary to acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis or pyresis.
  • HIV Human Immunodeficiency Virus
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • HIV-3 HIV-3
  • HIV entry into the T lymphocyte requires T lymphocyte activation.
  • Other viruses, such as HrV-1, HIV-2 infect T lymphocytes after T Cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation.
  • Monokines are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with monokine activity such as by inhibition of monokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection.
  • Monocytes, macrophages, and related cells such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T-cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al.. The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, (1989)].
  • Monokines such as TNF
  • TNF have been shown to activate HIV replication in monocytes and/or macrophages [See Poli, et al.. Proc. Natl. Acad. Sci., 87:782-784 (1990)]
  • inhibition of monokine production or activity aids in limiting HIV progression as stated above for T-cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalo virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalo virus
  • Interleukin-8 is a chemotactic factor first identified and characterized in 1987.
  • LL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysaccharide (LPS).
  • Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit NeutrophilsMany different names have been applied to IL-8, such as neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
  • NAP-1 neutrophil attractant/activation protein- 1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutrophil activating factor
  • T-cell lymphocyte chemotactic factor T-cell lymphocyte chemotactic factor.
  • IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophil into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
  • LL- 1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions.
  • the inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
  • cytokine suppressive anti-inflammatory drugs i.e. compounds which are capable of inhibiting cytokines, such as LL- 1 , IL-6, IL-8 and TNF.
  • This invention relates to the novel compounds of Formula (I) and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier.
  • This invention relates to a method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • This invention more specifically relates to a method of inhibiting the production of IL- 1 , IL-8 or TNF in a mammal in need thereto, which comprises administering to said mammal an effective amount of a compound of Formula (I). Accordingly, the present invention provides for a compound of the Formula : wherein
  • Rl is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, which ring is substituted with a substituted C1.4 alkoxy or a substituted Ci-4 alkylthio group, and is additionally optionally substituted independently by C alkyl, halogen, hydroxyl, Ci-4 alkoxy, C]-4 alkylthio, C1-.4 alkylsulfinyl, CH2OR12, amino, mono and di- C ⁇ - alkyl substituted amino, N(R ⁇ o)C(O)R c or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents
  • Re is hydrogen, Ci-6 alkyl, C3.7 cycloalkyl, aryl, arylCi_4 alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclyl, or heterocyclylCi-4alkyl C1-4 alkyl;
  • R2 is an optionally substituted C3-7 cycloalkyl, or C3.7cycloalkylC1.10 alkyl;
  • R3 is heterocyclyl, heterocyclylCi-io alkyl or Rs;
  • R5 is hydrogen, -4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties
  • R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NRi 5;
  • R8 is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi-io alkyl, (CRioR20)nORl l, (CRl ⁇ R2 ⁇ )nS(O) m Ri8, (CR ⁇ oR2 ⁇ )nNHS(O) 2 Rl8v (CRio 20)n Rl3Rl4; wherein the ary
  • R9 is hydrogen, -C(Z)Ri 1 or optionally substituted Ci-io alkyl, S(O)2Rl8, optionally substituted aryl or optionally substituted aryl-Ci-4 alkyl;
  • RlO and R20 is ea ch independently selected from hydrogen or C ⁇ _4 alkyl;
  • Rn is hydrogen, or Ri8;
  • Rl2 is hydrogen or Ri6;
  • Rl3 and R14 is each independently selected from hydrogen or optionally substituted Ci-4 alkyl, optionally substituted aryl or optionally substituted aryl-C ⁇ .4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or
  • Rl5 is hydrogen, Ci-4 alkyl or C(Z)-Ci-4 alkyl
  • R 16 is C 1-4 alkyl, halo-substituted-Ci-4 alkyl, or C3..7 cycloalkyl
  • Rl8 is Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylCi-io alkyl, heterocyclyl, heterocyclyl-C 1.1 oalkyl, heteroaryl or heteroarylalkyl;
  • Z is oxygen, or sulfur; or a pharmaceutically acceptable salt thereof.
  • novel compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of cytokine inhibition or production.
  • cytokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section, but in particular viral infections.
  • viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FLV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
  • suitable Ri moieties includes 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 6-isoquinolinyl, 4-quinazolinyl, 1-imidazolyl and 1-benzimidazolyl, of which the 4-pyridyl, 4-pyrimidinyl and 4-quinolyl are preferred. More preferred is a substituted 4-pyrimidinyl or a substituted 4-pyridyl moiety, and most preferred is a substituted 4-pyrimidinyl ring.
  • the Rl moieties are substituted at least one time by a substituted Ci-4 alkoxy moiety or a substituted Cj-4 alkylthio.
  • a preferred ring placement of the Rj substituent on the 4- pyridyl derivative is the 2-position, such as 2-methoxy-4-pyridyl.
  • a preferred ring placement on the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methoxy- pyrimidinyl.
  • Ci-4 alkoxy or C 1.4 alkylthio moiety is substituted on the alkyl chain by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy, such as hydroxyethyoxy; Ci-io alkoxy, such as a methoxymethoxy , S(O)m alkyl, wherein m is 0, 1 or 2; amino, mono & di-substituted amino, such as in the NR7R17 group, i.e.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy such as hydroxyethyoxy
  • Ci-io alkoxy such as a methoxymethoxy , S(O)m alkyl, wherein m is 0, 1 or 2
  • amino, mono & di-substituted amino such as in the NR7R17 group, i.e.
  • the Ri substituents are tertbutylaminoethoxy, or hydroxyethoxy.
  • Suitable additional substituents for the Rl heteroaryl rings are C1-4 alkyl, halo, OH, Ci-4 alkoxy, C1.4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di-Cj-6 alkyl substituted amino, N(R ⁇ o)C(O)Rc, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15.
  • the alkyl group in the mono- and di-Ci-6 alkyl substituted moiety may be halo substituted, such as in trifluoro- i.e., trifluoromethyl or trifluroethyl.
  • Ri optional substituent is N(R ⁇ o)C(O) R c , wherein R ⁇ is hydrogen, Ci-6 alkyl, 03.7 cycloalkyl, aryl, arylC ⁇ .4 alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclyl, or heterocyclylCi-4alkyl Ci-4 alkyl, R c is preferably Ci-6 alkyl; preferably Rio is hydrogen.
  • R c moieties in particular the Ci-6 alkyl group may be optionally substituted, preferably from one to three times, preferably with halogen, such as fluorine, as in trifluoromethyl or trifluroethyl.
  • R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents. More preferably R4 is a phenyl or naphthyl ring.
  • Suitable substitutions for R4 when this is a 4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6- naphth-2-yl moiety are one or two substituents each of which are independently selected from halogen, -SR5, -SOR5, -OR12, CF3, or -(CRioR20)vNRio 20. and for other positions of substitution on these rings preferred substitution is halogen, -S(O) m R3, -OR3, CF3, -
  • substituents for the 4-position in phenyl and naphth-1-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro and chloro and -SR5 and -SOR5 wherein R5 is preferably a Ci-2 alkyl, more preferably methyl; of which the fluoro and chloro is more preferred, and most especially preferred is fluoro.
  • Preferred substituents for the 3-position in phenyl and naphth-1-yl rings include: halogen, especially fluoro and chloro; -OR3, especially Ci-4 alkoxy; CF3, NR10R2O. such as amino; -NR ⁇ oC(Z)R3, especially -NHCO(Ci-io alkyl); -NR ⁇ oS(O) m 'R8, especially -NHS ⁇ 2(C ⁇ _ ⁇ o alkyl), and -SR3 and -SOR3 wherein R3 is preferably a -2 alkyl, more preferably methyl.
  • R3 may also include hydrogen.
  • the R4 moiety is an unsubstituted or substituted phenyl moiety. More preferably, R4 is phenyl or phenyl substituted at the 4-position with fluoro and or substituted at the 3-position with fluoro, chloro, C1-4 alkoxy, methane-sulfonamido or acetamido, or R4 is a phenyl di-substituted at the 3,4-position independently with chloro or fluoro, more preferably chloro. Most preferably, R4 is a 4-fluorophenyl.
  • Z is oxygen, or sulfur, preferably oxygen.
  • R2 is an optionally substituted C3-7cycloalkyl, or an optionally substituted C3-7cycloalkyl Ci-io alkyl.
  • R2 is a C3-7cycloalkyl, of which the cycloalkyl group is preferably a C4-7 ring, more preferably a C4 or C6 ring, most preferably a Cfr ring, which ring is optionally substituted.
  • the C3-7cycloalkyl ring may substituted one to three times independently by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; Ci-io alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1, or 2, such as methyl thio, methylsulfmyl or methyl sulfonyl; S(O) m aryl; cyano; nitro; amino, mono & di-substituted amino, such as in the NR7R17 group, wherein R7 and Ri 7 are as defined in Formula (I); or where the R7R17 may cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from oxygen, sulfur or NR15 (wherein R15 is as defined for Formula (I)); N(R ⁇ o)C(O)Xi (wherein Rio is as defined for Formula (I), and X
