WO1995003297A1 - Imidazoles for treating cytokine mediated disease - Google Patents

Imidazoles for treating cytokine mediated disease Download PDF

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Publication number
WO1995003297A1
WO1995003297A1 PCT/US1994/008297 US9408297W WO9503297A1 WO 1995003297 A1 WO1995003297 A1 WO 1995003297A1 US 9408297 W US9408297 W US 9408297W WO 9503297 A1 WO9503297 A1 WO 9503297A1
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Prior art keywords
alkyl
hydrogen
pyridyl
optionally substituted
imidazole
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PCT/US1994/008297
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French (fr)
Inventor
Jerry Leroy Adams
Timothy Francis Gallagher
John C. Lee
John Richard White
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Smithkline Beecham Corporation
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Priority to AU76295/94A priority Critical patent/AU7629594A/en
Publication of WO1995003297A1 publication Critical patent/WO1995003297A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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 IL-1
  • Tumor Necrosis Factor TNF
  • IL-1 Interleukin-1
  • TNF Tumor Necrosis Factor
  • 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. £, 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.
  • 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.
  • AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV).
  • HIV Human Immunodeficiency Virus
  • T lymphocyte activation requires T lymphocyte activation.
  • Other viruses such as HTV-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.
  • T lymphocyte Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIN replication.
  • Monokines specifically T ⁇ F, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation.
  • interference with monokine activity such as by inhibition of monokine production, notably T ⁇ F
  • monokine production notably T ⁇ F
  • an HTV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HTV 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.
  • Th ⁇ ese 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
  • T ⁇ F has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalia virus
  • influenza virus influenza virus
  • herpes virus herpes virus
  • Interleukin -8 is a chemotactic factor first identified and characterized in 1987.
  • IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and ketainocytes. Its production from endothelidl cells is induced by IL-1, T ⁇ F, or lipopolysachharide (LPS).
  • IL-1 mononuclear cells
  • fibroblasts endothelial cells
  • LPS lipopolysachharide
  • Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit ⁇ eutrophils.
  • IL-8 nerve growth factor-8
  • ⁇ AP-1 neutophil attractant/activation protein-1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutophil 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 neutophils, T-lymphocutes, 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/CD18) 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 neutophils into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
  • IL- 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 drags i.e. compounds which are capable of inhibiting cytokines, such as IL-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 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 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-8 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 TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • Compounds of Formula (I) are represented by the structure:
  • Rl is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from Ci -4 alkyl, halogen, Ci-4 alkoxy, Ci-4 alkylthio, NR ⁇ )R20 > or N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or
  • R2 is hydrogen, -(CRi ()R20)n OR12, heterocyclyl, heterocyclylC l- 10 alkyl, Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3_ ⁇ cycloalkyl, C3-.7 cycloalkylCi-io alkyl, C5-7 cycloalkenyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi-io alkyl, (CR ⁇ oR2 ⁇ )n'ORi3.
  • R3 is or Q-(Y ⁇ ) t ;
  • Q is an aryl or heteroaryl group; t is a number having a value of 1, 2 or 3; Z is oxygen or sulfur; n is 0 or an integer from 1 to 10;
  • Yl is independently selected from hydrogen, C ⁇ _5 alkyl, halo-substituted C ⁇ _5 alkyl, halogen, or -(CR ⁇ oR2 ⁇ )nY2;
  • Y 2 is -OR8, -N ⁇ 2, -S(0) m 'Rn, -SRs, -S(O) m 'OR8, -S(O) m NR8R 9 , -NR 8 R 9 , -O(CRi 0 R20)nNR8R9, -C(0)R8, -CO2R8, -CO2(CRi 0 R 2 o)n I CONR 8 R9, -ZC(O)R 8 , -CN, -C(Z)NR 8 R 9 , -NR ⁇ 0 C(Z)R 8 , -C(Z)NR 8 OR 9 , -NR ⁇ 0 C(Z)NR 8 R 9 , -NR ⁇ oS(O) m Rll,
  • R4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l-yl or 5-naphth-2-yl substitiuent, is halo, cyano, -C(Z)NR7R ⁇ , -C(Z)OR23, -(CRioR20)m"*COR3 6 , SR5, -SOR5, -OR3 6 , halo-substituted-Ci-4 alkyl, C ⁇ _4 alkyl, -ZC(Z)R 36 , -NR ⁇ 0 C(Z)R 2 3, or -(CR ⁇ 0 R2 ⁇ )m m NR ⁇ oR20 and which, for other positions of substitution, is halo, cyano, -C(Z)NR ⁇ 5R26.
  • R 6 is C ⁇ _4 alkyl, halo-substituted-Ci-4 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl or Q3-5 cycloalkyl;
  • R 7 and R1 7 is each independently selected from hydrogen or C 1 - 4 alkyl or R7 and R 17 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 NR2 2 ;
  • R8 is hydrogen, heterocyclyl, heterocyclylalkyl or Rn;
  • R9 is hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R 8 and R 9 may 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 NR1 2 ;
  • R lO and R 20 is each independently selected from hydrogen or Ci-4 alkyl;
  • Rn is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • R l2 is hydrogen, -C(Z)Ri3 or optionally substituted C ⁇ _ 4 alkyl, optionally substituted aryl, optionally substituted arylC ⁇ _4 alkyl, or S(O)2R25;
  • Rl3 is hydrogen, Ci-io alkyl C3-7 cycloalkyl, heterocyclyl, heterocyclylC ⁇ _ 10 alkyl , aryl, arylCi-io alkyl, heteroaryl or heteroaryl Ci-io alkyl;
  • R14 and R24
  • Rl8 and R19 is each independently selected from hydrogen, Ci-4 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl or together denote a oxygen or sulfur;
  • R 2 1 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3-7 cycloalkyl, aryl, aryl C 1 -4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Ci-io alkanoyl ;
  • R22 is Rio or C(Z)-C ⁇ _4 alkyl
  • R 23 is C ⁇ _ 4 alkyl, halo-substituted-C ⁇ _ 4 alkyl, or C3-5 cycloalkyl;
  • R3 6 is hydrogen or R2 3 ;
  • R25 is Ci-io alkyl, C3_7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Ci-ioalkyl, heteroaryl or heteroarylalkyl;
  • R27 is hydrogen, cyano, C ⁇ _4 alkyl, C3-7 cycloalkyl, or aryl; or a pharmaceutically acceptable salt thereof; and excluding 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-5-(4-pyridyl)imidazole, and
  • 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 retovirus infections, such as but not limited to feline immunodeficiency virus (FTV), bovine immunodeficiency viras, or canine immunodeficiency viras or other retroviral infections.
  • preferred Ri moieties are 4-pyrimidinyl, 4-pyridyl or 4- quinolyl groups of which the 4-pyrimidinyl and the 4-pyridyl are preferred. These groups are preferably substituted with a Ci-4 alkyl, in particular methyl, or a
  • NRlO R 20 group preferably where Rio and R20 are both hydrogen. More preferred is the 4-pyridyl derivative substituted at the 2-position with a C1-4 alkyl, especially 2- methyl-4-pyridyl, or the 4-pyrimidinyl derivative substituted at the 2-position with C ⁇ _ 4 alkyl or N ⁇ oR20» m ore preferably with NR ⁇ oR20 > and Rio and R20 are preferably hydrogen.
  • R2 is preferably an optionally substituted Ci-io alkyl, an optionally substituted aryl, an optionally substituted heterocyclic alkyl or an optionally substituted heterocyclic ring.
  • the alkyl chain while being of 1 to 10 carbons in length is preferably from 2 to 4 carbons, more preferably 3 in length.
  • the alkyl chain is preferably substituted by an aryl, heteroaryl or heterocyclic moiety, or the alkyl chain is interrupted by an oxygen [(CR ⁇ oR2 ⁇ )n'0 R 13] or sulfur group[(CRioR20)n'S(O) m R25] (which may be optionally oxidized) or by an optionally substituted amine derivative [(CR ⁇ oR2 ⁇ )n'NR8 9L
  • R2 is may also be hydrogen when R4 is not an unsubstituted pyridyl and R3 a substitututed phenyl.
  • Preferred optionally substituted alkyl groups include, methyl S(O) m Ci-4 alkyl- (wherein m is 0, 1 or 2), a methylsulfonamido alkyl-, an aryloxyalkyl-, such as phenoxyalkyl-, or an alkoxyalkyl-, such as ethoxy alkyl, optionally substituted (mono- or di-) amine derivatives include, aminoalkyl-, diethylaminoalkyl, (phenylmethyl-N- methyl)aminoalkyl, (phenylmethyl)amino-l-propyl, or the amino substituents may cyclize to form a 5 to 7 membered heteroring and optionally contain an additional heteroatom, such as a morpholino, pyrrolidinyl, or a piperidinyl group, such as piperidinyl alkyl, pyrrolidinylalkyl, morpholinoalkyl, wherein the alky
  • R2 is an optionally substituted C ⁇ _ ⁇ o alkyl, an optionally substituted heterocyclyl ring, an optionally substituted heterocyclylC i- 10 alkyl, an optionally substituted aryl, (CR ⁇ oR2 ⁇ )n' R8 9, or (CR ⁇ oR2 ⁇ )n'C(Z)ORi3 group.
  • the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group.
  • this alkyl moiety is from 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group.
  • Preferred heterocyclic alkyl groups include but are not limited to, morpholino ethyl, morpholino propyl, pyrrollidinyl propyl, and piperidinyl propyl moieties.
  • the heterocyclyl ring may be optionally substituted one to four times independently by halogen; Ci-4 alkyl; aryl, such as phenyl; aryl alkyl, such as benzyl- wherein the aryl or aryl alkyl moieties themselves may be optionally substituted (as in the definition section below); C(O)ORi3, such as the C(O)Ci-4 alkyl or C(O)OH moieties; C(O)H; C(O)C ⁇ _4 alkyl, hydroxy substituted Ci-4 alkyl, Ci-4 alkoxy, S(O) m Ci-4 alkyl (wherein m is 0, 1, or 2), NR10R20 (wherein Rio and R20 are independently hydrogen or C ⁇ _4alky
  • R2 is an optionally substituted heterocyclyl
  • the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group.
  • the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself.
  • the ring is a piperidine or pyrrole, more preferably piperidine.
  • the heterocyclyl ring may be optionally substituted one to four times independently by the same substituents noted above for the heterocyclic alkyl groups.
  • the ring is a piperidine
  • the ring is attached to the imidazole at the 4-position, and the substituents are directly on the available nitrogen, i.e. a 1-Formyl- 4-piperidine, l-benzyl-4-piperidine, l-methyl-4-piperidine, l-ethoxycarbonyl-4- piperidine.
  • the ring is substituted by an alkyl group and the ring is attached in the 4- position, it is preferably substituted in the 2 or 6 position or both, such as 2,2,6,6- tetramethyl-4-piperidine.
  • the ring is a pyrrole
  • the ring is attached to the imidazole at the 3-position, and the substituents are aldo directly on the available nitrogen.
  • the substitution on the heterocyclic ring is preferably the same regardless if it is a heterocyclic or heterocylic alkyl moiety.
  • the cycloalkyl group is preferably a C5 to C6 ring which ring may be optionally substituted one or more 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, methylsulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR7R17 group; 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 O/N/S; C ⁇ _ ⁇ o alkyl, such as methyl, e
  • R8 and R9 are each independently selected from hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl or an optionally substituted aryl- Ci-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 NR12. It is recognized that in some instances this can yield the same moiety as a heterocyclic Ci-io alkyl moiety noted above which is also a suitable R2 variable.
  • R and R9 are independently hydrogen, Ci-4 alkyl, preferably methyl, or benzyl.
  • n term is preferably 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group.
  • Preferred groups include, but are not limited to, aminopropyl, (N-methyl-N-benzyl)aminopropyl, (N-Phenylmethyl)amino- 1 -propyl, or diethylamino propyl.
  • R13 is suitably hydrogen, C1-4 alkyl, especially methyl.
  • the n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
  • Preferred groups include, but are not limited to, carboxymethyl- 1 -butyl, carboxy- 1 -propyl, or 2-acetoxyethyl.
  • R2 is a (CRioR20)n'S(O) m
  • R25 group m is 0, 1, or 2
  • Ri8 is preferably aryl, especially phenyl, or Ci-io alkyl, especially methyl.
  • the n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
  • R13 is suitably hydrogen, aryl, especially phenyl, or Ci-io alkyl, especially methyl or ethyl.
  • the n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
  • Ri8 is suitably alkyl, especially methyl.
  • the n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
  • R2 is a optionally substituted aryl, the aryl is preferably phenyl.
  • the aryl ring may be optionally substituted one or more times, preferably by one or two substituents, independently selected from C1.4 alkyl, halogen, especially fluoro or chloro, (CRioR20)tORl3, (wherein t is 0, or an integer of 1 to 4), -(CRioR20)t NR 10 R 20 > especially amino or mono- or di-alkylamino -(CRioR20)tS(O) m R25, wherein m is 0, 1 or 2 ; - SH-, -(CR ⁇ oR2 ⁇ )n-NR8 R 9,
  • -NR ⁇ oC(Z)R8 such -NHCO(C ⁇ _ ⁇ o alkyl)
  • -NR ⁇ oS(O) m R25 such as -NHSO2(Ci-iO alkyl)
  • the phenyl is substituted in the 3 or 4- position by -(CRioR20)tS(O) m R25, and R25 is preferably Ci-ioalkyl, especially methyl.
  • R2 is an optionally substituted heteroaryl or heteroarylalkyl group
  • the ring may be optionally substituted one or more times, preferably by one or two substituents, independently selected from one or more times, by C 1-4 alkyl, halogen, especially fluoro or chloro, (CRioR20)tORl3, -(CR ⁇ oR20)t Rl ⁇ R20 , especially amino or mono- or di-alkylamino -(CRioR20)tS(O) m R25, wherein m is 0, 1 or 2 ; - SH-, -(CRioR20)n-NR8R9, -NR ⁇ oC(Z)R8 (such -NHCO(Ci-io alkyl)); -NR ⁇ oS(O)m R 25 (such as -NHSO2(Ci-io alkyl)); t is 0, or an integer of 1 to 4.
  • R2 is a (CRi ⁇ R 20)n'OC(Z)Ri3, or (CRioR20)n'OC(Z)NR8R9 moiety, or any similarly substituted group that n' is preferably at least 2 which will allow for the synthesis of stable compounds.
  • R3 is or Q-(Yl)t ; and Q is an aryl or heteroaryl group.
  • Q is a heteroaryl moiety it is a 2- or 3-thiophene.
  • R3 is a substituted phenyl. More preferred Q is phenyl. Q is independently substituted 1 to 3 times by Yl.
  • t is 1 or 2. More preferably, when R 3 is mono-substituted phenyl, the substituent is located at the 4-position.
  • Q is substituted by 1 or 2 substituents which include halogen, C1-5 alkyl and -(CR ⁇ 0 R2 ⁇ )nY2 wherein Y 2 is -OR8, -NO2, -S(O) m -R ⁇ , -SR8, -S(O)mNR 8 R 9 ; -NR 8 R 9) -O(CRi 0 R20)nNR8 R 9.
  • substituents which include halogen, C1-5 alkyl and -(CR ⁇ 0 R2 ⁇ )nY2 wherein Y 2 is -OR8, -NO2, -S(O) m -R ⁇ , -SR8, -S(O)mNR 8 R 9 ; -NR 8 R 9) -O(CRi 0 R20)nNR8 R 9.
  • Preferred substituents Yi for use in R3 when the aryl or heteroaryl group Q is mono-substituted include -(CR ⁇ oR 2 ⁇ )nY 2 wherein: n is 0, 1, 2 or 3, preferably 0 or 1; and Y 2 is -OR8, especially where R 8 is hydrogen or Ci-io alkyl; -NO2; -S(O) m 'Rn, especially where Rn is Ci-io alkyl; -SR8, especially where R 8 is Ci-io alkyl;
  • -S(O) m NR 8 R especially where R8 and R 9 is each hydrogen or CMO alkyl or Rs and R together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally includes another heteroatom selected from oxygen, sulfur or NR12 and m is 2; n' is 1 to 10; -NR 8 R , especially where R 8 and R 9 is each hydrogen, methyl or benzyl or R and R together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally includes another heteroatom selected from oxygen, sulfur or NR12; -O(CR ⁇ oR2 ⁇ )nNR 8 R 9 , especially where R8 and R 9 is each Ci-io alkyl; -0(0)1 ⁇ , especially where R 8 is hydrogen or C ⁇ _ ⁇ o alkyl; -CO2R 8 , especially where R is hydrogen or CMO alkyl; -CO2(CR l o R 2 0 )n , CONR 8 R 9 R 9
  • Preferred substituents for use in R 3 when the aryl or heteroaryl group Q is disubstituted include those hereinbefore listed for use when Q is mono-substituted and, as further substituent(s), halogen and CMO alkyl.
  • R3 is phenyl substituted with two or three substituents
  • the alkyl moieties preferably have from one to three carbons, more preferably one.
  • Preferred ring positions for two substituents are the 3- and 4- positions and, for three substituents, the 3-, 4- and 5- positions.
  • the substituent at the 3- and 5-positions is preferably C ⁇ _2 alkyl, such as methyl, or halogen, such as bromo, fluoro or chloro, while the substituent at the 4-position is preferably hydroxyl.
  • n is 0 or 1 and Y 2 is -OH, -S(O) m 'Rl 1, especially where Rn is CMO alkyl;
  • -SRs especially where R 8 is Ci-io alkyl;
  • -NRsR 9 especially where R 8 and R9 is hydrogen, alkyl, aryl alkyl, or aryl or R 8 and R together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring, more prefereably the R and R 9 terms in the NR R 9 moiety are hydrogen, methyl or benzyl; -CO2R8, especially where R 8 is hydrogen or CMO alkyl; rS(O) m 'NR 8 R 9 , especially where Rs and R 9 is each hydrogen or C ⁇ _ ⁇ o alkyl; -NR ⁇ oS(O) m Rn, especially where where
  • Yi is methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, methylsulfonyl, N,N-dimethylaminomethyl, N-benzyl-N-methylaminomethyl, N-morpholinomethyl, methanesulfonamido, sulphonamidomethyl, 5-methyl-4,5- dihydro-l,2,4-oxadiazol-3-yl or 5,5-dimethyl-4,5-dihydro-l,2,4-oxadiazol-3-yl.
  • R4 is a halosubstituted phenyl, naphth-1-yl, or naphth- 2-yl ring.
  • R4 is a halosubstituted phenyl, and preferably the halogen is fluorine, more preferably in the 4-position
  • R2 is a C1.4 alkyl (branched and unbranched), such as isopropyl, butyl, t-butyl, n-propyl, a methylthio propyl, a methylsulfinyl propyl, an amino propyl, N-methyl-N-benzylamino propyl group, (phenylmethyl)amino-l -propyl, diethylamino propyl, cyclopropyl methyl, morpholinyl butyl, morpholinyl propyl, morpholinyl ethyl, l-Formyl-4-piperidinyl, l-benzyl-4- piperidinyl, l-methyl-4-piperidinyl, l-ethoxycarbonyl-4-piperidinyl, phenyl substituted by halogen, thioalkyl or sulfmyl alkyl such as a methylthio,
  • R4 is a 2-methyl- 4-pyridyl or 2-amino-pyrimidinyl.
  • R2 is other than hydrogen, when R4 is an unsubstituted 4-pyridyl and R3 is substituted phenyl.
  • Exemplified compounds herein include:
  • 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 Yi in R3 comprises a carboxy group.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quarternary ammonium cations. The following terms, as used herein, refer to:
  • halo all halogens, that is 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, isopropyl, n-butyl, .yec-butyl, is ⁇ -butyl, tert-butyl, and the like;
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”) - 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, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole;
  • heterocyclic (on its own or in any combination, such as “heterocyclylalkyl”) - a saturated or wholly 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, imidazolidine or pyrazolidine;
  • aralkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean an aryl, heteroaryl or heterocyclic moiety as respectively defined above said group connected to Ci- alkyl group as also defined above unless otherwise indicated.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted Ci-ioalkyl
  • C ⁇ _ ⁇ o 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.
  • Ci-io alkyl such CF3
  • 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, Ci-io alkyl, or CF3.
  • the compounds of the present invention 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.
  • compounds of formula (I) may be prepared by condensing an ⁇ -diketone of formula (II): R1COCOR4 (H) wherein Ri and R4 are as hereinbefore defined, or an equivalent thereof, with an aldehyde of the formula (III):
  • Suitable equivalents of the ⁇ -diketone are well known to those skilled in the art and include the corresponding ⁇ -keto-oxime and ⁇ -dioxime.
  • Suitable equivalents of the aldehyde of formula (HI) are well known in the art and include the corresponding oxime and acetal.
  • Ammonia, or a source thereof, is preferably used in excess, with at least a dimolar amount being used in the case of the ⁇ -diketone and at least an equimolar amount in the case of the ⁇ -keto-oxime.
  • Suitable sources of ammonia include ammonium salts of organic carboxylic acids, such as an ammonium C ⁇ _ 6 alkanoate, for instance ammonium acetate and ammonium formate, preferably ammonium acetate, and carboxylic amides, in particular of formic acid, such as formamide.
  • An ammonium salt is generally used in large excess and in the presence of an acid, such as a C ⁇ _ 6 carboxylic acid which acid may also be used as a solvent for the reaction. If formamide is used, this may be used in excess, as the reaction solvent.
  • An alternative solvent such as ethanol or dimethyl sulphoxide (Lantos et al, J Het Chem, 19, 1375, 1982) may be used.
  • An additional solvent may also be employed, for instance, dimethyl formamide may be used with formamide.
  • the reaction is generally carried out at elevated temperatures, for instance under reflux conditions, and if desired, in a sealed vessel optionally under pressure and/or an inert gas atmosphere, for instance nitrogen.
  • a further suitable source of ammonia is hydroxylamine, in which case the initially formed imidazole is an N-hydroxy-N-oxide imidazole. This may then be reduced to the corresponding N-hydroxy imidazole by treating with a suitable reducing agent such as. sodium borohydride, in an appropriate solvent such as methanol, following the method of Akange and Allan, Chem and Ind, 5 Jan 1975, 38.
  • a suitable reducing agent such as. sodium borohydride
  • an appropriate solvent such as methanol
  • N-hydroxy-N-oxide imidazoles may be readily obtained by treating an ⁇ -diketone of formula (II) with an aldehyde of formula (II) with about two equivalents of hydroxylamine or the corresponding aldoxime and about one equivalent of hydroxylamine, under proton catalysis.
  • the N-oxide may be obtained by the acid catalysed condensation of the corresponding ⁇ -dioxime or ⁇ -keto-oxime with an aldoxime of the aldehyde of formula (HI).
  • This may then be converted to the a- diketone 3 by a Swem oxidation of which any number of potentially useful variations 0 are known and may be used.
  • the a-diketone 3 is then cyclised to an imidazole 4, a compound of formula (I), by heating 3 with a substituted benzaldehyde in a mixture of ammonium acetate, as the source of ammonia, and an appropriate solvent, for example acetic acid or DMSO.
  • the imidazole 4 may then be transformed into other imidazoles 5 by appropriate functional group interconversion procedures.
  • Scheme I also 5 illustrates the preparation of a protected ⁇ -hydroxyketone 2a, by condensing the anion of 1 with an appropriately activated carbonyl derivative of a substituted benzamide, such as the N-methoxy-N-methylamide, to yield a protected a-hydroxyketone.
  • This adduct 2a may then be directly converted to the imidazole 5, using a combination of a copper (II) salt, such as copper (II) acetate, as an oxidising agent and ammon-ium 0 acetate as a source of ammonia.
  • the ⁇ -hydroxyketone 2a may also be deprotected and
  • Scheme II illustrates the use of an a-keto-oxime for preparing a compound of formula (I).
  • a heterocyclic ketone 7 is prepared by adding the anion of 4-methyl- quinoline (prepared by treatment thereof with an alkyl lithium, such as n-butyl lithium) to an N-alkyl-O-alkoxybenzamide.
  • the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone 7.
  • the ⁇ -keto- oxime 8 is then prepared from 7 using standard conditions, such as reaction with sodium nitrite, and this may then be reacted with a benzaldehyde to afford an N- hydroxyimidazole 9, a compound of formula (I) in which R 2 is hydroxy. This may converted to 10, a further compound of formula (I) in which R2 is hydrogen, by treating it with a deoxygenating agent such as phosphorus trichloride or a trialkyl phosphite, such as trimethyl or triethylphosphite.
  • a deoxygenating agent such as phosphorus trichloride or a trialkyl phosphite, such as trimethyl or triethylphosphite.
  • a compound of formula (I) may be obtained by treating an a-hydroxyketone compound of formula (HA):
  • R'CHOHCOR" wherein one of R' and R" is Ri and the other is R4 a suitably protected derivative thereof or the a-hydroxy-oxime or a-haloketone derivative thereof, with an oxidising agent capable of converting said compound into the corresponding a-diketone, in the presence of an aldehyde of formula (HI) or an equivalent thereof, and a source of ammonia.
  • Suitable oxidising agents include, for example, an oxidising heavy metal salt, preferably an organic copper (II) salt, such as copper (II) acetate or copper (II) citrate.
  • the reaction may be effected in a solvent such as acetic acid, under reflux conditions.
  • a lower alkanol solvent such as methanol or ethanol
  • a temperature in the region of from 30 to 100°C see The Chemistry of Heterocyclic Compounds, Imidazole and its derivatives, part I, ed. Weissberger, Interscience Publishers, Inc., New York, 1953, 38). This approach is also illustrated in Scheme I.
  • a compound of formula (I) may be obtained by treatment with a compound of formula (XI) as described later.
  • an inert solvent such as a halogenated hydrocarbon solvent, for example chloroform
  • Suitable reactive esters include esters of strong organic acids such as a lower alkane sulphonic or aryl sulphonic acid, for instance, methane or/?-toluene sulphonic acid.
  • the amidine of formula (IN) 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 of formula (IN) may be obtained by standard methods, see for instance, Garigipati R, Tetrahedron Letters, 190, 31, 1989.
  • a compound of formula (I) may be obtained by treating an iminoether of formula (V):
  • R 3 C NOR (V) wherein R3 is as hereinbefore defined and R is CMO alkyl, aryl or aryl C1-4 alkyl, with an ⁇ -aminoketone of the formula (VI):
  • N-substituted compounds of formula (I) may be prepared by treating the anion of an amide of formula (VII):
  • R4CN (VIE) wherein R4 is as hereinbefore defined, or
  • R4COHal (DC) wherein R4 is as hereinbefore defined and Hal is halogen, or a corresponding anhydride, to give a bw-acylated intermediate which is then treated with a source of ammonia, such as ammonium acetate.
  • a source of ammonia such as ammonium acetate.
  • compounds of formula (I) may be prepared by treating a compound of formula (X): R , COCHR"X c COR 3 (X) wherein R', R" and R 3 are as hereinbefore defined and Xc is O or NH, with a source of ammonia, as hereinbefore described, under imidazole ring forming conditions or cyclising the corresponding Schiffs base, formed by treating the compound of formula (X) in which Xc is NH with an amine R 2 NH 2 , for instance thermally or with the aid of a cyclising agent such as phosphoras oxychloride or phosphoras 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 phosphoras oxychloride or phosphoras pentachloride
  • Compounds of formula (X) may be obtained, for instance, by acylating the corresponding a-keto-oxime (Xc is NH) or a-hydroxyketone (X c is O) with an acyl halide of the formula R 3 COHal wherein R 3 is as hereinbefore defined, or the corresponding anhydride, under standard acylating conditions.
  • compounds of formula (I) may be prepared by coupling a suitable derivative of a compound of formula (XI): wherein: T2 is a nitrogen protecting group or R2, other than hydrogen; and Ti is hydrogen, T3 is Q and T4 is R4; Ti is Ri, T3 is hydrogen and T4 is R4; or Ti is Ri, T3 is Q and T4 is hydrogen , in which Ri, R2, R3, R4 and Q are as hereinbefore defined; with: (i) when Ti is hydrogen, a suitable derivative of the heteroaryl ring RiH, under, ring coupling conditions, to effect coupling of the heteroaryl ring Ri to the imidazole nucleus at position 5; (ii) when T3 is hydrogen, a suitable derivative of the aryl or heteroaryl ring QH, under ring coupling conditions, to effect coupling of the ring Q to the imidazole nucleus at position 2; or (iii) when T 4 is hydrogen, a suitable derivative of the aryl ring R
  • an organometallic synthetic equivalent of an anion of one component is coupled with a reactive derivative of die second component, in the presence of a suitable catalyst.
  • the anion equivalent may be formed from either the imidazole of formula (XI), 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 (XI) or the aryl/heteroaryl rings include organometallic derivatives such as organomagnesium, organozinc, organostannane and boronic acid derivatives and suitable reactive derivatives include the the bromo, iodo, fluorosulfonate and trifluoromethanesulphonate derivatives. Suitable procedures are described in WO 91/19497, the disclosure of which is herewith incorporated.
  • Suitable organomagnesium and organozinc derivatives of a compound of formula (XI) 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 (II) catalyst, following the procedure of Kumada et al., Tetrahedron Letters, 22, 5319 (1981).
  • a ring coupling catalyst such as a palladium (O) or palladium (II) catalyst
  • Suitable such catalysts include tetr ⁇ fa ' 5- (triphenylphosphine)palladium and PdCl2[l,4-b 5-(diphenylphosphino)-butane], optionally in the presence of lithium chloride and a base, such as triethylamine.
  • a nickel (II) catalyst such as Ni(II)Cl 2 (l,2-biphenylphosphino)ethane, may also be used for coupling an aryl ring, following the procedure of Pridgen, 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 (XI) or the bromo derivative thereof with an alkyllithium compound to yield the corresponding lithium reagent by deprotonation or transmetallation, respectively. This lithium intermediate may then be treated with an excess of a magnesium halide or zinc halide to yield the corresponding organometallic reagent.
  • a trialkyltin derivative of the compound of formula (XI) 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 ⁇ / ⁇ ' 5-(triphenylphosphine)- palladium, by the method described in by Stille, J. Amer. Chem.
  • Trialkyltin derivatives may be conveniently obtained by metallation of the corres-ponding compound of formula (XI) with a lithiating agent, such as j-butyl-lithium or «-butyllithium, in an ethereal solvent, such as tetrahydrofuran, or treatment of the bromo derivative of the corresponding compound of formula (XI) with an alkyl lithium, followed, in each case, by treatment with a trialkyltin halide.
  • a lithiating agent such as j-butyl-lithium or «-butyllithium
  • an ethereal solvent such as tetrahydrofuran
  • bromo- derivative of a compound of formula (XI) may be treated with a suitable heteroaryl or aryl trialkyl tin compound in the presence of a catalyst such as tetr ⁇ / ⁇ Ktriphenyl-phosphine)-palladium, under conditions similar to those described above.
  • a catalyst such as tetr ⁇ / ⁇ Ktriphenyl-phosphine
  • a suitable derivative of a compound of formula (XI), 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 to-(triphenylphosphine)-palladium or PdCl2[l,4-b ⁇ * 5-
  • a palladium catalyst such as tetr to-(triphenylphosphine)-palladium or PdCl2[l,4-b ⁇ * 5-
  • 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.
  • a trialkylborate ester such as triethyl, tri-wo-propyl or tributylborate
  • due regard must be exercised with respect to functional groups present in the compunds of formula (XI).
  • amino and sulfur substituents should be non-oxidised or protected and the N-l nitrogen of a compound of formula (XI) be protected, if an NH compound is finally required.
  • Nitro, bromo, iodo and hydroxyl groups should preferably be avoided in compounds of formula (XI) in which Ti is hydrogen.
  • Compounds of formula (XI) are imidazoles and may be obtained by any of the procedures herein before described for preparing compounds of formula (I).
  • an a-halo-ketone R 4 COCH 2 Hal for compounds of formula (XI) in which Ti is hydrogen
  • R ⁇ COCH2Hal for compounds of formula (XI) in which T 4 is hydrogen
  • an amidine of formula (TV) or a salt thereof in an inert solvent such as a halogenated hydrocarbon solvent, for instance chloroform, at a moderately elevated temperature, and, if necessary, in the presence of a suitable condensation agent such as a base.
  • a suitable condensation agent such as a base.
  • an a-diketone of formula (IT) may be condensed with a formaldehyde, or an equivalent thereof, in the presence of a source of ammonia.
  • Suitable bromo derivatives of the compound of formula (XI) may be obtained by brominating the corresponding compound of formula (XI) under standard brominating conditions, for instance bromine in a solvent such as dichloromethane or THF.