  • R a is a 1 ,3-dioxyalkylene group of the formula -O-(CH2)s-O-, wherein s is 1 to 3, preferably s is 2 yielding a 1 ,3-dioxyethylene moiety.
  • Rb is hydrogen, a pharmaceutically acceptable cation, aroyl or a Ci-io alkanoyl group.
  • R is NR21R22; - ⁇ 1-6'- halosubstituted alkyl 1-6; hydroxy substituted alkyl 1-6; alkenyl 2-6 > aryl or heteroaryl optionally substituted by halogen, alkyl 1-6 , halosubstituted alkyl 1 -6, hydroxyl, or alkoxy ⁇ .(,.
  • R21 is H or alkyl 1 -6.
  • the ring may be saturated or contain more than one unsaturated bond.
  • R6 is NR21R22, and more preferably R21 and R22 are hydrogen.
  • a preferred ring placement on the cyclohexyl ring, particularly when it is a C6 ring, is the 4-position.
  • cyclohexyl ring When the cyclohexyl ring is disubstituted it is preferably disubstituted at the 4 position, such as in:
  • R 1 ' and R ⁇ ' are independently the optional substitutents indicated above for R2-
  • R* and R ⁇ are hydrogen, hydroxy, alkyl, substituted alkyl, optionally substituted alkynyl, aryl, arylalkyl, NR7R17, and N(R ⁇ o)C(O)R ⁇ 1.
  • alkyl is Ci-4 alkyl, such as methyl, ethyl, or isopropyl; NR7R17 and NR7R17 alkyl, such as amino, methylamino, aminomethyl, aminoethyl; substituted alkyl such as in cyanomethyl, cyanoethyl, nitroethyl, pyrrolidinyl; optionally substituted alkynyl, such as propynyl or ethynyl; aryl such as in phenyl; arylalkyl, such as in benzyl; or together R ⁇ and R ⁇ are a keto functionality.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted Ci-ioalkyl
  • Ci-io alkoxy such as methoxy or ethoxy
  • S(O)m alkyl wherein m is 0, 1 or 2, such as methyl thio, methylsulfinyl or methyl sulfonyl
  • amino, mono & di-substituted amino such as in the NR7R17 group; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S
  • Ci-io alkyl, cycloalkyl, or cycloalkyl alkyl group such as methyl, ethyl, propyl, isopropyl, t-butyl, etc.
  • halosubstituted Ci-io alkyl such CF3
  • halosubstituted Ci-io alkoxy an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O) m alkyl; amino, mono & di-substituted amino, such as in the NR7R17 group; alkyl, or CF3.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • halo or halogens
  • halogens include the halogens: chloro, fluoro, bromo and iodo.
  • C ⁇ _ ⁇ oalkyl or "alkyl” - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, wo-butyl, tert-butyl, n-pentyl and the like.
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkenyl is used herein to mean cyclic radicals, preferably of 5 to
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as “heterocyclylalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
  • aralkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Ci-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety as also defined herein unless otherwise indicate.
  • the compounds of the present invention may exist as stereoisomers, regioisomers, or diastereiomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
  • Exemplified compounds of Formula (I) include: -[2-(2-Hydroxyethoxy)pyrimidin-4-yl]-4-(4-fluorophenyl)-l-(4-oxocyclohexyl)- imidazole; 5-[2-(2-Hydroxyethoxy)]pyrimidin-4-yl)-4-(4-fluorophenyl)-l-(4-hydroxy cyclohexyl)- imidazole;
  • the compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in Schemes I to XI below. The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I) having a variety of different Ri, R2, and R4 groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the imidazole nucleus has been established, further compounds of Formula (I) may be prepared by applying standard techniques for functional group interconversion, well known in the art.
  • -C(O)NRi3Ri4 from -CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR13R14 in CH3OH; -OC(O)R3 from -OH with e.g., ClC(O)R3 in pyridine; -NR ⁇ o-C(S)NRi3Ri4 from -NHR10 with an alkylisothiocyante or thiocyanic acid; NR ⁇ C(O)OR6 from -NHR6 with the alkyl chloroformate; NR ⁇ oC(O)NRi3Ri4 from -NHR10 by treatment with an isocyanate, e.g.
  • catalytic metal cyanide e.g. NaCN
  • HNR13R14 in CH3OH
  • -OC(O)R3 from -OH with e.g., ClC(O)R3 in pyridine
  • R4 is as defined for Formula (I) and Ar is an optionally substituted aryl as defined herein.
  • Ar is phenyl optionally substituted by C ⁇ _4alkyl, C .4 alkoxy or halo.
  • Ar is phenyl or 4-methylphenyl, i.e. a tosyl derivative.
  • Compounds of Formula (II) are belived novel, provided than when Ar is tosyl, and p is 0 or 2, then R4 is not an unsubstituted phenyl.
  • Precursors of the groups Rj, R2 and R4 can be other Rl, R2 and R4 groups which can be interconverted by applying standard techniques for functional group interconversion.
  • a compound of the formula (I) wherein R2 is halo -substituted C ⁇ . ⁇ Q alkyl can be converted to the corresponding C ⁇ _ ⁇ o alkylN3 derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding C _iQalkylNH2 compound, which in turn can be reacted with Ri S(0)2X wherein X is halo (e.g., chloro) to yield the corresponding C ⁇ _ ⁇ oalkylNHS(0)2Ri8 compound.
  • C ⁇ _ ⁇ o-alkylNRi3Ri4 compound or can be reacted with an alkali metal salt of RisSH to yield the corresponding C ⁇ _ ⁇ oalkylSRi compound.
  • the compounds of Formula (I) are suitably prepared by reacting a compound of the Formula (II) with a compound of the Formula (LU) wherein p is 0 or 2, Rj, R2 and R4 are as defined herein, for Formula (I), or are precursors of the groups
  • R , R2 and R4, and Ar is an optionally substituted phenyl group, and thereafter if necessary converting a precursor of Ri, R2 and R4 to a group Ri, R2 and R4. It is recognized that
  • R2NH2 which is reacted with RiCHO to form the imine, Formula (III) the R2 moiety when it contains a reactive functional group, such as a primary or secondary amine, an alcohol, or thiol compound the group must be suitably protected.
  • Suitable protecting groups may be found in, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981, whose disclosure is inco ⁇ orated herein by reference.
  • R2 is contains as a substituent group a heterocyclic ring, such as a piperidine ring, the nitrogen is protected with groups such as t-Boc, CO2RI8. or a substitued arylalkyl moiety.
  • the reaction is performed at ambient temperature or with cooling (e.g. -50° to 10°) or heating in an inert solvent such as methylene chloride, DMF, tetrahydrofuran, toluene, acetonitrile, or dimethoxyethane in the presence of an appropriate base such as 1,8- diazabicyclo [5.4.0.] undec-7-ene (DBU) or a guanidine base such as 1,5,7-triaza-bicyclo [4.4.0] dec-5-ene (TBD).
  • DBU 1,8- diazabicyclo [5.4.0.] undec-7-ene
  • TBD 1,5,7-triaza-bicyclo [4.4.0] dec-5-ene
  • the intermediates of formula (II) have been found to be very stable and capable of storage for a long time.
  • p is 2.
  • a strong base such as an amine base
  • the commercially available TBD is preferred although t-butoxide, Li+ or Na+, or K+ hexamethyldisilazide may also be used.
  • methylene chloride is the prefered solvent
  • other halogenated solvents such as chloroform or carbon tetrachloride
  • ethers such as THF, DME, DMF, diethylether, t-butyl methyl ether; as well as acetonitrile, toluene or mixtures thereof can be utiltized.
  • the reaction may take place from about -20°C to about; 40°C, preferably from about 0°C to about 23 °C, more preferably from about 0°C to about 10°C, and most preferably about 4°C for reactions involving an Ri group of pyrimidine.
  • Ri is pyridine
  • it is recognized that varying the reations conditions of both temperature and solvent may be necessary, such as decreasing temperatures to about - 50°C or changing the solvent to THF.
  • compounds of Formula (I) may be prepared by coupling a suitable derivative of a compound of Formula (IX):
  • Ti is hydrogen and T4 is R4 , or alternatively Ti is Ri and T4 is H in which Ri, R2 and R4 are as hereinbefore defined; with: (i) when Ti is hydrogen, a suitable derivative of the heteroaryl ring RlH, under ring coupling conditions, to effect coupling of the heteroaryl ring Ri to the imidazole nucleus at position 5; (ii) when T4 is hydrogen, a suitable derivative of the aryl ring R4H, under ring coupling conditions, to effect coupling of the aryl ring R4 to the imidazole nucleus at position 4.
  • an organometallic synthetic equivalent of an anion of one component is coupled with a reactive derivative of the second component, in the presence of a suitable catalyst.
  • the anion equivalent may be formed from either the imidazole of Formula (IX), in which case the aryl/heteroaryl compound provides the reactive derivative, or the aryl/heteroaryl compound in which case the imidazole provides the reactive derivative.
  • suitable derivatives of the compound of Formula (LX) or the aryl/heteroaryl rings include organometallic derivatives such as organomagnesium, organozinc, organostannane and boronic acid derivatives and suitable reactive derivatives include the bromo, iodo, fluorosulfonate and trifluoromethanesulphonate derivatives.
  • organometallic derivatives such as organomagnesium, organozinc, organostannane and boronic acid derivatives
  • suitable reactive derivatives include the bromo, iodo, fluorosulfonate and trifluoromethanesulphonate derivatives.
  • (IX) may be reacted with a halogen, fluorosulfonate or triflate derivative of the heteroaryl or aryl ring, in the presence of a ring coupling catalyst, such as a palladium (O) or palladium
  • Suitable such catalysts include tetr ⁇ /t ⁇ -(triphenylphosphine)palladium and PdCl2[l,4-fci.s-(diphenylphosphino)-butane], optionally in the presence of lithium chloride and a base, such as triethylamine.
  • a nickel (II) catalyst such as Ni(II)Cl2(l,2- biphenylphosphino)ethane, may also be used for coupling an aryl ring, following the procedure of Pridgen et al., J. Org. Chem, 1982, 47, 4319.