  • Compounds of formula (I) may also be prepared by a process which comprises reacting a compound of formula (XI), wherein Ti is hydrogen, with an N-acyl heteroaryl salt, according to the method disclosed in US patents 4,803,279, 4,719,218 and 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.
  • 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 (XI) 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 incorporated in their entirety.
  • Suitable oxidising systems include sulfur in an inert solvent or solvent mixture, such as decalin, decalin and diglyme, /j-cymene, xylene or mesitylene, under reflux conditions, or, preferably, potassium t-butoxide in t-butanol with dry air or oxygen.
  • 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 ⁇ oR2 ⁇ )n' as defined in Formula (I).
  • Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.
  • R4 may be an alkylsulfinyl, arylsulfinyl, alkylsulfonyl, or arylsulfonyl are prodrags which are reductively converted in vivo to the corresponding alkylthio or arylthio form.
  • Pharmaceutically acid addition salts of compounds 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.
  • Example 1 2-(4-Cyanophenyl)-4-(4-fluorophenyI)-5-(4-pyridyl)-lH-imidazole a) To a solution of 2-(4-cyanophenyl)-4-(4-fluorophenyl)-N-l-hydroxy-5-(4- pyridyl)imidazole (4.5 g, 13.2 mmol) [See 1(b) below] in DMF (50 mL) was added triethyl phosphite (3.4 mL, 20 mmol), and the resulting mixture was heated at 100 °C for 2 h.
  • Example 4 4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-lH-imidazole
  • 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)- lH-imidazole 3. g, 9.8 mmol
  • KMnO4 1.5 g, 9.8 mmol
  • the title compound was prepared using the same procedure as described in Example 2, except using 4-(4-Fluorophenyl)-2-(3-methylsulfinylphenyl)-5-(4- pyridyl)- 1 H-imidazole.
  • Example 11 4-(4-FluorophenyI)-2-(thiophen-2-yl)-5-(4-pyridyl)-lH-imidazole
  • Example 22 4-(4-Fluorophenyl)-2-(4-methylsulfmylphenyl)-l-(N- morpholinopropyl)-5-(4-pyridyl)imidazole;
  • Example 23 4-(4-Fluorophenyl)-2-(4-methylthiophenyl)- 1 -(N-morpholinopropyl)-5- (4-pyridyl)imidazole;
  • Example 24 4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-l-(N-morpholino- propyl)-5-(4-pyridyl)imidazole;
  • Example 25 4-(4-Fluorophenyl)- l-(methylthio- l-propyl)-2-([4-N-morpholino- methyl]phenyl)-5-(4-pyridyl)imidazole;
  • Example 26 4-
  • Example 27 4-(4-Fluorophenyl)- 1 -(methylsulfonyl- l-propyl)-2-([4-N-morpholino- methyl]phenyl)-5-(4-pyridyl)imidazole.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacutre 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 producution by such mammal's cell, such as but not limited to monocytes and/or macrophages.
  • Compounds of formula 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. Accordingly, the present invention provides a method of treating a cytokine- mediated disease which comprises administering an effective cyto-dne-interferring 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 IL-1, IL-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.
  • 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, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs.
  • 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,
  • compositions 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 (I).
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenoviras and the Herpes group of viruses, such as but not limited to, Herpes Zoster and Herpes Simplex.
  • CMV Cytomegalovirus
  • this invention relates to a method of treating a mammal afflicted with a human immunodeficiency viras (HIN) which comprises administering to such mammal an effective T ⁇ F inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • HIN human immunodeficiency viras
  • T ⁇ F 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, the lentiviras infections such as equine infectious anaemia viras, caprine arthritis viras, visna viras, or the maedi virus, or the retrovirases, such as feline immunodeficiency viras (FT ), bovine immunodeficiency viras, or canine immunodeficiency virus.
  • 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 IL-1 or T ⁇ F 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.
  • cytokine production such as by IL-1 or T ⁇ F 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.
  • 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.
  • IL-8 IL-8
  • IL-1, TNF, and IL-6 inflammatory cytokines
  • 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 neutophil infiltration.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine, in particular IL-1, 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-8 or TNF
  • Abnormal levels of IL-1, IL-8 or TNF constitute: (i) levels of free (not cell bound) IL-1, D - 8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1, IL-8 or TNF; or (iii) the presence of IL-1, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1, IL-8 or TNF, respectively, is produced.
  • the compounds of Formula (I) are inhibitors of cytokines, specifically IL-1, IL-8 and TNF is based upon the effects of the compounds 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-6, IL-1, IL-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 (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in
  • 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 IL-1, IL-6 or IL-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.
  • Lymphokines are generally referred to as being produced by lymphoctye 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 suppresive 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 HTV-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 cachectin
  • 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), or pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drag 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 (lb) 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. It will be appreciated that the form and character of the pharmaceutically acceptable carrier 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.
  • 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 25mg. 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. They 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 ⁇ leic 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 esteror 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 formua (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 were 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 (lxl ⁇ were plated in 24-well plates at a concentration of 1-2 million/ml per well. The cells were allowed to adhere for 2 hours, after which time non-adherent cells were removed by gentle washing. Test compounds were then added to the cells for lh before the addition of lipopolysaccharide (50 ng/ml), and the cultures were incubated at 37°C for an additional 24h. At the end of this period, culture super- natants were removed and clarified of cells and all debris.
  • Human peripheral blood monocytes were 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 were plated at a density of 1x10 ⁇ cells/ml medium/well in 24-well multi-dishes. The cells were allowed to adhere for 1 hour after which time the supernatant was aspirated and fresh medium (1ml, RPMI-1640, Whitaker Biomedical Products, Whitaker, CA) containing 1% fetal calf serum plus penicillin and streptomycin (10 units/ml) added.
  • the cells were incubated for 45 minutes in the presence or absence of a test compound at lnM- lOmM dose ranges (compounds were solubilized in dimethyl sulfoxide/ethanol, such that the final solvent concen-tration in the culture medium was 0.5% dimethyl sulfoxide/0.5% ethanol).
  • Bacterial lipopoly-saccharide E. coli 055:B5 [LPS] from Sigma Chemicals Co.
  • was then added 100 ng/ml in 10 ml phosphate buffered saline
  • cultures incubated for 16-18 hours at 37°C in a 5% CO2 incubator.
  • 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 IL-1 production, at non-toxic doses.
  • Interleukin- 8 (IL-8)
  • 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 binding assay was developed using soluble cystosolic fraction from THP.l cells and a radiolabeled compound. For instance, a suitable radiolabeled compound of the
  • CSAIDTM cytokine inhibitor class herein is 4-(Fluorophenyl)-2-(4-hydroxyphenyl-3,5- t2)-5-(4-pyridyl)imidazole.
  • the THP.l cytosol was routinely prepared from cell lysate obtained by nitrogen cavitation followed by a 10 K x g low speed and a 100 K x g high speed centrifugation, the supernatant of which was designated as the cytosolic fraction. THP.l cytosol was incubated with appropriately diluted radioligand at room temperature for a pre-determined time to allow the binding to achieve equilibrium.
  • the sample was added to a G-10 column and eluted with 20 mm TRN, 50mMb - mercaptoethanol, NaN3 The fraction encompassing the void volume was collected and the radioactivity was assessed by liquid scintillation counting. This was determined to reflect bound radioligand since the radioactive signal was abrogated by the presence of excess cold ligand in the incubation mixture or when there was no cytosolic fraction present.
  • Compounds of Formula (I) at various doses were added to the binding assay to achieve inhibition of binding of the radiolabel. IC50S as well as
  • Ki values were determined by regression analysis and scatchard plot analysis respectively. There is generally excellent correlation between the IC50 of compounds tested in both the binding assay and the bioassay and can be used interchangeably in many cases.
  • 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. Alternatively, whole cells or cytosolic fractions comprising the cytokine specific binding protein may be employed in the creening protocol. Regardless of the form of the binding protein, a plurality of compounds are contacted with the binding protein under conditions sufficient to form a compound/ binding protein complex and compound capable of forming, enhancing or interfering with said complexes are detected.
  • Binding Assay is performed as follows: MATERIALS: Incubation buffer: 20 mM Tris, 1 mM MgC_2, 20 mM Hepes, 0.02% NaN3, store at 4°C. Elution buffer: 20 mM Tris, 50 mM 2-mercaptoethanol, NaN3, store at 4°C.
  • G-lO Sephadex add 100 g Sephadex G-10 (Pharmacia, Uppsala, Sweden) to 400 mL dd H2O and allow to swell at room temperature for 2 hours. Decant fines and wash 3 times. Add NaN3 and qs with dd H2O to 500 mLs. and store at 4°C.
  • Assemble Columns Straw column, filter frit and tip (Kontes, SP 420160-000,
  • Binding reaction mixture 100 ⁇ L cytosol, 10 uL cold Compound I or EtOH control, 10 ⁇ L 3 H-Compound I (molar concentration depends on nature of study).

Abstract

Novel 2,4,5-triaryl imidazole compounds and compositions for use in therapy, such as cytokine mediated diseases.

Description

Imidazoles for Treating Cytokine Mediated Disease
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.
BACKGROUNDOFTHE.INVENTION:
Interleukin-1 (IL-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. £, 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.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These 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 β cells. Dinarello, J. Clinical Immunology. 5 (5), 287-297 (1985), reviews the biological activities which have been attributed to IL-1. It should be noted that some of these effects have been described by others as indirect effects of IL-1.
Excessive or unregulated 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. host reaction, 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 results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIN-1, HIV-2 and HIN-3. As a consequence of HIN infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIN entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as HTV-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. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIN replication. Monokines, specifically TΝF, 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 TΝF, in an HTV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HTV 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. Th^ese 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 HTV Infection, Advances in Immunology, Vol. 57, (1989)]. Monokines, such as TΝF, have been shown to activate HTV replication in monocytes and/or macrophages [See Poli, et al.. Proc. Νatl. Acad. Sci., 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T-cells.
TΝF has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.
Interleukin -8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and ketainocytes. Its production from endothelidl cells is induced by IL-1, TΝF, or lipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Νeutrophils. Many different names have been applied to IL-8, such as neutophil attractant/activation protein-1 (ΝAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutophils, T-lymphocutes, 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/CD18) 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 neutophils into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
IL- 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.
There remains a need for treatment, in this field, for compounds which are cytokine suppressive anti-inflammatory drags, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.
SUMMARY OF THE INVENTION
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 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 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-8 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 TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I). Compounds of Formula (I) are represented by the structure:
Figure imgf000006_0001
wherein:
Rl is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from Ci -4 alkyl, halogen, Ci-4 alkoxy, Ci-4 alkylthio, NRκ)R20> or N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or
NR22; R2 is hydrogen, -(CRi ()R20)n OR12, heterocyclyl, heterocyclylC l- 10 alkyl, Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3_γ cycloalkyl, C3-.7 cycloalkylCi-io alkyl, C5-7 cycloalkenyl, aryl, arylCi-io alkyl, heteroaryl, heteroarylCi-io alkyl, (CRιoR2θ)n'ORi3. (CRiθR2θ)n'S(O)mR25> (CRioR20)n'NHS(O)2R25» (CRιoR2θ)n'NR8R9» (CRlθR2θ)n'Nθ2, (CRioR20)n'CN, (CRioR20)n'SO2R25, (CRιoR2θ)n'S(O)mNR8R9,
(CRioR20)n'C(Z)Ri3, (CRioR20)n,C(Z)ORi3, (CRιoR2θ)n'C(Z)NR8R9, (CRιoR2θ)n'C(Z)NRi3θRi2, (CRιoR2θ)n'NRlθC(Z)Ri3, (CRιoR2θ)n,NRlθC(Z)NR8R9, (CRιoR2θ)n,N(OR2l)C(Z)NR8R9, (CRioR20)n,N(OR2l)C(Z)Ri3, (CRioR20)n,C(=NOR2l)Rl3, (CRιoR2θ)n'NRlθC(=NR27)NR8R9. (CRιoR2θ)n'OC(Z)NR8R9,
(CRιoR2θ)n'NRlθC(Z)NR8R9, (CRιoR2θ)n'NRlθC(Z)ORιo, 5-(R25 )-l,2,4- oxadizaol-3-yl or 4-(Ri2)-5-(Ri8Ri9)-4,5-dihydro-l,2,4-oxadiazol-3-yl;wherein the aryl, arylalkyl. heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl moieties may be optionally substituted; n' is an integer having a value of 1 to 10; m is 0, or the integer 1 or 2;
R3 is or Q-(Yι)t ;
Q is an aryl or heteroaryl group; t is a number having a value of 1, 2 or 3; Z is oxygen or sulfur; n is 0 or an integer from 1 to 10;
Yl is independently selected from hydrogen, Cι_5 alkyl, halo-substituted Cι_5 alkyl, halogen, or -(CRιoR2θ)nY2; Y2 is -OR8, -Nθ2, -S(0)m'Rn, -SRs, -S(O)m'OR8, -S(O)mNR8R9, -NR8R9, -O(CRi0R20)nNR8R9, -C(0)R8, -CO2R8, -CO2(CRi0R2o)nI CONR8R9, -ZC(O)R8, -CN, -C(Z)NR8R9, -NRι0C(Z)R8, -C(Z)NR8OR9, -NRι0C(Z)NR8R9, -NRιoS(O)mRll, -N(OR2ι)C(Z)NR8R9, -N(OR2ι)C(Z)R8, -C(=NOR2ι)R8, -NRioC(=NRi5)SRn, -NRι0C(=NRι5)NR8R9, -NRι0C(=CRi4R24)SRn,
-NRlθC(=CRi4R24)NR8R95 -NRι0C(O)C(O)NR8R9, -NRι0C(O)C(O)ORι0, -C(=NRi3)NR8R9, -C(=NORi3)NR8R9, -C(=NR13)ZRn, -OC(Z)NR8R9, -NRιoS(O)mCF3, -NRi0C(Z)ORio, 5-(Rι8)-l,2,4-oxadizaol-3-yl or 4-(Ri2)-5- (Rl8Rl )-4,5-dihydro-l,2,4-oxadiazol-3-yl; m' is a number having a value of 1 or 2;
R4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l-yl or 5-naphth-2-yl substitiuent, is halo, cyano, -C(Z)NR7Rπ, -C(Z)OR23, -(CRioR20)m"*COR36, SR5, -SOR5, -OR36, halo-substituted-Ci-4 alkyl, Cι_4 alkyl, -ZC(Z)R36, -NRι0C(Z)R23, or -(CRι0R2θ)mmNRιoR20 and which, for other positions of substitution, is halo, cyano, -C(Z)NRι<5R26. -C(Z)OR8, -(CRιoR2θ)m"COR8, -S(O)mR8, -ORs, halo-substituted-Cχ_4 alkyl, -C1-4 alkyl, -(CRιoR2o)m"NRιoC(Z)R8, -NRι0S(O)m ,Rll, -NRιoS(O)m'NR7Ri7 -ZC(Z)R8 or -(CRιoR2θ)m,NRi6R26; wherein m" is 0 to 5 and m'" is 0 or 1; R5 is hydrogen, Cχ_4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties -SR5 being -SNR7R17 and -SOR5 being -SOH;
R6 is Cι_4 alkyl, halo-substituted-Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or Q3-5 cycloalkyl;
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 NR22;
R8 is hydrogen, heterocyclyl, heterocyclylalkyl or Rn;
R9 is hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and R9 may 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 NR12;
RlO and R20 is each independently selected from hydrogen or Ci-4 alkyl; Rn is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; Rl2 is hydrogen, -C(Z)Ri3 or optionally substituted Cχ_4 alkyl, optionally substituted aryl, optionally substituted arylCι_4 alkyl, or S(O)2R25; Rl3 is hydrogen, Ci-io alkyl C3-7 cycloalkyl, heterocyclyl, heterocyclylC ι_ 10 alkyl , aryl, arylCi-io alkyl, heteroaryl or heteroaryl Ci-io alkyl; R14 and R24 is each independently selected from hydrogen, alkyl, nitro or cyano; Rl5 is hydrogen, cyano, C1-4 alkyl, C3_7 cycloalkyl or aryl; Rl6 and R26 is each independently selected from hydrogen or optionally substituted
Ci-4 alkyl, optionally substituted aryl or optionally substituted aryl-Cι.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 NR12 ; Rl8 and R19 is each independently selected from hydrogen, Ci-4 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl or together denote a oxygen or sulfur; R21 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3-7 cycloalkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Ci-io alkanoyl ;
R22 is Rio or C(Z)-Cι_4 alkyl;
R23 is Cχ_4 alkyl, halo-substituted-Cι_4 alkyl, or C3-5 cycloalkyl; R36 is hydrogen or R23;
R25 is Ci-io alkyl, C3_7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Ci-ioalkyl, heteroaryl or heteroarylalkyl;
R27 is hydrogen, cyano, Cι_4 alkyl, C3-7 cycloalkyl, or aryl; or a pharmaceutically acceptable salt thereof; and excluding 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-5-(4-pyridyl)imidazole, and
2-phenyl-4-phenyl-5-(4-pyridyl)imidazole.