  • Suitable reaction solvents include hexamethylphosphor-amide.
  • suitable derivatives include 4-bromo- and 4-iodo-pyridine and the fluorosulfonate and triflate esters of 4-hydroxy pyridine.
  • suitable derivatives for when the aryl ring is phenyl include the bromo, fluorosulfonate, triflate and, preferably, the iodo-derivatives.
  • Suitable organomagnesium and organozinc derivatives may be obtained by treating a compound of Formula (LX) or the bromo derivative thereof with an alkyllithium compound to yield the corresponding lithium reagent by deprotonation or transmetallation, respectively.
  • a trialkyltin derivative of the compound of Formula (IX) may be treated with a bromide, fluorosulfonate, triflate, or, preferably, iodide derivative of an aryl or heteroaryl ring compound, in an inert solvent such as tetrahydrofuran, preferably containing 10% hexamethylphosphoramide, in the presence of a suitable coupling catalyst, such as a palladium (0) catalyst, for instance tetr ⁇ r ⁇ s-(triphenylphosphine)-palladium, by the method described in by Stille, J. Amer.
  • Trialkyltin derivatives may be conveniently obtained by metallation of the corresponding compound of Formula ( C) with a lithiating agent, such as s-butyl-lithium or n-butyllithium, in an ethereal solvent, such as tetrahydrofuran, or treatment of the bromo derivative of the corresponding compound of Formula (IX) with an alkyl lithium, followed, in each case, by treatment with a trialkyltin halide.
  • a lithiating agent such as s-butyl-lithium or n-butyllithium
  • an ethereal solvent such as tetrahydrofuran
  • the bromo- derivative of a compound of Formula (IX) may be treated with a suitable heteroaryl or aryl trialkyl tin compound in the presence of a catalyst such as tetr ⁇ &is-(triphenyl-phosphine)-palladium, under conditions similar to those described above.
  • a catalyst such as tetr ⁇ &is-(triphenyl-phosphine)-palladium
  • a suitable derivative of a compound of Formula (IX), such as the bromo, iodo, triflate or fluorosulphonate derivative may be reacted with a heteroaryl- or aryl-boronic acid, in the presence of a palladium catalyst such as tetr ⁇ /c ⁇ -(triphenylphosphine)-palladium or PdCl2[l,4-b s-(diphenyl-phosphino)-butane] in the presence of a base such as sodium bicarbonate, under reflux conditions, in a solvent such as dimethoxyethane (see Fischer and Haviniga, Rec. Trav. Chim.
  • Non-aqueous conditions for instance, a solvent such as DMF, at a temperature of about 100°C, in the presence of a Pd(II) catalyst may also be employed (see Thompson W J et al, J Org Chem, 49, 5237, 1984).
  • Suitable boronic acid derivatives may be prepared by treating the magnesium or lithium derivative with a trialkylborate ester, such as triethyl, tri-wo-propyl or tributylborate, according to standard procedures.
  • an inert solvent such as a halogenated hydrocarbon solvent, for instance chloroform
  • Suitable reactive esters include esters of strong organic acids such as a lower alkane sulphonic or aryl sulphonic acid, for instance, methane or p-toluene sulphonic acid.
  • the amidine is preferably used as the salt, suitably the hydrochloride salt, which may then be converted into the free amidine in situ , by employing a two phase system in which the reactive ester is in an inert organic solvent such as chloroform, and the salt is in an aqueous phase to which a solution of an aqueous base is slowly added, in dimolar amount, with vigorous stirring.
  • Suitable amidines may be obtained by standard methods, see for instance, Garigipati R, Tetrahedron Letters, 190, 31, 1989.
  • Compounds of Formula (I) may also be prepared by a process which comprises reacting a compound of Formula (IX), wherein Ti is hydrogen, with an N-acyl heteroaryl salt, according to the method disclosed in US patent 4,803,279; US patent 4,719,218 and US patent 5,002,942, to give an intermediate in which the heteroaryl ring is attached to the imidazole nucleus and is present as a 1,4-dihydro derivative thereof, which intermediate may then be subjected to oxidative-deacylation conditions (Scheme II).
  • the heteroaryl salt for instance a pyridinium salt, may be either preformed or, more preferably, prepared in situ by adding a substituted carbonyl halide (such as an acyl halide, an aroyl halide, an arylalkyl haloformate ester, or, preferably, an alkyl haloformate ester, such as acetyl bromide, benzoylchloride, benzyl chloroformate, or, preferably, ethyl chloroformate) to a solution of the compound of Formula (IX) in the heteroaryl compound RiH or in an inert solvent such as methylene chloride to which the heteroaryl compound has been added.
  • a substituted carbonyl halide such as an acyl halide, an aroyl halide, an arylalkyl haloformate ester, or, preferably, an alkyl haloformate ester, such as acetyl bro
  • Suitable deacylating and oxidising conditions are described in U.S. Patent Nos. 4,803,279, 4,719,218 and 5,002,942, which references are hereby inco ⁇ orated by reference in their entirety.
  • Suitable oxidizing systems include sulfur in an inert solvent or solvent mixture, such as decalin, decalin and diglyme, p-cymene, xylene or mesitylene, under reflux conditions, or, preferably, potassium t-butoxide in t-butanol with dry air or oxygen. S decalm. ⁇ or K -butoxide/a.r
  • compounds of Formula (I) may be prepared by treating a compound of Formula (X) thermally or with the aid of a cyclising agent such as phosphorus oxychloride or phosphorus pentachloride (see Engel and Steglich, Liebigs Ann Chem, 1978, 1916 and Strzybny et al., J Org Chem, 1963, 28, 3381).
  • a cyclising agent such as phosphorus oxychloride or phosphorus pentachloride
  • Compounds of Formula (X) may be obtained, for instance, by acylating the corresponding ⁇ -keto-amine with an activated formate derivative such as the corresponding anhydride, under standard acylating conditions followed by formation of the imine with R 2 NH 2 .
  • the aminoketone may be derived from the parent ketone by oxamination and reduction and the requisite ketone may in turn be prepared by decarboxylation of the beta-ketoester obtained from the condensation of an aryl (heteroaryl) acetic ester with the RjCOX component.
  • a heterocyclic ketone (XI) is prepared by 0 adding the anion of the alkyl heterocycle such as 4-methyl-quinoline (prepared by treatment thereof with an alkyl lithium, such as n-butyl lithium) to an N-alkyl-O-alkoxybenzamide, ester, or any other suitably activated derivative of the same oxidation state.
  • the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone (XI). 5
  • N-substituted compounds of Formula (I) may be prepared by treating the anion of an amide of Formula (XII):
  • the amide may be prepared as illustrated in scheme V by alkyiation of the formamide with R1CH2X. Deprotonation of this amide with a strong amide base, such as lithium di-wo-propyl amide or sodium b/s-(trimethylsilyl)amide, followed by addition of an excess of an aroyl chloride yields the bis-acylated compound which is then closed to an imidazole compound of Formula (I), by heating in acetic acid containing ammonium acetate. Alternatively, the anion of the amide may be reacted with a substituted aryl nitrile to produce the imidazole of Formula (I) directly.
  • a strong amide base such as lithium di-wo-propyl amide or sodium b/s-(trimethylsilyl)amide
  • reaction employs heating the 2-amino pyrimidine dialkoxy acetal with acetic anhydride in the presence of a catalytic amount of concentrated sulfuric acid, which simultaneously acetylates the amine and leads to the exchange of one of the alkoxy groups for an acetoxy group.
  • the resultant compound is converted to the aldehyde by deacetylation with a catalytic amount of an alkoxide salt and the corresponding alcohol solvent, e.g. Na+ methoxide and methanol.
  • alcohol solvent e.g. Na+ methoxide and methanol.
  • higher yields can be obtained by first acetylating the amine with acetic anhydride and then affecting exchange by subsequent addition of concentrated sulfuric acid.
  • tertiary and aromatic amines such as pyridine, and triethylamine gave no reaction under certain test conditions, but more basic types such as DBU, and 4-dimethylamino pyridine (DMAP) while slow, did produce some yields and hence may be suitable for use herein.
  • the pyrimidine aldehydes of Scheme VI can be condensed with a primary amine, to generate an imine, which may suitably be isolated or reacted in situ, with the desired isonitrile in the presence of a variety of suitable bases, and solvents as described herein to afford the 5-(4-pyrimidinyl)-imidazoles, wherein R2 and R4 are as defined herein for Formula (I) compounds.
  • Suitable bases include an amine, a carbonate, a hydride, or an alkyl or aryl lithium reagent; or mixtures thereof.
  • Bases include, but are not limited to, potassium carbonate, sodium carbonate, primary and secondary amines, such as t-butylamine, diisopropyl amine, mo ⁇ holine, piperidine, pyrrolidine, and other non-nucleophilic bases, such as DBU, DMAP and 1,4- diazabicyclo[2.2.2]octane (DABCO).
  • Suitable solvents for use herein include but are not limited to N,N-dimethyl- formamide (DMF), MeCN, halogenated solvents, such as methylene chloride or chloroform, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols, such as methanol or ethanol, benzene, toluene, DME or EtOAc.
  • the solvent is DMF, DME, THF, or MeCN, more preferably DMF.
  • Product isolation may generally be accomplished by adding water and filtering the product as a clean compound. The mixture is non-nucleophilic, thus no isonitrile decomposition occurs.