FULL DESCRIPTION OF THE INVENTION
The 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. In particular, 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. Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retovirus infections, such as but not limited to feline immunodeficiency virus (FTV), bovine immunodeficiency viras, or canine immunodeficiency viras or other retroviral infections.
In Formula (I), preferred Ri moieties are 4-pyrimidinyl, 4-pyridyl or 4- quinolyl groups of which the 4-pyrimidinyl and the 4-pyridyl are preferred. These groups are preferably substituted with a Ci-4 alkyl, in particular methyl, or a
NRlOR20 group, preferably where Rio and R20 are both hydrogen. More preferred is the 4-pyridyl derivative substituted at the 2-position with a C1-4 alkyl, especially 2- methyl-4-pyridyl, or the 4-pyrimidinyl derivative substituted at the 2-position with Cι_ 4 alkyl or N ιoR20» more preferably with NRιoR20> and Rio and R20 are preferably hydrogen.
In Formula (I), R2 is preferably an optionally substituted Ci-io alkyl, an optionally substituted aryl, an optionally substituted heterocyclic alkyl or an optionally substituted heterocyclic ring. The alkyl chain while being of 1 to 10 carbons in length is preferably from 2 to 4 carbons, more preferably 3 in length. The alkyl chain is preferably substituted by an aryl, heteroaryl or heterocyclic moiety, or the alkyl chain is interrupted by an oxygen [(CRιoR2θ)n'0R13] or sulfur group[(CRioR20)n'S(O)mR25] (which may be optionally oxidized) or by an optionally substituted amine derivative [(CRιoR2θ)n'NR8 9L Other substituted alkyl groups include (CRioR20)n'C(Z)ORi3, (CRioR20)n'NHS(O)2R25, (CRioR20)n'C(Z)Ri3, or (CRιoR2θ)n'C(=NOR2l)Rl3. R2 is may also be hydrogen when R4 is not an unsubstituted pyridyl and R3 a substitututed phenyl.
Preferred optionally substituted alkyl groups include, methyl S(O)mCi-4 alkyl- (wherein m is 0, 1 or 2), a methylsulfonamido alkyl-, an aryloxyalkyl-, such as phenoxyalkyl-, or an alkoxyalkyl-, such as ethoxy alkyl, optionally substituted (mono- or di-) amine derivatives include, aminoalkyl-, diethylaminoalkyl, (phenylmethyl-N- methyl)aminoalkyl, (phenylmethyl)amino-l-propyl, or the amino substituents may cyclize to form a 5 to 7 membered heteroring and optionally contain an additional heteroatom, such as a morpholino, pyrrolidinyl, or a piperidinyl group, such as piperidinyl alkyl, pyrrolidinylalkyl, morpholinoalkyl, wherein the alkyl is preferably 1 to 10 carbons in length is preferably from 2 to 4 carbons, more preferably 3 in length. It is recognized that if the amine derivatives cyclize the terms may overlap that of the heterocyclic alkyl derivatives.
More preferably R2 is an optionally substituted Cι_ιo alkyl, an optionally substituted heterocyclyl ring, an optionally substituted heterocyclylC i- 10 alkyl, an optionally substituted aryl, (CRιoR2θ)n' R8 9, or (CRιoR2θ)n'C(Z)ORi3 group. When R2 is an optionally substituted heterocyclyl Ci-io alkyl group, the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. Preferably this alkyl moiety is from 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group. Preferred heterocyclic alkyl groups include but are not limited to, morpholino ethyl, morpholino propyl, pyrrollidinyl propyl, and piperidinyl propyl moieties. The heterocyclyl ring may be optionally substituted one to four times independently by halogen; Ci-4 alkyl; aryl, such as phenyl; aryl alkyl, such as benzyl- wherein the aryl or aryl alkyl moieties themselves may be optionally substituted (as in the definition section below); C(O)ORi3, such as the C(O)Ci-4 alkyl or C(O)OH moieties; C(O)H; C(O)Cι_4 alkyl, hydroxy substituted Ci-4 alkyl, Ci-4 alkoxy, S(O)mCi-4 alkyl (wherein m is 0, 1, or 2), NR10R20 (wherein Rio and R20 are independently hydrogen or Cι_4alkyl).
When R2 is an optionally substituted heterocyclyl the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. When the ring is optionally substituted the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself. Preferably the ring is a piperidine or pyrrole, more preferably piperidine. The heterocyclyl ring may be optionally substituted one to four times independently by the same substituents noted above for the heterocyclic alkyl groups.
Preferably if the ring is a piperidine, the ring is attached to the imidazole at the 4-position, and the substituents are directly on the available nitrogen, i.e. a 1-Formyl- 4-piperidine, l-benzyl-4-piperidine, l-methyl-4-piperidine, l-ethoxycarbonyl-4- piperidine. If the ring is substituted by an alkyl group and the ring is attached in the 4- position, it is preferably substituted in the 2 or 6 position or both, such as 2,2,6,6- tetramethyl-4-piperidine. Simiarly, if the ring is a pyrrole, the ring is attached to the imidazole at the 3-position, and the substituents are aldo directly on the available nitrogen. The substitution on the heterocyclic ring is preferably the same regardless if it is a heterocyclic or heterocylic alkyl moiety.
When R2 is an optionally substituted C3_7cycloalkyl, or an optionally substituted C3_7cycloalkyl Ci-io alkyl, the cycloalkyl group is preferably a C5 to C6 ring which ring may be optionally substituted one or more 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, methylsulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR7R17 group; 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 O/N/S; Cι_ιo alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy substituted Ci- lOalkyl; C(O)ORi3, such as the free acid or methyl ester derivative; an optionally substituted aryl, such as phenyl; an optionally substituted arylalkyl, such as benzyl of phenethyl; and further where these aryl moieties may also be substituted one to two times by halogen; hydroxy; Ci-io alkoxy; S(O)m alkyl; amino, mono & di-substituted amino, such as in the NR7R17 group; alkyl or halosubstituted alkyl. When R2 is (CRιoR2θ)n' R8R9, R8 and R9 are as defined in Formula (I), preferably R8 and R9 are each independently selected from hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl or an optionally substituted aryl- Ci-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 NR12. It is recognized that in some instances this can yield the same moiety as a heterocyclic Ci-io alkyl moiety noted above which is also a suitable R2 variable. Preferably R and R9 are independently hydrogen, Ci-4 alkyl, preferably methyl, or benzyl. The n term is preferably 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group. Preferred groups include, but are not limited to, aminopropyl, (N-methyl-N-benzyl)aminopropyl, (N-Phenylmethyl)amino- 1 -propyl, or diethylamino propyl.
When R2 is a (CRιoR2θ)n'C(Z)ORi3 group, R13 is suitably hydrogen, C1-4 alkyl, especially methyl. The n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group. Preferred groups include, but are not limited to, carboxymethyl- 1 -butyl, carboxy- 1 -propyl, or 2-acetoxyethyl.
When R2 is a (CRioR20)n'S(O)mR25 group m is 0, 1, or 2, and Ri8 is preferably aryl, especially phenyl, or Ci-io alkyl, especially methyl. The n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
When R2 is a (CRioR20)n'ORl3 group, R13 is suitably hydrogen, aryl, especially phenyl, or Ci-io alkyl, especially methyl or ethyl. The n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.
When R2 is a (CRιoR2θ)n'NHS(O)2Rl8 group, Ri8 is suitably alkyl, especially methyl. The n term is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group. When R2 is a optionally substituted aryl, the aryl is preferably phenyl. The aryl ring may be optionally substituted one or more times, preferably by one or two substituents, independently selected from C1.4 alkyl, halogen, especially fluoro or chloro, (CRioR20)tORl3, (wherein t is 0, or an integer of 1 to 4), -(CRioR20)tNR10R20 > especially amino or mono- or di-alkylamino -(CRioR20)tS(O)mR25, wherein m is 0, 1 or 2 ; - SH-, -(CRιoR2θ)n-NR8R9,
-NRιoC(Z)R8 (such -NHCO(Cι_ιo alkyl)); -NRιoS(O)mR25 (such as -NHSO2(Ci-iO alkyl)). Preferably the phenyl is substituted in the 3 or 4- position by -(CRioR20)tS(O)mR25, and R25 is preferably Ci-ioalkyl, especially methyl.
When R2 is an optionally substituted heteroaryl or heteroarylalkyl group the ring may be optionally substituted one or more times, preferably by one or two substituents, independently selected from one or more times, by C 1-4 alkyl, halogen, especially fluoro or chloro, (CRioR20)tORl3, -(CRιoR20)t RlθR20 , especially amino or mono- or di-alkylamino -(CRioR20)tS(O)mR25, wherein m is 0, 1 or 2 ; - SH-, -(CRioR20)n-NR8R9, -NRιoC(Z)R8 (such -NHCO(Ci-io alkyl)); -NRιoS(O)mR25 (such as -NHSO2(Ci-io alkyl)); t is 0, or an integer of 1 to 4.
One skilled in the art would readily recognize that when R2 is a (CRiθR20)n'OC(Z)Ri3, or (CRioR20)n'OC(Z)NR8R9 moiety, or any similarly substituted group that n' is preferably at least 2 which will allow for the synthesis of stable compounds.
Suitably, R3 is or Q-(Yl)t ; and Q is an aryl or heteroaryl group. Preferably when Q is a heteroaryl moiety it is a 2- or 3-thiophene. Preferably R3 is a substituted phenyl. More preferred Q is phenyl. Q is independently substituted 1 to 3 times by Yl. Preferably t is 1 or 2. More preferably, when R3 is mono-substituted phenyl, the substituent is located at the 4-position.
Preferably Q is substituted by 1 or 2 substituents which include halogen, C1-5 alkyl and -(CRι0R2θ)nY2 wherein Y2 is -OR8, -NO2, -S(O)m-Rπ, -SR8, -S(O)mNR8R9; -NR8R9) -O(CRi0R20)nNR8R9. -C(O)Rs, -CO2 R8, -Cθ2(CRι0R2θ)n1 CONR8R9, -CN; -C(Z)NR8R9, -NRιoS(O)mRn, -NRι0C(Z)R8, -NRι0C(Z)NR8R9, -C(Z)NR8OR9, -N(OR2ι)C(Z)NR8R9, -NRιoC(=NRi5)NR8R9, -C(=NORι3)NR8R9, 5-(Rι8)- 1,2,4- oxadizaol-3-yl and 4-(Ri2)-5-(Rι 8Rι9)-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl.
Preferred substituents Yi for use in R3 when the aryl or heteroaryl group Q is mono-substituted include -(CRιoR2θ)nY2 wherein: n is 0, 1, 2 or 3, preferably 0 or 1; and Y2 is -OR8, especially where R8 is hydrogen or Ci-io alkyl; -NO2; -S(O)m'Rn, especially where Rn is Ci-io alkyl; -SR8, especially where R8 is Ci-io alkyl;
-S(O)mNR8R , especially where R8 and R9 is each hydrogen or CMO alkyl or Rs and R together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally includes another heteroatom selected from oxygen, sulfur or NR12 and m is 2; n' is 1 to 10; -NR8R , especially where R8 and R9 is each hydrogen, methyl or benzyl or R and R together with the nitrogen to which they are attached form a 5 to 7 membered ring which optionally includes another heteroatom selected from oxygen, sulfur or NR12; -O(CRιoR2θ)nNR8R9, especially where R8 and R9 is each Ci-io alkyl; -0(0)1^, especially where R8 is hydrogen or Cι_ιo alkyl; -CO2R8, especially where R is hydrogen or CMO alkyl; -CO2(CRloR20)n, CONR8R9, especially where R and R9 is hydrogen or Cι_ιo alkyl; -CN; -C(Z)NR R , especially where R8 and R9 is hydrogen or CMO alkyl; -NRιoS(O)mRn, especially where Rχo is hydrogen or CMO alkyl and Rn is CMO alkyl or a halosubstituted ; -NRχoC(Z)R8, especially where R8 is CMO alkyl and Rio is hydrogen and Z is oxygen; -C(Z)NR8OR9, especially where R8 and R9 is each hydrogen and Z is oxygen; -NRιoC(Z)NR R , especially where R8 and R9 is each hydrogen or Cχ_ιo alkyl and Z is oxygen; -N(OR2i)C(Z)NR R9, especially where R8 especially where R8, R9 and R21 is each hydrogen or Cι_ιo alkyl and Z is oxygen; -C(=NORi3)NR R , especially where R , R9 and R13 is each hydrogen;
Figure imgf000013_0001
especially where R8 and R9 is hydrogen, C O alkyl or arylalkyl and R15 is cyano; and 5-(Rι8)- 1,2,4- oxadizaol-3-yl and 4-(Ri2)-5-(Rι8Rι )-4,5-dihydro-l,2,4-oxadiazol-3-yl, especially where R12 is hydrogen and Rι8 and Rι is each hydrogen or CMO alkyl or together are oxo.
Preferred substituents for use in R3 when the aryl or heteroaryl group Q is disubstituted include those hereinbefore listed for use when Q is mono-substituted and, as further substituent(s), halogen and CMO alkyl. When R3 is phenyl substituted with two or three substituents, the alkyl moieties preferably have from one to three carbons, more preferably one. Preferred ring positions for two substituents are the 3- and 4- positions and, for three substituents, the 3-, 4- and 5- positions. The substituent at the 3- and 5-positions is preferably Cι_2 alkyl, such as methyl, or halogen, such as bromo, fluoro or chloro, while the substituent at the 4-position is preferably hydroxyl.
More preferably, for R3 substituents wherein Yi is (CRιoR20)nY2. n is 0 or 1 and Y2 is -OH, -S(O)m'Rl 1, especially where Rn is CMO alkyl; -SRs, especially where R8 is Ci-io alkyl; -NRsR9, especially where R8 and R9 is hydrogen, alkyl, aryl alkyl, or aryl or R8 and R together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring, more prefereably the R and R9 terms in the NR R9 moiety are hydrogen, methyl or benzyl; -CO2R8, especially where R8 is hydrogen or CMO alkyl; rS(O)m'NR8R9, especially where Rs and R9 is each hydrogen or Cι_ιo alkyl; -NRιoS(O)mRn, especially where Rχo is hydrogen and Rn is CMO alkyl or 5-(Rι8)-l,2,4-oxadizaol-3-yl and 4-(Ri2)-5-(Rι8Rι )-4,5-dihydro- l,2,4-oxadiazol-3-yl, especially where R12 is hydrogen and Rι8 and Rι is hydrogen or CMO alkyl or together are oxo. Most preferably, Yi is methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, methylsulfonyl, N,N-dimethylaminomethyl, N-benzyl-N-methylaminomethyl, N-morpholinomethyl, methanesulfonamido, sulphonamidomethyl, 5-methyl-4,5- dihydro-l,2,4-oxadiazol-3-yl or 5,5-dimethyl-4,5-dihydro-l,2,4-oxadiazol-3-yl.
In Formula (I), suitably R4 is a halosubstituted phenyl, naphth-1-yl, or naphth- 2-yl ring. Preferably R4 is a halosubstituted phenyl, and preferably the halogen is fluorine, more preferably in the 4-position
A preferred grouping of formula (I) are those compounds wherein R2 is an optionally substituted Cι_ιo alkyl, optionally substituted C3-7cycloalkyl, or an optionally substituted C3_7cycloalkyl Ci-io alkyl, an optionally substituted aryl, an optionally substituted heterocyclic alkyl, an optionally substituted heterocyclic, optionally substituted heteroaryl or heteroarylalkyl, (CRιoR2θ)n'0R13 , (CRι0R20)n'S(O)mR25, (CRiθR2θ)n,NR8R9, (CRioR2θ)n'C(Z)ORi3, (CRlO 20)n'NHS(O)2R25. (CRιoR2θ)n'C(Z)Ri3, or (CRioR20)n'C(=NOR2l)Rl3; and Ri, R3, and R4 are as defined for Formula (I).