  • the yields may drop to about 20% but little difference is expected between 0°C and 25°C. Consequently, temperature ranges below 0 °C, and above 80 °C are contemplated as also being within the scope of this invention. Preferably, the temperature ranges are from about 0°C to about 25°C. For pu ⁇ oses herein, room tempature, which is depicted as 25°C, but it is recognized that this may vary from 20°C to 30°C.
  • the imine is preferably formed in situ in a solvent.
  • This preferred synthesis is a process which occurs as a one-pot synthesis.
  • the reaction may further include a base, such as potassium carbonate prior to the addition of the isonitrile.
  • the piperidine nitrogen may be required to be protected as shown below.
  • Reaction conditions such as solvents, bases, temperatures, etc. are similar to those illustrated and discussed above for the isolated imine as shown in Scheme VIII.
  • the in situ formation of the imine may require dehydrating conditions, or may require acid catalysis.
  • the preferred method of synthesis for compounds of Formula (I) also provides for a suitable and reliable method for introduction of an S(O)malkyl moiety on the pyrimidine (Rl group) by using, for instance, the 2-methylthio pyrimidine aldehyde derivative, as is also described in the Examples section.
  • Another embodiment of the present invention is the novel hydrolysis of 2- thiomethylpyrimidine acetal to 2-thiomethylpyrimidine aldehyde, as shown in Scheme X below.
  • the preferred synthesis involves the use of AcOH (fresh) as solvent and concentrated H2SO4 under heating conditions, preferably a catalytic amount of sulfuric acid. Heating conditions include temperatures from about 60 to 85°C, preferably from about 70° to about 80°C as higher temperatures show a darkening of the reaction mixture. After the reaction is completed the mixture is cooled to about room temperature and the acetic acid is removed.
  • An alternative procedure to this involves heating the acetal in 3N HCL at 40°C for about 18 hours, cooling and extracting the bicarbonate neutralized solution into EtOAc.
  • the final 2-aminopyrimidin-4-yl imidazole compounds of Formula (I), as well as similar pyridine containing compounds can be prepared by one of three methods: 1) direct reaction of the 2-aminopyrimidine imine with the isonitrile; 2) condensation of the 2- acetamidopyrimidine imine with the isonitrile followed by removal of the acetamido group and 3) oxidation of the 2-methylthiopyrimidine derivative to the corresponding sulfoxide followed by displacement with the desired amine.
  • any suitable R2 moiety or R4 moiety may be added in this manner if it can be prepared on the primary amine.
  • any suitable R4 can be added via the isonitrile route.
  • a compound of the Formula (II) may be prepared by dehydrating a compound of the Formula (IV)-Scheme I, wherein Ar, R4 and p are as defined herein.
  • Suitable dehydrating agents include phosphorus oxychloride, oxalyl chloride, thionyl chloride, phosgene, or tosyl chloride in the presence of a suitable base such as triethylamine or dusopropylethylamine, or similar bases, etc. such as pyridine.
  • suitable base such as triethylamine or dusopropylethylamine, or similar bases, etc. such as pyridine.
  • Suitable solvents are dimethoxy ether, tetrahydrofuran, or halogenated solvents, preferably THF. The reaction is most efficent when the reaction temperatures are kept between -10°C and 0°C.
  • the compounds of formula (IV)-Scheme I may be prepared by reacting a compound of the formula (V)-Scheme I, R4CHO where R4 is as defined herein, with ArS(0)pH and formamide with or without water removal, preferably under dehydrating conditions, at ambient or elevated temperature e.g. 30° to 150°, conveniently at reflux, optionally in the presence of an acid catalyst.
  • an acid catalyst Alternatively trimethysilylchloride can be used in place of the acid catalyst.
  • acid catalysts include camphor- 10-sulphonic acid, formic acid, p-toluenesulphonic acid, hydrogen chloride or sulphuric acid.
  • the conversion of the substituted aldehyde to the tosylbenzyl formamide may be accomplished by heating the aldehyde, 1 -Scheme XI, with an acid, such as p-toluene- sulfonic acid, formic acid or camphorsulfonic acid; with formamide and p-toluene-sulfinic acid [under reaction conditions of about 60°C for about 24 hours].
  • an acid such as p-toluene- sulfonic acid, formic acid or camphorsulfonic acid
  • formamide and p-toluene-sulfinic acid under reaction conditions of about 60°C for about 24 hours.
  • no solvent is used.
  • the reaction may give poor yields ( ⁇ 30%) when solvents, such as DMF, DMSO, toluene, acetonitrile, or excess formamide are used.
  • Another embodiment of the present invention is the synthesis of the tosyl benzyl formamide compound, achieved by reacting the bisformamide intermediate, 2-Scheme XI, with p-toluenesulfinic acid.
  • preparation of the bis-formamide from the aldehyde is accomplished by heating the aldehyde with formamide, in a suitable solvent with acid catalysis. Suitable solvents are toluene, acetonitrile, DMF, and DMSO or mixtures thereof.
  • Acid catalysts are those well known in the art, and include but are not limited to hydrogen chloride, p-toluenesulfonic acid, camphorsulfonic acid, and other anhydrous acids.
  • the reaction can be conducted at temperatures ranging from about 25°C to 110°C, preferably about 50°C, suitably for about 4 to about 5 hours, longer reaction times are also acceptable. Product decomposition and lower yields may be observed at higher temperatures (>70°C) at prolonged reactions times. Complete conversion of the product generally requires water removal from the reaction mixture.
  • Preferred conditions for converting a bis-formamide derivative to the tosyl benzyl formamide are accomplished by heating the bisformamide in a suitable solvent with an acid catalyst and p-toluenesulfinic acid.
  • Solvents for use in this reaction include but are not limited to toluene, and acetonitrile or mixtures thereof. Additional mixtures of these solvents with DMF, or DMSO may also be used but may result in lower yields.
  • Temperatures may range from about 30°C to about 100°C. Temperatures lower than 40°C and higher than 60°C are not preferred as the yield and rate decreases. Preferably the range is from about 40 to 60°C, most preferably about 50°C.
  • acids used include but are not limited to, toluenesulfonic acid, camphorsulfonic acid, and hydrogen chloride and other anhydrous acids.
  • the bisformamide is heated in toluene: acetonitrile in a 1: 1 ratio, with p-toluenesulfinic acid and hydrogen chloride.
  • Another embodiment of the present invention is the preferred synthetic route for synthesis of the tosylbenzyl formamide compound which is accomplished using a one-pot procedure. This process first converts the aldehyde to the bis-formamide derivative and subsequently reacts the bis-formamide derivative with toluenesulfinic acid.
  • reaction conditions employ a catalyst, such as trimethylsilyl chloride (TMSC1), in a preferred solvent, toluene:acetonitrile, preferably in a 1 : 1 ratio.
  • TMSC1 trimethylsilyl chloride
  • a reagent, such as TMSC1 is preferred which reacts with water produced therein and at the same time produces hydrogen chloride to catalyze the reaction.
  • TMSC1 trimethylsilyl chloride
  • three suitable reaction conditions for use herein include 1 ) use of a dehydrating agent which also provides hydrogen chloride, such as TMSC1; or by 2) use of a suitable dehydrating agent and a suitable source of acid source, such as but not limited to, camphorsulfonic acid, hydrogen chloride or toluenesulfonic acid; and 3) alternative dehydrating conditions, such as the azeotropic removal of water, and using an acid catalyst and p-toluene sulfinic acid.
  • a dehydrating agent which also provides hydrogen chloride, such as TMSC1
  • a suitable dehydrating agent and a suitable source of acid source such as but not limited to, camphorsulfonic acid, hydrogen chloride or toluenesulfonic acid
  • alternative dehydrating conditions such as the azeotropic removal of water, and using an acid catalyst and p-toluene sulfinic acid.
  • Compounds of the formula (II) where p is 2 may also be prepared by reacting in the presence of a strong base a compound of the formula (VI) -Scheme I, R4CH2NC with a compound of the formula (V ⁇ )-Scheme I, ArSO2Li wherein R4 and Ar are as defined herein and Li is a leaving group such as halo, e.g. fluoro.
  • Suitable strong bases include, but are not limited to, alkyl lithiums such as butyl lithium or lithium diisopropylamide (van
  • the compounds of formula (V ⁇ )-Scheme I may be prepared by reacting a compound of the formula (VILI)-Scheme I, R4CH2NH2 with an alkyl formate (e.g. ethylformate) to yield an intermediate amide which can be converted to the desired isonitrile by reacting with well known dehydrating agent, such as but not limited to oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.
  • an alkyl formate e.g. ethylformate
  • dehydrating agent such as but not limited to oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.
  • a compound of the formula (VIII) - Scheme I may be converted to a compound of the formula (VI)- Scheme I by reaction with chloroform and sodium hydroxide in aqueous dichloromethane under phase transfer catalysis.
  • the compounds of the formula (III) - Scheme I may be prepared by reacting a compound of the formula R CHO with a primary amine R2NH2.
  • amino compounds of the formula (VIII) - Scheme I are known or can be prepared from the corresponding alcohols, oximes or amides using standard functional group interconversions.
  • Cycloalkanones such as 1 -Scheme XII may be converted to cycloalkylamines such as 2-Scheme XII by conventional procedures for reductive amination such as oxime formation with hydroxylamine in H 2 O followed by reduction of the oxime to the amine by standard conditions such as catalytic hydrogenation with Raney Ni in an H 2 atmosphere.
  • the resulting cycloalkylamines such as 2-Scheme XII may be reacted with aryl aldehydes such as 2-aminopyrimidinyl-4-carboxaldhyde in non-hydroxylic organic solvents to form imines such as 3-Scheme XII.
  • catalytic acid such as toluenesulfonic acid
  • dehydrating conditions such as azeotropic removal of water in refluxing benzene
  • Imines such as 3-Scheme XII may be converted to 1 ,4 diaryl imidazoles alkylated with cycloalkyl groups by reaction with isonitriles such as 4-fluorophenyl- tolylthiomethylisocyanide in the presence of a base such as l,5,7-triazabicyclo[4.4.0]-dec-5- ene (TBD) in organic solvents such as CH 2 C1 .
  • the alcohol 10-Scheme XIII may be prepared by reducing the ketone of 6-Scheme 13 with a suitable reducing agent, such as NaBH4.
  • R] is may be an optionally substituted alkyl, aryl or a heteroaryl group and R2 is either an OH, NH2 or SH, or R* and R2 together can form a C3-7 cycloalkyl ring, such as, for example a pyrrolidine or piperdine ring.
  • ketone 1 can be reacted with any organomettalic reagent (RiM) to afford the corresponding alcohol 2 (wherein R ⁇ can be hydrogen or any optionally susbtituted alkyl aryl, arylalkyl, heteocyclic, heterocyclic alkyl, etc. moiety).
  • R ⁇ can be hydrogen or any optionally susbtituted alkyl aryl, arylalkyl, heteocyclic, heterocyclic alkyl, etc. moiety.
  • the alcohol 2 can be converted to the neopentyl amine 3, by using the classical Ritter reaction well known by those of skill in th art.
  • the amine 3 can be acylated or sulfonylated.
  • the ketone 1 can be can be transformed into an spirooxirane 4 by reagents such as dimethylsulfonium methylide and dimethyl sulfoxonium methylide.
  • reagents such as dimethylsulfonium methylide and dimethyl sulfoxonium methylide.
  • the oxirane 4 can be ring opened with a plethora of nucleophiles such as hydroxides, thiolates, amines, organometallic reagents (such as the well known organo-cuprate or organo-aluminum reagents, etc.).
  • the ketone 1 -Scheme XVII may also be subjected to reductive amination by any primary or secondary amines to afford amines 6-Scheme XVIII.
  • RT and R 2 can be any alkyl or aryl group.Ri and R 2 can also be a part of a ring
  • Suitable protecting groups for use with hydroxyl groups and the imidazole nitrogen are well known in the art and described in many references, for instance. Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981. Suitable examples of hydroxyl protecting groups include silyl ethers, such as t-butyldimethyl or t- butyldiphenyl, and alkyl ethers, such as methyl connected by an alkyl chain of variable link, (CR ⁇ oR20)n- Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.
  • compositions of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal's cell, such as but not limited to monocytes and/or macrophages.
  • Compounds of Formula (I) are capable of inhibiting proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use in therapy.
  • IL-1, IL-6, IL-8 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions.
  • the inhibition of these pro-inflammatory cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
  • Compounds of Formula (I) are capable of inhibiting inducible proinflammatory proteins, such as COX-2, also referred to by many other names such as prostaglandin endoperoxide synthase-2 (PGHS-2) and are therefore of use in therapy.
  • COX-2 also referred to by many other names
  • PGHS-2 prostaglandin endoperoxide synthase-2
  • These proinflammatory lipid mediators of the cyclooxygenase (CO) pathway are produced by the inducible COX-2 enzyme.
  • Regulation, therefore of COX-2 which is responsible for the these products derived from arachidonic acid, such as prostaglandins affect a wide variety of cells and tissues are important and critical inflammatory mediators of a wide variety of disease states and conditions. Expression of COX-1 is not effected by compounds of Formula (I).
  • This selective inhibition of COX-2 may alleviate or spare ulcerogenic liability associated with inhibition of COX- 1 thereby inhibiting prostoglandins essential for cytoprotective effects.
  • inhibition of these pro-inflammatory mediators is of benefit in controlling, reducing and alleviating many of these disease states.
  • Most notably these inflammatory mediators, in particular prostaglandins, have been implicated in pain, such as in the sensitization of pain receptors, or edema. This aspect of pain management therefore includes treatment of neuromuscular pain, headache, cancer pain, and arthritis pain.
  • Compounds of Formula (I) or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.
  • the present invention provides a method of inhibiting the synthesis of COX-2 which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides for a method of prophylaxis treatment in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.
  • the present invention provides a method of treating a cytokine- mediated disease which comprises administering an effective cytokine-interfering amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive or unregulated LL-1, EL-8 or TNF production by such mammal's cell, such as, but not limited to, monocytes and/or macrophages.
  • this invention relates to a method of inhibiting the production of IL- 1 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • LL- 1 production is implicated in exacerbating and/or causing the disease.
  • diseases states include rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL-1 activity to diabetes, pancreatic ⁇ cells and Alzheimer's disease.
  • this invention relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs.
  • allograft rejections fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.
  • AIDS cachexia secondary to infection or malignancy
  • AIDS cachexia secondary to acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • viruses of Formula (I) are also useful in the treatment of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • the viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibiting-compounds of Formula (1).
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the He ⁇ es group of viruses, such as but not limited to, He ⁇ es Zoster and He ⁇ es Simplex.
  • this invention relates to a method of treating a mammal afflicted with a human immunodeficiency virus (HLV) which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • HBV human immunodeficiency virus
  • Compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than in humans, in need of inhibition of TNF production.
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
  • lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
  • the compounds of Formula (I) may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive cytokine production, such as by LL-1 or TNF respectively, such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
  • Compounds of Formula (I) have also been shown to inhibit the production of LL-8 (Interleukin-8, NAP).
  • this invention relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • LL-8 LL-8 production is implicated in exacerbating and/or causing the disease.
  • diseases are characterized by massive neutrophil infiltration such as, psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with increased LL-8 production which is responsible for the chemotaxis of neutrophils into the inflammatory site.
  • IL-8 In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the unique property of promoting neutrophil chemotaxis and activation. Therefore, the inhibition of IL-8 production would lead to a direct reduction in the neutrophil infiltration.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF, production such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state.
  • cytokine in particular IL-1, IL-6, IL-8 or TNF
  • Abnormal levels of IL-1, IL-6, LL-8 or TNF for instance in the context of the present invention, constitute: (i) levels of free (not cell bound) LL-1, LL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1, IL-6, LL-8 or TNF; or (iii) the presence of LL-1, LL-6, LL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1, LL-6, LL-8 or TNF, respectively, is produced.
  • the compounds of Formula (I) are inhibitors of cytokines, specifically LL-1, LL-6, LL-8 and TNF is based upon the effects of the compounds of Formulas (I) on the production of the IL-1, IL-8 and TNF in in vitro assays which are described herein.
  • the term "inhibiting the production of IL-1 (IL-6, IL-8 or TNF)” refers to: a) a decrease of excessive in vivo levels of the cytokine (IL- 1 , IL-6, LL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels; c) a down regulation, by inhibition of the direct synthesis of the cytokine (LL-1, LL-6, LL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (LL-1, LL-6, LL-8 or TNF)
  • TNF mediated disease or disease state refers to any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another monokine to be released, such as but not limited to LL-1, LL-6 or LL-8.
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
  • monokines such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B-lymphocytes.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin- 1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • cytokine interfering or "cytokine suppressive amount” refers to an effective amount of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