More preferred are those compounds wherein R2 is a C1.4 alkyl (branched and unbranched), such as isopropyl, butyl, t-butyl, n-propyl, a methylthio propyl, a methylsulfinyl propyl, an amino propyl, N-methyl-N-benzylamino propyl group, (phenylmethyl)amino-l -propyl, diethylamino propyl, cyclopropyl methyl, morpholinyl butyl, morpholinyl propyl, morpholinyl ethyl, l-Formyl-4-piperidinyl, l-benzyl-4- piperidinyl, l-methyl-4-piperidinyl, l-ethoxycarbonyl-4-piperidinyl, phenyl substituted by halogen, thioalkyl or sulfmyl alkyl such as a methylthio, methylsulfinyl or methylsulfonyl moiety; and Ri, R3, and R4 are as defined for Formula (I).
Further preferred compounds of Formula (I) are those wherein Ri is an optionally substituted 4-pyridyl or pyrimidinyl; and more preferably R4 is a 2-methyl- 4-pyridyl or 2-amino-pyrimidinyl. Other groupings include those where R2 is hydrogen, and R3 is a 2- or 3- thiophene, or a substituted phenyl wherein the substituents are selected from methyl thio, methylsulfinyl, methylsulfonyl, methoxy, N-morpholinomethyl, -CH2NH2, or -C(=NOH)NH2; provided that when R4 is phenyl than the methylthio, methylsulfinyl, methylsulfonyl groups are in the 2- or 3- position of the phenyl ring; and R4 is a halosubstituted phenyl, naphth-1-yl, or naphth-2-yl; or a phamaceutically acceptable salt thereof.
Most preferred are those compounds wherein R2 is other than hydrogen, when R4 is an unsubstituted 4-pyridyl and R3 is substituted phenyl.
Exemplified compounds herein include:
4-[4-(4-Fluorophenyl)-5-(4-pyridyl)imidazol-2-yl]benzamidoxime; 4-(l-Napthyl)-2-(4-methylsulfmylphenyl)-5-(4-pyridyl)imidazole; 4-(l-Napthyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole;
4-(2-Napthyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole;
4-(2-Napthyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(3-thiophene)-5-(4-pyridyl)imidazole; 4-(4-Fluorophenyl)-2-(2-thiophene)-5-(4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Huorophenyl)-2-(3-methylsulfonylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(2-methylthiophenyl)-5-(4-pyridyl)imidazole; 4-(4-Fluorophenyl)-2-(2-methylsulfmylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Huorophenyl)-2-(2-methylsulfonylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-l-methyl-5-(4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(4-methylsulfιnylphenyl)-l-(N-morpholinopropyl)-5- (4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-l-(N-morpholinopropyl)-5- (4-pyridyl)imidazole;
4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-l-(N-mo hol-nopropyl)-5- (4-pyridyl)imidazole; 4-(4-Fluorophenyl)- 1 -(methylthio- l-propyl)-2-([4-N-morpholinomethyl]phenyl)-5- (4-pyridyl)imidazole;
4-(4-Fluorophenyl)-l-(methylsulfinyl-l-propyl)-2-([4-N-morpholinomethyl]phenyl)-5- (4-pyridyl)imidazole;
4-(4-Fluorophenyl)- 1 -(methylsulfonyl- 1 -propyl)-2-([4-N-morpholinomethyl]phenyl)- 5-(4-pyridyl)imidazole; or pharmaceutically acceptable salts thereof.
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. In addition, pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent Yi in R3 comprises a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quarternary ammonium cations. The following terms, as used herein, refer to:
• "halo" - all halogens, that is chloro, fluoro, bromo and iodo;
• "Cι_ 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, isopropyl, n-butyl, .yec-butyl, isσ-butyl, tert-butyl, and the like;
• "aryl" - phenyl and naphthyl;
• "heteroaryl" (on its own or in any combination, such as "heteroaryloxy") - 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, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole;
• "heterocyclic" (on its own or in any combination, such as "heterocyclylalkyl") - a saturated or wholly 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, imidazolidine or pyrazolidine;
• "aroyl" - a C(O)Ar, wherein Ar is as phenyl, napthyl, or aryl alkyl derivatives, such as benzyl and the like; • "alkanoyl" - a C(O)Ci-ioalkyl wherein the alkyl is as defined above;
• "sulfinyl" - the oxide S(O) of the corresponding sulfide, while the term "thio" refers to the sulfide;
• The term "aralkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to mean an aryl, heteroaryl or heterocyclic moiety as respectively defined above said group connected to Ci- alkyl group as also defined above unless otherwise indicated. As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci-ioalkyl; Cι_ιo 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. or cyclopropyl methyl; halosubstituted Ci-io alkyl, such CF3; 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, Ci-io alkyl, or CF3.
The compounds of the present invention 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.
For the purposes herein of nomenclature, the compounds of formula (I) are named by their position corresponding to:
Figure imgf000017_0001
Compounds of formula (I) are imidazole derivatives which may be readily prepared using procedures well-known to those skilled in the art, and described in, for instance, Comprehensive Heterocyclic Chemistry, ed Katritzky and Rees, Pergamon Press, 1984, 5, 457-497, from starting materials which are either commercially available or can be prepared from such by analogy with well-known processes. A key step in many such syntheses is the formation of the central imidazole nucleus, to give compounds of formula (I). Suitable procedures are described in ter alia US patent nos. 3,707,475 and 3,940,486 which are herein incorporated by reference in their entirety. These patents describe the synthesis of a-diketones and a-hydroxyketones (benzoins) and their subsequent use in preparing imidazoles and N-hydroxyl imidazoles. Thereafter, further compounds of formula (I) may be obtained by manipulating substituents in any of the groups Ri, R2, R3 and R4 using conventional functional group interconversion procedures.
In particular, in a first process, compounds of formula (I) may be prepared by condensing an α-diketone of formula (II): R1COCOR4 (H) wherein Ri and R4 are as hereinbefore defined, or an equivalent thereof, with an aldehyde of the formula (III):
R3CHO (ffl) wherein R3 is as hereinbefore defined, or an equivalent thereof, and, if necessary, with ammonia or a source thereof, under imidazole-ring forming conditions.
Suitable equivalents of the α-diketone are well known to those skilled in the art and include the corresponding α-keto-oxime and α-dioxime. Suitable equivalents of the aldehyde of formula (HI) are well known in the art and include the corresponding oxime and acetal. Ammonia, or a source thereof, is preferably used in excess, with at least a dimolar amount being used in the case of the α-diketone and at least an equimolar amount in the case of the α-keto-oxime.
Suitable sources of ammonia include ammonium salts of organic carboxylic acids, such as an ammonium Cι_6 alkanoate, for instance ammonium acetate and ammonium formate, preferably ammonium acetate, and carboxylic amides, in particular of formic acid, such as formamide. An ammonium salt is generally used in large excess and in the presence of an acid, such as a Cι_6 carboxylic acid which acid may also be used as a solvent for the reaction. If formamide is used, this may be used in excess, as the reaction solvent. An alternative solvent such as ethanol or dimethyl sulphoxide (Lantos et al, J Het Chem, 19, 1375, 1982) may be used. An additional solvent may also be employed, for instance, dimethyl formamide may be used with formamide. The reaction is generally carried out at elevated temperatures, for instance under reflux conditions, and if desired, in a sealed vessel optionally under pressure and/or an inert gas atmosphere, for instance nitrogen.
A further suitable source of ammonia is hydroxylamine, in which case the initially formed imidazole is an N-hydroxy-N-oxide imidazole. This may then be reduced to the corresponding N-hydroxy imidazole by treating with a suitable reducing agent such as. sodium borohydride, in an appropriate solvent such as methanol, following the method of Akange and Allan, Chem and Ind, 5 Jan 1975, 38. The N- hydroxy imidazole may in turn be converted to an imidazole of formula (I) in which R2 is hydrogen by treatment with a conventional deoxygenating agent such as phosphorus trichloride or a trialkylphosphite such as trimethyl- or triethyl-phosphite. N-hydroxy-N-oxide imidazoles may be readily obtained by treating an α-diketone of formula (II) with an aldehyde of formula (II) with about two equivalents of hydroxylamine or the corresponding aldoxime and about one equivalent of hydroxylamine, under proton catalysis. Alternatively, the N-oxide may be obtained by the acid catalysed condensation of the corresponding α-dioxime or α-keto-oxime with an aldoxime of the aldehyde of formula (HI). When the compound of formula (II) is an α-keto-oxime derivative, it will be appreciated that the product initially obtained will be a compound of formula (I) in which R2 is hydroxyl which may be converted into a compound of formula (I) in which R2 is hydrogen as described above.
It will be appreciated by those skilled in the art that in some instances, it will not be necessary to provide a separate source of ammonia as the α-diketone or aldehyde equivalent may already contain such a source. Examples of this include α- dioxime or α-keto-oxime and aldoxime. The compounds of formula (II) may be obtained by applying well-known synthetic procedures, some of which are illustrated in schemes I and π. Although these illustrate syntheses in which R4 is either 4-pyridyl or 4-quinolinyl, they may be equally applied to any of the other heteroaryl rings within the definition of R4 by 5 appropriate choice of starting material.
In Scheme I, the anion prepared from 1, by treatment with a strong base such as lithium di-i_rø -propylamide, is condensed with a substituted benz-aldehyde, to give, after removal of the protecting group, the diol 2. This may then be converted to the a- diketone 3 by a Swem oxidation of which any number of potentially useful variations 0 are known and may be used. The a-diketone 3 is then cyclised to an imidazole 4, a compound of formula (I), by heating 3 with a substituted benzaldehyde in a mixture of ammonium acetate, as the source of ammonia, and an appropriate solvent, for example acetic acid or DMSO. The imidazole 4 may then be transformed into other imidazoles 5 by appropriate functional group interconversion procedures. Scheme I also 5 illustrates the preparation of a protected α-hydroxyketone 2a, by condensing the anion of 1 with an appropriately activated carbonyl derivative of a substituted benzamide, such as the N-methoxy-N-methylamide, to yield a protected a-hydroxyketone. This adduct 2a may then be directly converted to the imidazole 5, using a combination of a copper (II) salt, such as copper (II) acetate, as an oxidising agent and ammon-ium 0 acetate as a source of ammonia. The α-hydroxyketone 2a may also be deprotected and
Figure imgf000019_0001
X = C02R, CHjNRj, CONR2, CHjNSOjR Y = F, S(O)nMe, n = 0-2
Scheme I Scheme II illustrates the use of an a-keto-oxime for preparing a compound of formula (I). A heterocyclic ketone 7 is prepared by adding the anion of 4-methyl- quinoline (prepared by treatment thereof with an alkyl lithium, such as n-butyl lithium) to an N-alkyl-O-alkoxybenzamide. Alternatively, the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone 7. The α-keto- oxime 8 is then prepared from 7 using standard conditions, such as reaction with sodium nitrite, and this may then be reacted with a benzaldehyde to afford an N- hydroxyimidazole 9, a compound of formula (I) in which R2 is hydroxy. This may converted to 10, a further compound of formula (I) in which R2 is hydrogen, by treating it with a deoxygenating agent such as phosphorus trichloride or a trialkyl phosphite, such as trimethyl or triethylphosphite. For compounds of formula (I) wherein R3 is -(CRι0R2θ)n-P(Z)-(XbRl3)2, the reagent OHC-(CRι0R2θ)n-P(Z)- (XbRi3)2 may be used instead of OHC-C6H4-X to make the appropriately substituted compound 9.
CH2l_i
Figure imgf000020_0001
Figure imgf000020_0002
10
Scheme II In a further process, a compound of formula (I) may be obtained by treating an a-hydroxyketone compound of formula (HA):
R'CHOHCOR" (HA) wherein one of R' and R" is Ri and the other is R4 a suitably protected derivative thereof or the a-hydroxy-oxime or a-haloketone derivative thereof, with an oxidising agent capable of converting said compound into the corresponding a-diketone, in the presence of an aldehyde of formula (HI) or an equivalent thereof, and a source of ammonia. Suitable oxidising agents include, for example, an oxidising heavy metal salt, preferably an organic copper (II) salt, such as copper (II) acetate or copper (II) citrate. The reaction may be effected in a solvent such as acetic acid, under reflux conditions. Alternatively, a lower alkanol solvent, such as methanol or ethanol, may be used, preferably at a temperature in the region of from 30 to 100°C (see The Chemistry of Heterocyclic Compounds, Imidazole and its derivatives, part I, ed. Weissberger, Interscience Publishers, Inc., New York, 1953, 38). This approach is also illustrated in Scheme I.
In a further process, a compound of formula (I) may be obtained by treatment with a compound of formula (XI) as described later. A compound of Formula (XI) is obtained by treating a compound (an amidine) of formula (IN): R3C(=ΝH)ΝHR2 (iv) wherein R2 and R3 are as hereinbefore defined, or a salt thereof, with a reactive ester of an α-hydroxyketone of formula (HA) or the corresponding α-haloketone, in an inert solvent such as a halogenated hydrocarbon solvent, for example chloroform, at a moderately elevated temperature and, if necessary, in the presence of a suitable condensation agent such as a base. Suitable reactive esters include esters of strong organic acids such as a lower alkane sulphonic or aryl sulphonic acid, for instance, methane or/?-toluene sulphonic acid. The amidine of formula (IN) 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 of formula (IN) may be obtained by standard methods, see for instance, Garigipati R, Tetrahedron Letters, 190, 31, 1989.
Compounds of Formula (IV) wherein R2 is methyl, for instance may be made by the route indicated below.
Figure imgf000022_0001
In a further process, a compound of formula (I) may be obtained by treating an iminoether of formula (V):
R3C=NOR (V) wherein R3 is as hereinbefore defined and R is CMO alkyl, aryl or aryl C1-4 alkyl, with an α-aminoketone of the formula (VI):
R,CHNH2COR" (VI) wherein one of R' and R" is Ri and the other is R4 in a suitable solvent
In a further process, N-substituted compounds of formula (I) may be prepared by treating the anion of an amide of formula (VII):
R1CH2NR2COR3 (VII) wherein Ri and R3 are as hereinbefore defined and R2 is as hereinbefore defined other than hydrogen, with:
(a) a nitrile of the formula (VIII):
R4CN (VIE) wherein R4 is as hereinbefore defined, or
(b) an excess of an acyl halide, for instance an acyl chloride, of the formula (IX):
R4COHal (DC) wherein R4 is as hereinbefore defined and Hal is halogen, or a corresponding anhydride, to give a bw-acylated intermediate which is then treated with a source of ammonia, such as ammonium acetate. This approach permits the regiospecific preparation of compound of formula (I) substituted at the 1 -position, as illustrated in Scheme HI. A primary amine RNH2 is treated with 4-chloromethylpyridine to give 11 which is then converted to the amide 12 by standard techniques. Deprotonation of 12 with a strong amide base, such as lithium di-wo-propyl amide or sodium bi_y-(trimethylsilyl)amide, followed by addition of an excess of an aroyl chloride yields the bw-acylated compound 13 which is then closed to an imidazole compound of formula (I), 14, by heating in acetic acid containing ammonium acetate. Alternatively, the anion of 12 may be reacted with a
Figure imgf000023_0001
Scheme HI
In a further process, compounds of formula (I) may be prepared by treating a compound of formula (X): R,COCHR"XcCOR3 (X) wherein R', R" and R3 are as hereinbefore defined and Xc is O or NH, with a source of ammonia, as hereinbefore described, under imidazole ring forming conditions or cyclising the corresponding Schiffs base, formed by treating the compound of formula (X) in which Xc is NH with an amine R2NH2, for instance thermally or with the aid of a cyclising agent such as phosphoras oxychloride or phosphoras pentachloride (see Engel and Steglich, Liebigs Ann Chem, 1978, 1916 and Strzybny et al., J Org Chem, 1963, 28, 3381). Compounds of formula (X) may be obtained, for instance, by acylating the corresponding a-keto-oxime (Xc is NH) or a-hydroxyketone (Xc is O) with an acyl halide of the formula R3COHal wherein R3 is as hereinbefore defined, or the corresponding anhydride, under standard acylating conditions.
In a further process, compounds of formula (I) may be prepared by coupling a suitable derivative of a compound of formula (XI):
Figure imgf000024_0001
wherein: T2 is a nitrogen protecting group or R2, other than hydrogen; and Ti is hydrogen, T3 is Q and T4 is R4; Ti is Ri, T3 is hydrogen and T4 is R4; or Ti is Ri, T3 is Q and T4 is hydrogen , in which Ri, R2, R3, R4 and Q are as hereinbefore defined; with: (i) when Ti is hydrogen, a suitable derivative of the heteroaryl ring RiH, under, ring coupling conditions, to effect coupling of the heteroaryl ring Ri to the imidazole nucleus at position 5; (ii) when T3 is hydrogen, a suitable derivative of the aryl or heteroaryl ring QH, under ring coupling conditions, to effect coupling of the ring Q to the imidazole nucleus at position 2; or (iii) 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.
Such aryl/heteroaryl coupling reactions are well known to those skilled in the art. In general, an organometallic synthetic equivalent of an anion of one component is coupled with a reactive derivative of die second component, in the presence of a suitable catalyst. The anion equivalent may be formed from either the imidazole of formula (XI), 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. Accordingly, suitable derivatives of the compound of formula (XI) or the aryl/heteroaryl rings include organometallic derivatives such as organomagnesium, organozinc, organostannane and boronic acid derivatives and suitable reactive derivatives include the the bromo, iodo, fluorosulfonate and trifluoromethanesulphonate derivatives. Suitable procedures are described in WO 91/19497, the disclosure of which is herewith incorporated.
Suitable organomagnesium and organozinc derivatives of a compound of formula (XI) 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 (II) catalyst, following the procedure of Kumada et al., Tetrahedron Letters, 22, 5319 (1981). Suitable such catalysts include tetrαfa'5- (triphenylphosphine)palladium and PdCl2[l,4-b 5-(diphenylphosphino)-butane], optionally in the presence of lithium chloride and a base, such as triethylamine. In addition, 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, J. Org. Chem, 1982, 47, 4319. Suitable reaction solvents include hexamethylphosphor-amide. When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-bromo- and 4- iodo-pyridine and the fluorosulfonate and triflate esters of 4-hydroxy pyridine. Similarly, 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 (XI) or the bromo derivative thereof with an alkyllithium compound to yield the corresponding lithium reagent by deprotonation or transmetallation, respectively. This lithium intermediate may then be treated with an excess of a magnesium halide or zinc halide to yield the corresponding organometallic reagent.
A trialkyltin derivative of the compound of formula (XI) 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 tetrα/α'5-(triphenylphosphine)- palladium, by the method described in by Stille, J. Amer. Chem. Soc, 1987, 109, 5478, US Patents 4,719,218 and 5,002,942, or by using a palladium (II) catalyst in the presence of lithium chloride optionally with an added base such as triethylamine, in an inert solvent such as dimethyl formamide. Trialkyltin derivatives may be conveniently obtained by metallation of the corres-ponding compound of formula (XI) with a lithiating agent, such as j-butyl-lithium or «-butyllithium, in an ethereal solvent, such as tetrahydrofuran, or treatment of the bromo derivative of the corresponding compound of formula (XI) with an alkyl lithium, followed, in each case, by treatment with a trialkyltin halide. Alternatively, the bromo- derivative of a compound of formula (XI) may be treated with a suitable heteroaryl or aryl trialkyl tin compound in the presence of a catalyst such as tetrα/αKtriphenyl-phosphine)-palladium, under conditions similar to those described above.
Boronic acid derivatives are also useful. Hence, a suitable derivative of a compound of formula (XI), 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 to-(triphenylphosphine)-palladium or PdCl2[l,4-bι*5-
(diphenylphosphino)-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. Pays Bas, 84, 439, 1965, SnieckusN., Tetrahedron Lett., 29, 2135, 1988 and Terashimia, M., Chem. Pharm. Bull., 11, 4755, 1985). Νon- aqueous conditions, for instance, a solvent such as DMF, at a temperature of about 100°C, in the presence of a Pd(ϋ) 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. In such coupling reactions, it will be readily appreciated that due regard must be exercised with respect to functional groups present in the compunds of formula (XI). Thus, in general, amino and sulfur substituents should be non-oxidised or protected and the N-l nitrogen of a compound of formula (XI) be protected, if an NH compound is finally required. Nitro, bromo, iodo and hydroxyl groups should preferably be avoided in compounds of formula (XI) in which Ti is hydrogen.
Compounds of formula (XI) are imidazoles and may be obtained by any of the procedures herein before described for preparing compounds of formula (I). In particular, an a-halo-ketone R4COCH2Hal (for compounds of formula (XI) in which Ti is hydrogen) or RιCOCH2Hal (for compounds of formula (XI) in which T4 is hydrogen) may be reacted with an amidine of formula (TV) or a salt thereof, in an inert solvent such as a halogenated hydrocarbon solvent, for instance chloroform, at a moderately elevated temperature, and, if necessary, in the presence of a suitable condensation agent such as a base. The preparation of suitable a-halo-ketones is described in WO 91/19497. For a compound of formula (XI) in which T3 is hydrogen, an a-diketone of formula (IT) may be condensed with a formaldehyde, or an equivalent thereof, in the presence of a source of ammonia. Suitable bromo derivatives of the compound of formula (XI) may be obtained by brominating the corresponding compound of formula (XI) under standard brominating conditions, for instance bromine in a solvent such as dichloromethane or THF. Compounds of formula (I) may also be prepared by a process which comprises reacting a compound of formula (XI), wherein Ti is hydrogen, with an N-acyl heteroaryl salt, according to the method disclosed in US patents 4,803,279, 4,719,218 and 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. 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 (XI) in the heteroaryl compound RiH or in an inert solvent such as methylene chloride to which the heteroaryl compound has been added. 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 incorporated in their entirety. Suitable oxidising systems include sulfur in an inert solvent or solvent mixture, such as decalin, decalin and diglyme, /j-cymene, xylene or mesitylene, under reflux conditions, or, preferably, potassium t-butoxide in t-butanol with dry air or oxygen.
Once the imidazole nucleus has been established, further compounds of formula (I) which may be prepared by applying standard techniques for functional group interconversion, for instance: -C(O)NR8R9 from -CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and.HNRgR9 in CH3OH; -OC(O)Rs from -OH with e.g.,ClC(O)Rs in pyridine; -NRιo-C(S)NRδR9 from -NHRio with an alkylisothiocyante or thiocyanic acid; NR6C(O)OR6 from -NHR with the alkyl chloroformate; -NRιoC(O)NRgR9 from -NHRio by treatment with an isocyanate, e.g. HN=C=O or RιoN=C=O; -NRιo-C(O)R8 from -NHRio by treatment with Cl- C(O)R8 in pyridine;
Figure imgf000027_0001
from -C(NRsR9)SR8 with H3NR8+OAc" by heating in alcohol; -C(NR8R9)SR8 fr°m -C(S)NR8R9 i R6-I m an inert solvent, e.g. acetone; -C(S)NRsR9 (where Rs or R9 is not hydrogen) from -C(S)NH2 with HNR8R9, -C(=NCN)-NR8R9 from ith NH2CN by heating in anhydrous alcohol, alternatively fro
Figure imgf000027_0002
by treatment with BrCN and NaOEt in EtOH;
Figure imgf000027_0003
from -NHRio by treatment with (R8S)2C=NCN; -NR10SO2R8 from -NHRio by treatment with CISQ2R8 by heating in pyridine; -NRιoC(S)R8 from -NRιoC(O)R8 by treatment with Lawesson's reagent [2,4-bw(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide]; -NRioSO2CF3 from -NHR6 with triflic anhydride and base; -NRιoC(O)-C(O)-OR8 from -NHRio with, e.g. methyloxalyl chloride and a base such as triethylamine; -NRιoC(O)-C(O)- NR8R9 from -NRιoC(O)-C(O)-OR8 with HNR8R9; and l-(NRιo)-2-imidazolyl from -C(=NH)NHRιo by heating with 2-chloroacetaldehyde in chloroform (wherein R^, R$, R9 and R10 are as hereinbefore defined).
Compounds of formula (I) in which R2 is hydrogen may be readily converted into further compounds of formula (I) in which R2 is other than hydrogen, for instance alkyl, by conventional procedures such as alkylation or acylation followed by reduction. Such methods are in general relatively inefficient as they lack regiospecificty and the desired N-l product has to be separated from the mixture of N- 1 and N-3 products, for instance by chromatography or fractional crystallisation.
Compounds of Formula (I) wherein R2 is methyl and Ri is 4-pyridyl or 4-(2- amino)pyrimidinyl for example may be made by the route indicated below.
Figure imgf000028_0001
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, (CRιoR2θ)n' as defined in Formula (I). Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.
It should be noted that the compounds of Formula (I),where R4 may be an alkylsulfinyl, arylsulfinyl, alkylsulfonyl, or arylsulfonyl are prodrags which are reductively converted in vivo to the corresponding alkylthio or arylthio form. Pharmaceutically acid addition salts of compounds 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 invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
Synthetic Examples
Example 1 2-(4-Cyanophenyl)-4-(4-fluorophenyI)-5-(4-pyridyl)-lH-imidazole a) To a solution of 2-(4-cyanophenyl)-4-(4-fluorophenyl)-N-l-hydroxy-5-(4- pyridyl)imidazole (4.5 g, 13.2 mmol) [See 1(b) below] in DMF (50 mL) was added triethyl phosphite (3.4 mL, 20 mmol), and the resulting mixture was heated at 100 °C for 2 h. After cooling, the mixture was poured into H2O, and the solid which formed was collected by filtration, washed with H2O and dried in vacuo to afford the title compound (4.0 g, 89%). Recrystallization from CH2θ2/MeOH gave white solid with a mp of 268-269 °C. b) 2-(4-Cyanophenyl)-4-(4-fiuorophenyl)-N-l-hydroxy-5-(4- pyridyI)imidazoIe The title compound was prepared using the same procedure (US 3,940,486) employed to prepare 2-(t-butyl)-4-(phenyl)-N- l-hydroxy-5-(4- pyridyl)imidazole, except using 4-fluoro-2-hydroxyimino-2-(4-pyridyl)acetophenone and 4-cyanobenzaldehyde: *H NMR (CDCI3): d 8.27 (d, 2H); 7.94 (d, 2H); 7.72 (d, 2H); 7.35 (d, 2H); 7.30 (dd, 2H); 6.96 (t, 2H).
Example 2
4-(4-FIuorophenyl)-2-(4-methylthiophenyI)-5-(4-pyridyI)-lH-imidazoIe
(a) l-(t-ButyldimethyIsilyloxy)-2-(4-fluorophenyI)-l-(4-pyridyl)ethanone
To a -20 °C solution of dϋsopropylamine (64.4 mL, 0.46 mol) and THF (120 mL) was added 207.8 mL (0.52 mol, 2.5 M solution in hexanes) of n-butyllithium dropwise over 15 min. The temperature was lowered to -15 °C and the mixture was stirred for 0.5 hr. The solution was cooled to -20 °C and 98.14 g (0.44 mol) of 4-(t- butyldimethylsilyloxy)methyl pyridine was added dropwise over 20 min. After stirring at -20°C for 45 min, a solution of 4-fluoro-N-methoxy-N-methylbenzamide (84.5 g, 0.46 mol) [See Ex. 10, step (a)] in THF (90 mL) was added dropwise over 0.5 hr. Once the addition was complete, the ice bath was removed and the reaction mixture was warmed to 0 °C for 1 hr, then stirred at it for 1.5 hr. The mixture was poured into a solution of NH4CI (98 g) and H2O (500 mL), then extracted with EtOAc (3 x 250 mL). The EtOAc extracts were washed with H2O and saturated NaCl, then dried over MgSO Evaporation of the solvent in vacuo afforded the title compound as an amber oil (114.2 g, 75%).
(b) 4-(4-Fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-lH-imidazole To a solution of l-(t-butyldimethylsilyloxy)-2-(4-fluorophenyl)-l-(4-pyridyl)ethanone (6.3 g, 18.3 mmol) in glacial acetic acid (125 mL) was added anhydrous copper (II) aetate (6.6 g, 36.5 mmol), ammonium acetate (14 g, 183 mmol) and 4- (methylthio)benzaldehyde (3.5 g, 22.9 mmol) and the mixture was heated at reflux. After 1 hr, the reaction was cooled then poured into a mixture of cone. NH4OH (175 mL), ice (100 mL) and EtOAc (100 mL). The resulting mixture was stirred for 15 min, then the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were washed with saturated NaCl and dried over MgSO Evaporation of solvent in vacuo gave an oil which was taken up in acetone. 3 N HCl was added dropwise to adjust the pH to 2-3; and the resulting solid was filtered. The title compound was isolated as the yellow hydrochloride salt (3.7 g, 51%).
Example 3 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-lH-imidazole
To a solution of 4-(4-fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-lH- imidazole (0.80 g, 2.2 mmol) [See Ex. 2 above] in glacial acetic acid (15 mL) was added a solution of K2S2O8 (0.72 g, 2.6 mmol) in H2O (20 mL). Additional glacial acetic acid (15 mL) was added to ensure homogeneity, and the resulting solution was stirred at rt for 18 h. The mixture was then poured into H2O, and the pH was adjusted to neutral by the addition of cone. NH4OH. The solid which formed was collected by filtration to afford the title com-pound (0.65 g, 78%) as a tan solid, which was recrystallized from MeOH: mp 250-252 °C.
Example 4 4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-lH-imidazole To a solution of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)- lH-imidazole (3.7 g, 9.8 mmol) [See Ex. 3 above] in 1:103 N HCI/H2O (88 mL) was added a solution of KMnO4 (1.5 g, 9.8 mmol) in H2O (15 mL). After stirring at rt for 1 h, additional KMnθ4 (0.15 g, 0.9 mmol) was added, and stirring was continued for 15 min. The mixture was then poured into saturated aqueous Na2SO3 (200 mL), and the pH was adjusted to slightly acidic by the addition of 3 N HCl, then to neutral by the addition of 2.5 N NaOH. The solid which formed was collected by filtration, washed successively with H2O and MeOH and recrystallized three times from MeOH to afford the title compound (0.63 g, 16%): mp 148-149 °C.
Example 5 4-(4-FIuorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 2(b), except using 3-(methylthio)-benzaldehyde.
Example 6 4-(4-Fluorophenyl)-2-(3-methyIsulfinylphenyI)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 3, except using 4-(4-Fluorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)- lH-imidazole.
Example 7
4-(4-FIuorophenyl)-2-(3-methylsulfonylphenyl)-5 4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 2, except using 4-(4-Fluorophenyl)-2-(3-methylsulfinylphenyl)-5-(4- pyridyl)- 1 H-imidazole.
Example 8 4-(4-Fluorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 2 (b), except using 2-(methylthio)-benzaldehyde.
Example 9 4-(4-Fluorophenyl)-2-(3-methyIsulfinylphenyI)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 3, except using 4-(4-Fluorophenyl)-2-(2-methylthiophenyl)-5-(4-pyridyl)- 1 H-imidazole.
Example 10 4-(4-Fluorophenyl)-2-(2-methylsulfonylphenyl)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 2, except using 4-(4-Fluorophenyl)-2-(2-methylsulfinylphenyl)-5-(4- pyridyl)- 1 H-imidazole. Example 11 4-(4-FluorophenyI)-2-(thiophen-2-yl)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 2(b), except using 2-thiophene carboxaldehyde.
Example 12 4-(4-Fluorophenyl)-2-(thiophen-3-yl)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 81(b), except using 3-thiophene carboxaldehyde.
Example 13 4-(naphth-l-yI)-2-(4-methyIthiophenyl)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 2 (a), except using l-naphth-(N-methoxy-N-methyl)amide.
Example 14 4-(naphth-2-yl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 2(a), except using 2-naphth-(N-methoxy-N-methyl)amide.
Example 15 4-(naphth-l-yl)-2-(4-methyIsulfinylphenyI)-5-(4-pyridyI)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 3, except using 4-(naphth-l-yl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-lH- imidazole.
Example 16 4-(naphth-2-yl)-2-(4-methylsulfinyIphenyl)-5-(4-pyridyI)-lH-imidazole
The title compound was prepared using the same procedure as described in Example 3, except using 4-(naphth-2-yl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-lH- imidazole.
Example 17 2-(4-Cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyI)-lH-imidazoIe The title compound was prepared using the same procedure as described in
Example 2 (b), except using 4-cyanobenzaldehyde, mp 268-269. Example 18 2-(4-AminomethyIphenyl)-4-phenyl-5-(4-pyridyl)-imidazole
To a solution of 2-(4-cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-lH- imidazole (2.5 g, 7.3 mmol) [See Ex. 17 above] in THF (50 mL) was added LiAlHφ (7.3 mL of 1 M solution in THF, 7.3 mmol), and the resulting mixture was heated at reflux for 2 h, at which time tic analysis indicated that the reaction was incomplete. Additional LiAlH4 (4.0 mL, 4.0 mmol) was added and heating was continued for 30 min. The mixture was allowed to cool, then poured into 2.5 N NaOH and extracted with THF. The organic extract was washed with saturated aqueous NaCl and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 9:1 CHCl3/MeOH, followed by 90:10:1 CHCl3/MeOH/NH3. The material that was isolated was triturated with E-2O to afford the title compound (1.5 g, 60%): mp 214-215 °C.