  • the cytokine referred to in the phrase "inhibition of a cytokine, for use in the treatment of a HIV-infected human” is a cytokine which is implicated in (a) the initiation and or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and or replication and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ and TNF- ⁇ are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF” unless specifically delineated otherwise.
  • a new member of the MAP kinase family alternatively termed CSBP, p38, or RK, has been identified independently by several laboratories recently. Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin- 1 and tumor necrosis factor.
  • the cytokine biosynthesis inhibitors have been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors are of aid in determining the signalling pathways involvement in inflammatory responses. In particular, for the first time a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages.
  • the cytokine inhibitors were subsequently tested in a number of animal models for anti-inflammatory activity. Model systems were chosen that were relatively insensitive to cyclooxygenase inhibitors in order to reveal the unique activities of cytokine suppressive agents. The inhibitors exhibited significant activity in many such in vivo studies.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy it will normally be Formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.
  • This invention also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
  • Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions inco ⁇ orating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the Formulation and not deleterious to the recipient thereof.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • a wide variety of pharmaceutical forms can be employed.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • Compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the Formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid
  • Formulations of the active ingredient for external application may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the Formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100° C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration, such as an aerosol Formulation or a metered dose inhaler may be prepared by conventional techniques.
  • the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg kg, more preferably from about 0.5 mg to 15mg.
  • the daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg kg, and more preferably from about 0.5 mg to 15mg/kg.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • IL-1 Interleukin - 1
  • Human peripheral blood monocytes are isolated and purified from either fresh blood preparations from volunteer donors, or from blood bank buffy coats, according to the procedure of Colotta et al, J Immunol, 132, 936 (1984). These monocytes (lxlo are plated in 24-well plates at a concentration of 1-2 million ml per well. The cells are allowed to adhere for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds are then added to the cells for about 1 hour before the addition of lipopolysaccharide (50 ng/ml), and the cultures are incubated at 37°C for an additional 24 hours. At the end of this period, culture supernatants are removed and clarified of cells and all debris.
  • Culture supernatants are then immediately assayed for IL-1 biological activity, either by the method of Simon et al., J. Immunol. Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate a Interleukin 2 producing cell line (EL-4) to secrete IL-2, in concert with A23187 ionophore) or the method of Lee et al. , J. ImmunoTherapy, 6 ( 1 ), 1 - 12 ( 1990) (ELISA assay).
  • TNF Tumour Necrosis Factor
  • Human peripheral blood monocytes are isolated and purified from either blood bank buffy coats or plateletpheresis residues, according to the procedure of Colotta, R. et al, J Immunol, 132(2), 936 (1984).
  • the monocytes are plated at a density of lxlO 6 cells/ml medium well in 24-well multi-dishes. The cells are allowed to adhere for 1 hour after which time the supernatant is aspirated and fresh medium (1ml, RPMI- 1640, Whitaker
  • IL-1 and TNF inhibitory activity does not seem to correlate with the property of the compounds of Formula (I) in mediating arachidonic acid metabolism inhibition. Further the ability to inhibit production of prostaglandin and/or leukotriene synthesis, by nonsteroidal anti-inflammatory drugs with potent cyclooxygenase and/or lipoxygenase inhibitory activity does not mean that the compound will necessarily also inhibit TNF or LL- 1 production, at non-toxic doses.
  • Interleukin -8 (IL-8 ):
  • HUV ⁇ C Primary human umbilical cord endothelial cells
  • CELL Systems Cell Systems, Kirland, Wa
  • CS-HBGF aFGF and heparin.
  • the cells are then diluted 20-fold before being plated (250 ⁇ l) into gelating coated 96-well plates. Prior to use, culture medium are replaced with fresh medium (200 ⁇ l).
  • Buffer or test compound (25 ⁇ l, at concentrations between 1 and lO ⁇ M) is then added to each well in quadruplicate wells and the plates incubated for 6h in a humidified incubator at 37°C in an atmosphere of 5% CO2- At the end of the incubation period, supernatant is removed and assayed for IL-8 concentration using an IL-8 ELISA kit obtained from R&D Systems (Minneapolis, MN). All data is presented as mean value (ng/ml) of multiple samples based on the standard curve. ICso's where appropriate are generated by non-linear regression analysis.
  • a radiocompetitive binding assay was developed to provide a highly reproducible primary screen for structure-activity studies. This assay provides many advantages over the conventional bioassays which utilize freshly isolated human monocytes as a source of cytokines and ELISA assays to quantify them. Besides being a much more facile assay, the binding assay has been extensively validated to highly correlate with the results of the bioassay.
  • a specific and reproducible cytokine inhibitor binding assay was developed using soluble cystosolic fraction from THP.1 cells and a radiolabeled compound.
  • CSBP cytokine specific binding protein
  • the binding protein may be in isolated form in solution, or in immobilized form, or may be genetically engineered to be expressed on the surface of recombinant host cells such as in phage display system or as fusion proteins.
  • CSBP KINASE ASSAY CSBP KINASE ASSAY
  • This assay measures the CSBP-catalyzed transfer of 32p f r ⁇ m [a-32p]ATP to threonine residue in an epidermal growth factor receptor (EGFR)-derived peptide (T669) with the following sequence: KRELVEPL7PSGEAPNQALLR (residues 661-681).
  • EGFR epidermal growth factor receptor
  • KRELVEPL7PSGEAPNQALLR residues 661-681.
  • Kinase reactions (total volume 30 ul) contain: 25 mM Hepes buffer, pH 7.5; 10 mM MgCl2; 170 uM ATPO); 10 uM Na ortho vanadate; 0.4 mM T669 peptide; and 20-80 ng of yeast-expressed purified CSBP2 (see Lee et al., Nature 300, n(72),
  • 32P/MgATP Reactions are incubated at 30 °C for 10 min and stopped by adding 10 ul of 0.3 M phosphoric acid.
  • 32P-labeled peptide is separated on phosphocellulose (Wattman, p81) filters by spotting 30 ul reaction mixture. Filters are washed 3 times with 75 mM phosphoric acid followed by 2 washes with H2O, and counted for 32P.
  • the Km of CSBP for ATP was determined to be 170 uM. Therefore, compounds screened at the Km value of ATP.
  • the following assay describes a method for determining the inhibitory effects of compounds of Formula (I) on human PGHS-2 protein expression in LPS stimulated human monocytes.
  • Human peripheral blood monocytes were isolated from buffy coats by centrifugation through Ficoll and Percoll gradients. Cells were seeded at 2 X 10 ⁇ /well in 24 well plates and allowed to adhere for 1 hour in RPMI supplemented with 1 % human AB serum, 20mM L-glutamine, Penicillin-Streptomycin and lOmM HEPES. Compounds were added at various concentrations and incubated at 37°C for 10 minutes. LPS was added at 50 ng/well (to induce enzyme expression) and incubated overnight at 37°C. The supernatant was removed and cells washed once in cold PBS.
  • the cells were lysed in lOO ⁇ l of cold lysis buffer(50mM Tris/HCl pH 7.5, 150mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300ug/ml DNAse, 0.1% TRITON X-100, ImM PMSF, ImM leupeptin, ImM pepstatin).
  • the lysate was centrifuged ( 10,000 X g for 10 min. at 4°C) to remove debris and the soluble fraction was subjected to SDS PAGE, analysis (12% gel). Protein separated on the gel were transferred onto nitrocellulose membrane by electrophoretic means for 2 hours at 60 volts.
  • the membrane was pretreated for one hour in PBS/0.1% Tween 20 with 5% non-fat dry milk. After washing 3 times in PBS/Tween buffer, the membrane was incubated with a 1:2000 dilution of a monospecific antiserum to PGHS-2 or a 1 : 1000 dilution of an antiserum to PGHs- 1 in PBS/Tween with 1 % BS A for one hour with continuous shaking. The membrane was washed 3X in PBS Tween and then incubated with a 1:3000 dilution of horseradish peroxidase conjugated donkey antiserum to rabbit Ig (Amersham) in PBS Tween with 1% BSA for one hour with continuous shaking. The membrane was then washed 3X in PBS Tween and the ECL immunodetection system (Amersham) was used to detect the level of expression of prostaglandin endoperoxide synthases-2.
  • Example 3 1-f4-OxocvclohexylV4-(4-fluorophenyiy5-r(2-isopropoxy pyrimidin-4-yl] imidazole a) 1 -(4-Ethylene ketal cyclohexylV4-(4-fluorophenyl>5-r(2-isopropoxy pyrimidin-4- yllimidazole A mixture of sodium metal (0.161 g, .7 mmol) and isopropanol (30 mL) was stirred with gentle heat until the sodium metal dissolved.
  • Example 8 l-(4-HydroxycyclohexylV4-(4-fluorophenylV5-f(2-isopropoxy pyrimidin-4-yllimidazole Following the procedure of example 2 except using the compound in example 3(b) afforded the title compound. mp 208 - 2H°C.