Example 19
2-(4-Biotinamidomethylphenyl)-l-memyl-4-phenyl-5-(4 yridyl)-imidazole
To a solution containing 2-(4-Aminomethylphenyl)-4-phenyl-5-(4-pyridyl)- imidazole (1 equivalent) in DMF was added N-hydroxysuccinimide biotin (1.2 eq). Follwing normal workup and chromatography the title compound was obtained: CIMS (NH3, m/z): 523 (M++H).
Example 20 4-(4-FluorophenyI)-l-methyl-2-(4-memylsuIfinyI)phenyI-5-(4-pyridyl)imidazole
(a) N-Methyl-4-(methyIthio)phenyl benzamidine - The title compound was prepared following the procedure fo Garigipati (Tetrahedron Lett. 1990, 31(14), 1969) except using methylamine hydrochloride and 4-(methylthio)-benzonitrile.
(b) 4-(4-Fluoro)phenyI-l-methyl-2-(4-methylthio)phenylimidazole - The title compound was prepared following the procedure of Fitzi (U. S. Patent 3,940,486) except using N-methyl-4-(methio)phenylbenzamidine and 2-chloro-4'- fluoroacetophenone.
(c) 4-(4-Fluoro)phenyl-l-methyl-2-(4-methylthio)phenyl-5-(4- pyridyl)imidazole -The title compound was prepared by the procedure of Lantos et al.
(J. Org. Chem. 1988, 53, 4223) except using 4(4-fluoro)phenyl-l-methyl-2-(4- methylthio)phenylimidazole. (d) 4-(4-Fluoro)phenyl-l-methyI-2-(4-methylsulfinyl)phenyl-5-(4- pyridyl)imidazole - The title compound was prepared by the same procedure as described in Example 20 except usuing 4-(4-fluoro)phenyl-l-methyl-2-(4- methylthio)phenyl-5-(4-pyridyl)imidazole: CIMS (NH3, m/z ): 392 (M+ + H).
Example 21 4-(4-FIuoro)phenyl-l-methyl-2-(4-methylthio)phenyl-5-[4-(2-amino)- pyrimidinyl]imidazole
(a) 4-(4-Fluoro)phenyl-l-methyl-2-(4-methythio)phenyl-5-tτi-n- butylstannylimidazole - The title compound was prepared by the procedure of Bender et al. (U. S. Patent 5,145,858 & US 5,002,941) except using 4-(4-fluoro)phenyl-l- methyl-2-(4-methylthio)phenylimidazole.
(b) 4-(4-Fluoro)phenyl-l-methyl-2-(4-methylthio)phenyl-5-[4-(2- methylthio)pyrimidinyl]imidazole - A mixture of 4-(4-Fluoro)phenyl-l-methyl-2-(4- memythio)phenyl-5-tri-n-butylstannylimidazole (0.25 g, 0.42 mmol), 4-iodo-2- methythiophenylpyrimidine (0.16 g, 0.63 mmol) [prepared by the procedure of Majeed et al. (Tetrahedron 1989, 45(4), 993)] and bis(triphenylphosphine)-palladium(II) dichloride (0.30 g, 0.42 mmol) in 1,2 dichloroethane (10 mL) was heated to reflux for 24 h. The reaction mixture was cooled to ambient temperature and a solution of saturated potassium fluoride in methanol (2 mL) was added. After stirring for 1 h at ambient temperature, the mixture was poured into water and extracted twice with dichloromethane. The organic layers were combined, washed with saturated aqueous sodium chloride, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography eluting with dichloromethane to afford the title compound as a yellow foam ( 0.14 g, 78%).
(c) 4-(4-Fluoro)phenyl-l-methyl-2-(4-methylsulfonyl)phenyI-5-[4-(2- methylsulfonyI)pyrimidinyl]imidazole - To a solution of 4-(4-Fluoro)phenyl-l- methyl-2-(4-methylthio)phenyl-5-[4-(2-methylthio)pyrimidinyl]imidazole (0.10 g, 0.24 mmol) in dichloromethane (10 mL) was added 80% -chloroperbenzoic acid (0.25 g, 1.2 mmol). After stirring at ambient temperature for 18 h, the reaction mixture was poured into saturated aqueous sodium carbonate and the layers were separated. The organic phase was washed with saturated aqueous sodium chloride, dried (MgSO4) and evaporated. The residue was purified by flash chromatography eluting successively with dichloromethane and 1% methanol in dichloromethane to afford the title compound as a yellow foam (0.11 g, 94%).
(d) 4-(4-Fluoro)phenyl-l-methyI-2-(4-methylthio)phenyl-5-[4-(2- amino)pyrimidinyl]imidazole - 4-(4-Fluoro)phenyl- l-methyl-2-(4-methylsulf onyl)- phenyl-5-[4-(2-methylsulfonyl)pyrimidinyl]imidazole (0.50 g, 0.10 mmol) was added to concentrated ammonium hydroxide (2 mL) and reaction mixture was heated to 150°C in a sealed vessel. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted twice with dichloromethane and once with 4% methanol in dichloromethane. The organic layers were combined and the solvent evaporated. The residue was purified by flash chromatography eluting successively with 2%, 4% and 10% methanol in dichloromethane followed by trituration with ether to afford the title compound as a white solid (0.017 g, 39%): CIMS (NH3, m z): 424 (M+ + H).
The following compounds may be made by analagous methods to those described above:
Example 22 4-(4-Fluorophenyl)-2-(4-methylsulfmylphenyl)-l-(N- morpholinopropyl)-5-(4-pyridyl)imidazole; Example 23 4-(4-Fluorophenyl)-2-(4-methylthiophenyl)- 1 -(N-morpholinopropyl)-5- (4-pyridyl)imidazole; Example 24 4-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-l-(N-morpholino- propyl)-5-(4-pyridyl)imidazole; Example 25 4-(4-Fluorophenyl)- l-(methylthio- l-propyl)-2-([4-N-morpholino- methyl]phenyl)-5-(4-pyridyl)imidazole; Example 26 4-(4-Fluorophenyl)-l-(methylsulfinyl-l-propyl)-2-([4-N-morpholino- methyl]phenyl)-5-(4-pyridyl)imidazole;
Example 27 4-(4-Fluorophenyl)- 1 -(methylsulfonyl- l-propyl)-2-([4-N-morpholino- methyl]phenyl)-5-(4-pyridyl)imidazole.
METHODS OF TREATMENT The compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used in the manufacutre 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 producution by such mammal's cell, such as but not limited to monocytes and/or macrophages. Compounds of formula 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. Accordingly, the present invention provides a method of treating a cytokine- mediated disease which comprises administering an effective cyto-dne-interferring amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In particular, 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 IL-1, IL-8 or TNF production by such mammal's cell, such as, but not limited to, monocytes and/or macrophages.
Accordingly, in another aspect, 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.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These 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, 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 β cells and Alzheimer's disease.
In a further aspect, 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
Excessive or unregulated 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, such as osteoporosis, reperfusion injury, graft vs. host reaction, 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. Compounds 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 (I). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenoviras and the Herpes group of viruses, such as but not limited to, Herpes Zoster and Herpes Simplex. Accordingly, in a further aspect, this invention relates to a method of treating a mammal afflicted with a human immunodeficiency viras (HIN) which comprises administering to such mammal an effective TΝF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
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 TΝF production. TΝF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to, the lentiviras infections such as equine infectious anaemia viras, caprine arthritis viras, visna viras, or the maedi virus, or the retrovirases, such as feline immunodeficiency viras (FT ), bovine immunodeficiency viras, or canine immunodeficiency virus.
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 IL-1 or TΝF 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 Formula (I) have also been shown to inhibit the production of IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, 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.
There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or causing the disease. These 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 IL-8 production which is responsible for the chemotaxis of neutrophils into the inflammatory site. 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 neutophil infiltration. The compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine, in particular IL-1, 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. Abnormal levels of IL-1, IL-8 or TNF, for instance in the context of the present invention, constitute: (i) levels of free (not cell bound) IL-1, D - 8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1, IL-8 or TNF; or (iii) the presence of IL-1, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1, IL-8 or TNF, respectively, is produced.
The discovery that the compounds of Formula (I) are inhibitors of cytokines, specifically IL-1, IL-8 and TNF is based upon the effects of the compounds on the production of the IL- 1 , IL-8 and TNF in in vitro assays which are described herein. As used 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-6, IL-1, IL-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 (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational 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.
As used herein, the term "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 IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease stated mediated by TNF.
As used herein, the term "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. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce 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 lymphoctye cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF-β).
As used herein, the term "cytokine interfering" or "cytokine suppresive 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.
As used herein, the cytokine referred to in the phrase "inhibition of a cytokine, for use in the treatment of a HTV-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.
As TNF-β (also known as lymphotoxin) has close structural homology with TNF-α (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-α and TNF-β are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise.
In order to use 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, therefore, 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), or pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drag 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 (lb) 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. It will be appreciated that the form and character of the pharmaceutically acceptable carrier 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. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, 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.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, 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 25mg. to about lg. When a liquid carrier is used, 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. In contrast, 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. They 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 σleic 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 esteror 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. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of 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 formua (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. For all methods of use disclosed herein for the compounds of formula (I), 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. It will also be recognized by one of skill in the art that 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.
BIOLOGICAL EXAMPLES
The cytokine-inhibiting effects of compounds of the present invention were determined by the following in vitro assays: Interleukin-1 (IL-1)
Human peripheral blood monocytes were 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 (lxlθ were plated in 24-well plates at a concentration of 1-2 million/ml per well. The cells were allowed to adhere for 2 hours, after which time non-adherent cells were removed by gentle washing. Test compounds were then added to the cells for lh before the addition of lipopolysaccharide (50 ng/ml), and the cultures were incubated at 37°C for an additional 24h. At the end of this period, culture super- natants were removed and clarified of cells and all debris. Culture supematants were 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-lto 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). Compounds of formula (I) were shown to be inhibitors of in vitro IL-1 produced by human monocytes. Tumor Necrosis Factor (TNF)
Human peripheral blood monocytes were 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 were plated at a density of 1x10^ cells/ml medium/well in 24-well multi-dishes. The cells were allowed to adhere for 1 hour after which time the supernatant was aspirated and fresh medium (1ml, RPMI-1640, Whitaker Biomedical Products, Whitaker, CA) containing 1% fetal calf serum plus penicillin and streptomycin (10 units/ml) added. The cells were incubated for 45 minutes in the presence or absence of a test compound at lnM- lOmM dose ranges (compounds were solubilized in dimethyl sulfoxide/ethanol, such that the final solvent concen-tration in the culture medium was 0.5% dimethyl sulfoxide/0.5% ethanol). Bacterial lipopoly-saccharide (E. coli 055:B5 [LPS] from Sigma Chemicals Co.) was then added (100 ng/ml in 10 ml phosphate buffered saline) and cultures incubated for 16-18 hours at 37°C in a 5% CO2 incubator. At the end of the incubation period, culture supematants were removed from the cells, centrifuged at 3000 rpm to remove cell debris. The supernatant was then assayed for TNF activity using either a radio-immuno or an ΕLISA assay, as described in WO 92/10190 and by Becker et al, J Immunol, 1991, 147, 4307. Compounds of formula (I) were shown to be inhibitors of in vitro TNF production.
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 IL-1 production, at non-toxic doses.
Interleukin- 8 (IL-8)
Primary human umbilical cord endothelial cells (HUVΕC) (Cell Systems, Kirland, Wa) were maintained in culture medium supplemented with 15% fetal bovine serum and 1% CS-HBGF consisting of aFGF and heparin. The cells were then diluted 20-fold before being plated (250μl) into gelating coated 96-well plates. Prior to use, culture medium was replaced with fresh medium (200μl). Buffer or test compound (25μl, at concentrations between 1 and lOμM) was 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 was removed and assayed for IL-8 concentration using an IL-8 ΕLISA kit obtained from R&D Systems (Minneapolis, MN). All data were presented as mean value (ng/ml) of multiple samples based on the standard curve. ICso's where appropriate were generated by non-linear regression analysis. The compounds of formula (I), examples 5, 8b and 9, demonstrated a dose dependent reduction in the production of IL-8 (a 50- 65% inhibition of IL-8).
Cytokine Specific Binding Protein Assay (CSPB)
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 binding assay was developed using soluble cystosolic fraction from THP.l cells and a radiolabeled compound. For instance, a suitable radiolabeled compound of the
CSAID™ cytokine inhibitor class herein is 4-(Fluorophenyl)-2-(4-hydroxyphenyl-3,5- t2)-5-(4-pyridyl)imidazole. In brief, the THP.l cytosol was routinely prepared from cell lysate obtained by nitrogen cavitation followed by a 10 K x g low speed and a 100 K x g high speed centrifugation, the supernatant of which was designated as the cytosolic fraction. THP.l cytosol was incubated with appropriately diluted radioligand at room temperature for a pre-determined time to allow the binding to achieve equilibrium. The sample was added to a G-10 column and eluted with 20 mm TRN, 50mMb - mercaptoethanol, NaN3 The fraction encompassing the void volume was collected and the radioactivity was assessed by liquid scintillation counting. This was determined to reflect bound radioligand since the radioactive signal was abrogated by the presence of excess cold ligand in the incubation mixture or when there was no cytosolic fraction present. Compounds of Formula (I) at various doses were added to the binding assay to achieve inhibition of binding of the radiolabel. IC50S as well as
Ki values were determined by regression analysis and scatchard plot analysis respectively. There is generally excellent correlation between the IC50 of compounds tested in both the binding assay and the bioassay and can be used interchangeably in many cases.
Patent Application USSN 08/123175 Lee et al., filed September 1993 whose disclosure is incorporated by reference herein in its entirey describes the above noted method for screening drugs to identify compounds which interact with and bind to the
CSBP. However, for purposes herein 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. Alternatively, whole cells or cytosolic fractions comprising the cytokine specific binding protein may be employed in the creening protocol. Regardless of the form of the binding protein, a plurality of compounds are contacted with the binding protein under conditions sufficient to form a compound/ binding protein complex and compound capable of forming, enhancing or interfering with said complexes are detected.
More specifically, the Binding Assay is performed as follows: MATERIALS: Incubation buffer: 20 mM Tris, 1 mM MgC_2, 20 mM Hepes, 0.02% NaN3, store at 4°C. Elution buffer: 20 mM Tris, 50 mM 2-mercaptoethanol, NaN3, store at 4°C.
G-lO Sephadex: add 100 g Sephadex G-10 (Pharmacia, Uppsala, Sweden) to 400 mL dd H2O and allow to swell at room temperature for 2 hours. Decant fines and wash 3 times. Add NaN3 and qs with dd H2O to 500 mLs. and store at 4°C. Assemble Columns: Straw column, filter frit and tip (Kontes, SP 420160-000,
420162-002). Lowsorb tubes (Nunc) used in binding reaction. THP.l cytosol spun at 15000 rpm for 5 min to clarify. THP.1 cytosol prepared by hypnotic treatment of cells and lysis by decompression in nitrogen. Nuclei and membrane fragments removed by differential centrifugation (10,000 g for 1 hour and 100,000 g for 1 hour). Compounds: Non-radioactive Compound I with corresponding EtOH control
(dilutions made in incubation buffer) and ^H-Compound I (dilutions in incubation buffer)
METHOD:
A. Column Preparation 1. Begin 30 min before anticipated elution of reaction mixture.
2. Add 3 mL of G-10 slurry to column for bed vol of 1.5 ml.
3. Rinse with 7 mL elution buffer (fill to top of column)
4. Cut columns down to size.
B. Sample Incubation 1. 15 min incubation at 4CC.
2. Binding reaction mixture; 100 μL cytosol, 10 uL cold Compound I or EtOH control, 10 μL 3H-Compound I (molar concentration depends on nature of study).
3. "Free" control = 100 μL incubation buffer in lieu of cytosol preparation.
C. Sample Elution
1. Elute at 4°C. 2. Add total reaction volume to G-10 column.
3. Add 400 μL elution buffer to column and discard eluate.
4. Add 500 μL elution buffer to column, collecting eluted volume in 20 ml scintillation vial. 5. Add 15 mL Ready Safe scintillation fluid.
6. Vortex and count in liquid scintillation counter for 5 minutes. Include a "total input counts control" (10 μL of labeled ligand). D. Data Analysis
1. Plot DPMS as ouptut in graphic form and analyze by regression analysis and "Lundon ligand binding" software for the determination of IC 50 and Kd/Ki respectively.
2. Rank order the IC50s of the tested compounds in the bioassay and compare to that generated by the binding assay and establish a correlation curve. The binding assay was further validated by the following criteria that THP.1 cytosol demonstrated saturable and specific binding of the radiolabeled compound.
Preparation of 4-(Fluorophenyl)-2-(4-hydroxyphenyl-3,5-t2)-5-(4-pyridyl)imidazole, (Compound I). A 2.9 mg (0.0059 mmol) portion of 2-(3,5-Dibromo-4-hydroχyphenyl)-4-(4- fluorophenyl)-5-(4-pyridyl)imidazole, Compound I(p), was dissolved in 0.95 mL of dry DMF and 0.05 mL of triethylamine in a 2.4 mL round bottom flask equipped with a small magnetic stirring bar. A 1.7 mg portion of 5% Pd/C (Engelhard lot 28845) was added, and the flask was attached to the stainless steel tritium manifold. The mixture was degassed through four freeze-pump-thaw cycles, then tritium gas (5.3 Ci, 0.091 mmol) was introduced. The reaction mixture was allowed to warm to room temperature and was stirred vigorously for 20h. The mixture was frozen in liquid nitrogen, the remaining tritium gas (2.4 Ci) was removed, and the flask was removed from the manifold. The reaction mixture was transferred, using 3 x 1 mL of methanol as rinsings, into a 10 mL round bottom flask, and the solvents were removed by static vacuum transfer. A 1.5 mL portion of methanol was added to the residue, then removed by static vacuum transfer. The latter process was repeated. Finally, the residue was suspended in 1.5 mL of ethanol and filtered through a syringe-tip Millipore filter (0.45 micron), along with 3 x ca. 1 mL ethanol rinsings. The total filtrate volume was determined to be 3.9 mL, and the total radioactivity, 94.2 mCi. Solution was determined to be 3.9 mL, and the total radioactivity, 94.2 mCi. HPLC analysis of filtrate (Partisil 5 ODS-3, 4.6 mm I.D. x 25 cm, 1 mL min of 70:30:01 water/acetonitrile/trifluoroacetic acid, Radiomatic Flo-One Beta radio detector with 3 mL/min of Ecoscint-H cocktail through a 0.75 mL cell) showed the presence of Compound I (R^ = 60 rain. ca. 37% of total radioactivity), and a discrete intermediate presumed to be the monobromo derivative Compound la (Rt = 11.8 min, ca. 9%). The filtrate solution was evaporated to near dryness with a stream of nitrogen, and the residue was dissolved in about 1.2 mL of the HPLC mobile phase. The solution was separated by HPLC as shown below, and the peaks corresponding to Compounds I and la and SB collected separately.
HPLC Method
Column Altex Ultrasphere
10 mm I.D. x 25 cm Mobile Phase 70:30:0.1 water/acetonitrile/trifluoroacetic acid Row Rate 5 mL/min
UV detection 210nm
Injection Volumes 0.05 - 0.4 m:
Retention Times 7.8 min Compound I
24 min Compound la The pooled Compound I fractions totaled 32 mL in volume and the radioactive concentration was 1.52 mCi/mL (total 48.6 m Ci). The pooled SB Compound la [3H] fractions (totaling 10.1 mCi) were evaporated to dryness and the residue was transferred quantitatively into a glass vial using 3.8 mL of absolute ethanol for further analysis.
An 8 mL (12.2 mCi) portion of Compound I was evaporated to dryness in vacuo at <35°C, then redissolved in 0.5 mL of mobile phase. The whole volume was injected into the HPLC system described above, and the appropriate peak was collected. Evaporation of the collected eluate in vacuo at <35°C and transfer of the yellow residue into a vial with absolute ethanol provided a solution (3.8 mL, 2.44 mCi mL) of Compound I. The portion of this solution used for NMR analyses was first evaporated to dryness using stream of nitrogen then taken up in CD3OD.
Analysis of 4-(4-Fluorophenyl)-2-(4-hydroxyphenyl-3,5--2)-5-(4- pyridyl)imidazole, Compound I. Radiochemical Purity by HPLC Method Column Ultrasphere Octyl, 5mm, 4.6 mm
I.D. x 25 cm, Beckman Mobile Phase 350:150:0.5(v/v/v) water/acetonitrile/trifluoroacetic acid Row Rate 1.0 mL/min
Mass detection UV at 210 nm
Radioactivity detection Ramona-D radioactivity flow detector Scintillator Tru-Count (Tru-Lab Supply Co.)
Row rate 5.0 mL/min
Cell volume 0.75 mL
Retention time 7.7 min Result i
Radioactive Concentration by Scintillation Counting Method
Scintillator Ready Safe (Beckman Instruments, Inc.)
Instrument TM Analytic model 6881
Efficiency Automated DPM calculation from quench curve
Result 2.44 mCi/mL
Specific Activity by Mass Spectrometry
Method CI-MS, NH3 reagent gas Result 20.0 Ci/mmol
3H Distribution.
Unlabeled 44%
Single Label 43%
Double Label 13%
3H NMR9 Method Instrument Brunker AM 400 Experiment Proton decoupled 3H NMR Proton non-decoupled 3H NMR Proton non-decoupled 3H NMR
Peak Referencing Solvent Peak of methanol d 3.3 Solvent Methanol-d4 Result Tritium is incorporated exclusively on the carbon atoms ortho to aromatic hydroxyl group Analytical Summary Assay Result
Radiochemical purity determined by HPLC 98.7%
Radioactivity concentration determined by scintillation 2.44 mCi/mL counting
Specific activity determined by mass spectrometry 20.0 Ci/mmol 3H NMR agrees with the proposed structure
Representative compounds of Formula (I), Examples 1 to 21 herein have all demonstrated positive inhibitory activity in this binding assay.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be constraed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is
1. A compound of the formula:
Figure imgf000049_0001
wherein:
Rl is 4-pyridyl, pyrimidinyl, or quinolyl, which is optionally substituted with one or two substituents each of which is independently selected from C1.4 alkyl, halogen, Ci-4 alkoxy, Ci-4 alkylthio, NR10R2O, or N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
R2 is an optionally substituted Ci-io alkyl, optionally substituted C3-7cycloalkyl, or an optionally substituted C3-7cycloalkyl Ci-io alkyl, an optionally substituted aryl, an optionally substituted heterocyclic alkyl, an optionally substituted heterocyclic, optionally substituted heteroaryl or heteroarylalkyl, (CRioR20)n'ORi3, (CRioR20)n'S(O)mR25, (CRlθR2θ)n,NR8R9,
(CRioR20)n'C(Z)ORi3, (CRlθR2θ)n'NHS(O)2R25. (CRlθR2θ)n'C(Z)Rl3, or (CRl0R20)n'C(=NOR2l)Rl3; n' is an integer having a value of 1 to 10; n is 0 or an integer from 1 to 10; m is 0, or the integer 1 or 2; R3 is or Q-(Yi)f, Q is an aryl or heteroaryl group; ' t is a number having a value of 1, 2 or 3; Z is oxygen or sulfur; Yi is independently selected from hydrogen, C1-5 alkyl, halo-substituted C1-5 alkyl, halogen, or -(CRιoR2θ)nY2; Y2 is -OR8, -NO2, -S(O)m'Rι 1, -SRg, -S(O)mOR8, -S(O)mNRgR9, -NR8R9, -O(CRι0R2θ)nNR8R9, -C(O)R8, -CO2R8, -^(CR^o CONR8R9, -ZC(O)R8, -CN, -C(Z)NR8R9, -NRι0C(Z)R8, -C(Z)NR8OR9, -NRι0C(Z)NR8R9, -NRι0S(O)mRι 1, -N(OR2i)C(Z)NRsR9, -N(OR2ι)C(Z)R8, -C(=NOR2ι)Rs,
-NRioC(=NRi5)SRn, -NRι0C(=NRι5)NR8R9, -NRι0C(=CRi4R24)SRll, -NRi0C(=CRi4R24)NR8R9, -NRι0C(O)C(O)NR8R9, -NRι0C(O)C(O)ORι0, -C(=NRi3)NR8R9, -C(=NORi3)NR8R9, -C(=NRι3)ZRιι, -OC(Z)NR8R9, -NRι0S(O)mCF , -NRi0C(Z)ORio, 5-(Rι8)-l,2,4-oxadizaol-3-yl or 4-(Rι2)-5- (Ri Rχ9)-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl; m' is a number having a value of 1 or 2;
R4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l-yl or 5-naphth-2-yl substitiuent, is halo, cyano, -C(Z)NR7Rπ, -C(Z)OR23, -(CRιoR2θ)m"'COR36, SR5, -SOR5, -OR36, halo-substituted-Ci-4 alkyl, CM alkyl, -ZC(Z)R36, -NRι0C(Z)R23, or -(CRιoR2θ)m"'NRιoR20 a d which, for other positions of substitution, is halo, cyano, -C(Z)NRi6R26» -C(Z)OR8, -(CRιoR2θ)m"COR8, -S(O)mR8, -ORs, halo-substituted-Ci-4 alkyl, -C1-4 alkyl, -(CRιoR2o)m"NRιoC(Z)R8, -NRιoS(O)m'Rn, -NRι0S(O)m'NR7Ri7 -ZC(Z)R8 or -(CRιoR2θ)m'NRi6R26; wherein m" is 0 to 5 and m'" is 0 or 1 ;
R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moeities -SR5 being -SNR7R17 and -SOR5 being -SOH; R6 is Ci-4 alkyl, halo-substituted-Cι_4 alkyl, C2-4 alkenyl, C2-4 alkynyl or C3-5 cycloalkyl; 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 NR22; R8 is hydrogen, heterocyclyl, heterocyclylalkyl or Rn; R9 is hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-.7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and R9 may 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 NR12; Rio and R20 is each independently selected from hydrogen or C 1.4 alkyl;
Rn is Ci-io alkyl, halo-substituted Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-.7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; Rl2 is hydrogen, -C(Z)Ri3 or optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted arylCι_4 alkyl, or S(O)2R25. R13 is hydrogen, Cμio alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclylC i- 10 alkyl , aryl, arylCi-io alkyl, heteroaryl or heteroaryl Ci-io alkyl; Rl4 and R24 is each independently selected from hydrogen, alkyl, nitro or cyano; Rl5 is hydrogen, cyano, C1-4 alkyl, 03.7 cycloalkyl or aryl; Rl6 and R26 is each independently selected from hydrogen or optionally substituted C 1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4 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 NR12; Rl and R19 is each independently selected from hydrogen, Ci-4 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl or together denote a oxygen or sulfur;
R21 is hydrogen, a pharmaceutically acceptable cation, Ci-io alkyl, C3_7 cycloalkyl, aryl, aryl Cι_4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or Ci-io alkanoyl ; R22 is Rio or C(Z)-Cι_4 alkyl; R23 is Cι_4 alkyl, halo-substituted-Cι_4 alkyl, or C3..5 cycloalkyl;
R36 is hydrogen or R23;
R25 is Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-Ci-ioalkyl, heteroaryl or heteroarylalkyl; R27 is hydrogen, cyano, Cι_4 alkyl, C3-7 cycloalkyl, or aryl; or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 wherein Ri is optionally substituted 4-pyridyl, or 4-pyrimidinyl group.
3. The compound according to Claim 2 wherein the optional substituent is selected from alkyl, amino, or mono- or di-alkyl amino.
4. The compound according to Claim 3 wherein R2 is an optionally substituted heterocyclic or heterocyclic alkyl moiety.
5. The compound according to Claim 2 wherein R2 is morpholino, pyrrolidinyl, piperidinyl group, piperidinylalkyl, pyrrolidinylalkyl, morpholinoalkyl, and phenoxyalkyl, all of which may be optionally substituted; ethoxyalkyl, aminoalkyl, diethylamino, (phenylmethyl-N-methyl)aminoalkyl, or (phenylmethyl)amino-l- propyl.
6. The compound according to Claim 5 wherein R2 is l-Formyl-4-piperidine, 1- benzyl-4-piperidine, 1 -methyl-4-piperidine, 1 -ethoxycarbonyl-4-piperidine.
7. The compound according to Claim 1 wherein R3, the group Q comprises an optionally substitued phenyl or thienyl moiety.
8. The compound according to Claim 7 wherein the substituent Q is phenyl substitued by halogen, halosubstituted alkyl, or -(CRιoR2θ)nγ2 and Y2 is -ORs, -S(O)m-Rn, -SR8, -S(O)mNR8R9, or -NR8R9.
9. The compound according to Claim 1 wherein R4 is optionally substitued phenyl, naphth-1-yl or naphth-2-yl wherein the 4-phenyl, 4-naphth-l-yl or 5-naphth-2- yl moiety are substituted by one or two substituents each independently selected from halogen, -SR5, -SOR5, -OR36, or -(CRιoR2θ)mNRιoR20> and for other positions of substitution on these rings the substitution is halogen, -S(O)mR8, -ORs, -(CRι0R2θ)mNRι6R26, -NRιoC(Z)R8 and -NRι0S(O)mRn.
10. A pharmaceutical composition comprising a compound according to any of Claims 1 to 9 and a pharmaceutically acceptable carrier or diluent.
11. A compound of formula (I) :
Figure imgf000052_0001
wherein:
Rl is an optionally substituted 4-pyridyl or pyrimidinyl; R2 is hydrogen, Cι_ιo alkyl, heterocyclic alkyl, methyl S(O)m C1.4 alkyl; R3 is a 2- or 3-thiophene, or a substituted phenyl wherein the substituents are selected from methyl thio, methylsulfinyl, methylsulfonyl, methoxy, N-morpholinomethyl or -C(=NOH)NH2; R4 is phenyl, naphth-1-yl, or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected halogen ,-SRs, -SOR5, -OR36, halo-substituted-Ci-4 alkyl, Cι_4 alkyl, or -(CRιoR2θ)mNRιoR20 wherein m is 1 or 2, R5 is hydrogen, C1-4 alkyl, or NR7R17, excluding the moeities -SR5 being -SNR7R17 and -SOR5 being -SOH; 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 NR10; RlO is hydrogen or Ci-4 alkyl; R36 is hydrogen, Cι_4 alkyl, halo-substituted-Cι_4 alkyl, or C3-5 cycloalkyl; or a pharmaceutically acceptable salt thereof.
12. The compound of formula (1), according to Claim 11, which is: 4-[4-(4-Ruorophenyl)-5-(4-pyridyl)imidazol-2-yl]benzamidoxime;
4-(l-Napthyl)-2-(4-memylsulfmylphenyl)-5-(4-pyridyl)imidazole;
4-(l-Napthyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole;
4-(2-Napthyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)imidazole;
4-(2-Napt_hyl)-2-(4-memylsulfinylphenyl)-5-(4-pyridyl)imidazole; 4-(4-Ruorophenyl)-2-(3-thiophene)-5-(4-pyridyl)imidazole;
4-(4-Ruorophenyl)-2-(2-thiophene)-5-(4-pyridyl)imidazole;
4-(4-Ruorophenyl)-2-(3-methylthiophenyl)-5-(4-pyridyl)imidazole;
4-(4-Ruorophenyl)-2-(3-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Ruorophenyl)-2-(3-methylsulfonylphenyl)-5-(4-pyridyl)imidazole; 4-(4-Ruorophenyl)-2-(2-methylthiophenyl)-5-(4-pyridyl)imidazole;
4-(4-Ruorophenyl)-2-(2-methylsulfinylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Ruorophenyl)-2-(2-methylsulfonylphenyl)-5-(4-pyridyl)imidazole;
4-(4-Ruorophenyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)imidazole; or pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising a compound according to Claim 11 or 12 and a pharmaceutically acceptable carrier or diluent.
14. A compound of formula (I), as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in therapy.
15. The use of a compound of formula (I), as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a cytokine mediated disease state.
16. A method of treating a cytokine mediated disease in a mammal which comprises administering to a mammal in need of such treatment an effective cytokine-interferring amount of a compound of formula (I) according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof.
17. The method according to claim 16 wherein the mammal is afflicted with a cytokine mediated disease selected from 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, osteoporosis, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, Crohn's disease, ulcerative colitis or pyresis.
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