Abstract

L'invention concerne de nouveaux composés imidazoles 1,4,5-substitués ainsi que des compositions destinées à être utilisées en thérapie.
PCT/US1997/000614 1996-01-11 1997-01-10 Nouveaux imidazoles cycloalkyle-substitues WO1997025047A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97904766A EP0883402A4 (fr) 1996-01-11 1997-01-10 Nouveaux imidazoles cycloalkyle-substitues
US09/101,525 US5929076A (en) 1997-01-10 1997-01-10 Cycloalkyl substituted imidazoles
JP52546597A JP2001508395A (ja) 1996-01-11 1997-01-10 新規シクロアルキル置換イミダゾール

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1018996P 1996-01-11 1996-01-11
US60/010,189 1996-01-11

Publications (1)

Publication Number Publication Date
WO1997025047A1 true WO1997025047A1 (fr) 1997-07-17

Family

ID=21744400

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/000614 WO1997025047A1 (fr) 1996-01-11 1997-01-10 Nouveaux imidazoles cycloalkyle-substitues

Country Status (3)

Country Link
EP (1) EP0883402A4 (fr)
JP (1) JP2001508395A (fr)
WO (1) WO1997025047A1 (fr)

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5864036A (en) * 1996-01-11 1999-01-26 Smithkline Beecham Corporation Substituted imidazole compounds
US5929076A (en) * 1997-01-10 1999-07-27 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
US6096739A (en) * 1996-03-25 2000-08-01 Smithkline Beecham Corporation Treatment for CNS injuries
US6100399A (en) * 1995-12-22 2000-08-08 Smithkline Beecham Corporation Synthesis for 4-aryl-5-pyrimidine imidazole substituted compounds
US6239279B1 (en) 1998-12-16 2001-05-29 Smithkline Beecham Corporation Synthesis for 4-aryl-5-pyrimidine imidazole substituted derivatives
US6251914B1 (en) 1997-07-02 2001-06-26 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
US6268370B1 (en) 1992-01-13 2001-07-31 Smithkline Beecham Corporation Compounds
JP2001519328A (ja) * 1997-10-07 2001-10-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｈｃｍｖ感染症治療のためのアゼチジノン誘導体
US6329526B1 (en) 1996-01-11 2001-12-11 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
US6414150B1 (en) 1996-08-21 2002-07-02 Smithkline Beecham Corporation 4,5-disubstituted imidazole compounds
US6489325B1 (en) 1998-07-01 2002-12-03 Smithkline Beecham Corporation Substituted imidazole compounds
US6503930B1 (en) 1997-05-22 2003-01-07 G.D. Searle & Company Pyrazole derivatives as p38 kinase inhibitors
US6512121B2 (en) 1998-09-14 2003-01-28 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6548520B1 (en) 1998-05-22 2003-04-15 Smithkline Beecham Corporation Substituted imidazoles having anti-cancer and cytokine inhibitory activity
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US6562832B1 (en) 1997-07-02 2003-05-13 Smithkline Beecham Corporation Substituted imidazole compounds
US6569871B1 (en) 1997-07-02 2003-05-27 Smithkline Beecham Corporation Substituted imidazole compounds
US6599910B1 (en) 1998-08-20 2003-07-29 Smithkline Beecham Corporation Substituted triazole compounds
US6610695B1 (en) 1997-06-19 2003-08-26 Smithkline Beecham Corporation Aryloxy substituted pyrimidine imidazole compounds
WO2003084539A2 (fr) * 2002-04-10 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions pharmaceutiques a base d'anticholinergiques et d'inhibiteurs de la kinase p38
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US6730683B2 (en) 1997-12-19 2004-05-04 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
US6759410B1 (en) 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
US6774127B2 (en) 1997-06-13 2004-08-10 Smithkline Beecham Corporation Pyrazole and pyrazoline substituted compounds
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
US6930101B1 (en) 1999-05-17 2005-08-16 The Regents Of The University Of California Thiazolopyrimidines useful as TNFα inhibitors
US6979686B1 (en) 2001-12-07 2005-12-27 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
US6982270B1 (en) 1999-11-23 2006-01-03 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US7053098B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-Dihydro-(1H) quinazolin-2-one compounds as CSBP/P38 kinase inhibitors
EP1707205A2 (fr) 2002-07-09 2006-10-04 Boehringer Ingelheim Pharma GmbH & Co. KG Compositions pharmaceutiques contenant un antichlinergique et un inhibiteur du p38 pour le traitement de maladies respiratoires
WO2007009146A1 (fr) * 2005-07-22 2007-01-25 Universität Wien 1-phenyle-imidazoles substitues en tant qu'inhibiteurs de cox-i
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
EP2116245A2 (fr) 2004-08-07 2009-11-11 Boehringer Ingelheim International GmbH combinaisons d'inhibiteurs de la kinase EGFR pour le traitement de désordres respiratoires et de l'appareil digestif
EP2384751A1 (fr) 2004-12-24 2011-11-09 Boehringer Ingelheim International Gmbh Médicaments pour le traitement ou la prévention des maladies fibrogènes
US20120245188A1 (en) * 2010-11-15 2012-09-27 Translational Genomics Research Institute Methods of treating memory loss and enhancing memory performance
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL110296A (en) * 1993-07-16 1999-12-31 Smithkline Beecham Corp Imidazole compounds process for their preparation and pharmaceutical compositions containing them
EP0802908A4 (fr) * 1995-01-12 2001-04-11 Smithkline Beecham Corp Nouveaux composes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPIDS ON STN, Derwent Information Ltd. (Columbus, Ohio, USA), AN 96-342044, ADAMS et al., "New 1,4,5-Tri Substituted Imidazola Derivs. - Used for Treating Cytokine - Mediated Disorders, e.g. Inflammation, Asthma, Arthritis, Sepsis or Stroke"; & WO,A,96 21452 (SMITHKLINE BEECHAM CORP), 18 July 1996. *
See also references of EP0883402A4 *

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6268370B1 (en) 1992-01-13 2001-07-31 Smithkline Beecham Corporation Compounds
US6875785B2 (en) 1995-06-02 2005-04-05 Pharmacia Corporation Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6100399A (en) * 1995-12-22 2000-08-08 Smithkline Beecham Corporation Synthesis for 4-aryl-5-pyrimidine imidazole substituted compounds
US5977103A (en) * 1996-01-11 1999-11-02 Smithkline Beecham Corporation Substituted imidazole compounds
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
US6329526B1 (en) 1996-01-11 2001-12-11 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
US5864036A (en) * 1996-01-11 1999-01-26 Smithkline Beecham Corporation Substituted imidazole compounds
US6096739A (en) * 1996-03-25 2000-08-01 Smithkline Beecham Corporation Treatment for CNS injuries
US6414150B1 (en) 1996-08-21 2002-07-02 Smithkline Beecham Corporation 4,5-disubstituted imidazole compounds
US5929076A (en) * 1997-01-10 1999-07-27 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
US6852740B2 (en) 1997-05-22 2005-02-08 G. D. Searle & Co. Pyrazole derivatives as p38 kinase inhibitors
US7153959B2 (en) 1997-05-22 2006-12-26 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
US6503930B1 (en) 1997-05-22 2003-01-07 G.D. Searle & Company Pyrazole derivatives as p38 kinase inhibitors
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6617324B1 (en) 1997-05-22 2003-09-09 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6774127B2 (en) 1997-06-13 2004-08-10 Smithkline Beecham Corporation Pyrazole and pyrazoline substituted compounds
US6610695B1 (en) 1997-06-19 2003-08-26 Smithkline Beecham Corporation Aryloxy substituted pyrimidine imidazole compounds
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
US6562832B1 (en) 1997-07-02 2003-05-13 Smithkline Beecham Corporation Substituted imidazole compounds
US6569871B1 (en) 1997-07-02 2003-05-27 Smithkline Beecham Corporation Substituted imidazole compounds
US6251914B1 (en) 1997-07-02 2001-06-26 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
JP2001519328A (ja) * 1997-10-07 2001-10-23 ベーリンガー インゲルハイム （カナダ） リミテッド Ｈｃｍｖ感染症治療のためのアゼチジノン誘導体
US6730683B2 (en) 1997-12-19 2004-05-04 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
US6548520B1 (en) 1998-05-22 2003-04-15 Smithkline Beecham Corporation Substituted imidazoles having anti-cancer and cytokine inhibitory activity
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
US6489325B1 (en) 1998-07-01 2002-12-03 Smithkline Beecham Corporation Substituted imidazole compounds
US6599910B1 (en) 1998-08-20 2003-07-29 Smithkline Beecham Corporation Substituted triazole compounds
US6512121B2 (en) 1998-09-14 2003-01-28 G.D. Searle & Co. Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US6861417B2 (en) 1998-11-04 2005-03-01 Smithkline Beecham Corporation Pyridin-4-YL or pyrimidin-4-YL substituted pyrazines
US6525059B1 (en) 1998-11-20 2003-02-25 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6239279B1 (en) 1998-12-16 2001-05-29 Smithkline Beecham Corporation Synthesis for 4-aryl-5-pyrimidine imidazole substituted derivatives
US7098216B2 (en) 1999-05-17 2006-08-29 The Regents Of The University Of California Thiazolopyrimidines useful as TNFα inhibitors
US6930101B1 (en) 1999-05-17 2005-08-16 The Regents Of The University Of California Thiazolopyrimidines useful as TNFα inhibitors
US7053098B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-Dihydro-(1H) quinazolin-2-one compounds as CSBP/P38 kinase inhibitors
US6759410B1 (en) 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
US6982270B1 (en) 1999-11-23 2006-01-03 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US6699884B2 (en) 2001-04-20 2004-03-02 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
US6979686B1 (en) 2001-12-07 2005-12-27 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
WO2003084539A2 (fr) * 2002-04-10 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions pharmaceutiques a base d'anticholinergiques et d'inhibiteurs de la kinase p38
WO2003084539A3 (fr) * 2002-04-10 2004-09-02 Boehringer Ingelheim Pharma Nouvelles compositions pharmaceutiques a base d'anticholinergiques et d'inhibiteurs de la kinase p38
EP1707205A2 (fr) 2002-07-09 2006-10-04 Boehringer Ingelheim Pharma GmbH & Co. KG Compositions pharmaceutiques contenant un antichlinergique et un inhibiteur du p38 pour le traitement de maladies respiratoires
EP2116245A2 (fr) 2004-08-07 2009-11-11 Boehringer Ingelheim International GmbH combinaisons d'inhibiteurs de la kinase EGFR pour le traitement de désordres respiratoires et de l'appareil digestif
EP2878297A1 (fr) 2004-12-24 2015-06-03 Boehringer Ingelheim International GmbH Médicaments pour le traitement ou la prévention des maladies fibrogènes
EP2384751A1 (fr) 2004-12-24 2011-11-09 Boehringer Ingelheim International Gmbh Médicaments pour le traitement ou la prévention des maladies fibrogènes
WO2007009146A1 (fr) * 2005-07-22 2007-01-25 Universität Wien 1-phenyle-imidazoles substitues en tant qu'inhibiteurs de cox-i
WO2008142031A1 (fr) 2007-05-18 2008-11-27 Institut Curie La p38alpha cible thérapeutique dans le cancer de la vessie
US20120245188A1 (en) * 2010-11-15 2012-09-27 Translational Genomics Research Institute Methods of treating memory loss and enhancing memory performance
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US10537560B2 (en) 2017-10-05 2020-01-21 Fulcrum Therapeutics. Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11291659B2 (en) 2017-10-05 2022-04-05 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD
US11479770B2 (en) 2017-10-05 2022-10-25 Fulcrum Therapeutics, Inc. Use of p38 inhibitors to reduce expression of DUX4
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

Also Published As

Publication number Publication date
EP0883402A1 (fr) 1998-12-16
EP0883402A4 (fr) 1999-08-11
JP2001508395A (ja) 2001-06-26

Similar Documents

Publication Publication Date Title
US6329526B1 (en) Cycloalkyl substituted imidazoles
AU726084C (en) Novel substituted imidazole compounds
WO1997025047A1 (fr) Nouveaux imidazoles cycloalkyle-substitues
AU709370B2 (en) Novel compounds
US5929076A (en) Cycloalkyl substituted imidazoles
EP0809499B1 (fr) Certains composes d'imidazole 1,4,5-trisubstitues utiles comme cytokine
EP0900083B1 (fr) Nouveaux composes d'imidazole substitues
US5739143A (en) Imidazole compounds and compositions
US6251914B1 (en) Cycloalkyl substituted imidazoles
US6218537B1 (en) Process for making pyridyl and pyrimidine substituted imidazole compounds
EP1037639A1 (fr) .0mposes d'imidazole heteroaryle substitues, leurs compositions et usages pharmaceutiques
AU699646C (en) Imidazole compounds
AP999A (en) Novel substituted imidazole compounds.
AU1827101A (en) Novel substituted imidazole compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: JP

Ref document number: 1997 525465

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1997904766

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 09101525

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1997904766

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997904766

Country of ref document: EP