WO2014167444A1 - Composés bicycliques substitués utilisés en tant qu'inhibiteurs de mpges-1 - Google Patents

Composés bicycliques substitués utilisés en tant qu'inhibiteurs de mpges-1 Download PDF

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WO2014167444A1
WO2014167444A1 PCT/IB2014/060122 IB2014060122W WO2014167444A1 WO 2014167444 A1 WO2014167444 A1 WO 2014167444A1 IB 2014060122 W IB2014060122 W IB 2014060122W WO 2014167444 A1 WO2014167444 A1 WO 2014167444A1
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alkyl
mmol
trifluoromethyl
dimethyl
compound
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PCT/IB2014/060122
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Laxmikant Atmaram Gharat
Abhisek Banerjee
Neelima Khairatkar-Joshi
Vidya Ganapati Kattige
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Glenmark Pharmaceuticals S.A.
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Publication of WO2014167444A1 publication Critical patent/WO2014167444A1/fr

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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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present application relates to substituted bicyclic compounds which may be useful as microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.
  • mPGES-1 microsomal prostaglandin E synthase-1
  • Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation is also a common cause of pain.
  • COX cyclooxygenase
  • PGE 2 is particularly known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE 2 , including "NSAIDs” (non-steroidal anti-inflammatory drugs) and “coxibs” (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE 2 .
  • NSAIDs non-steroidal anti-inflammatory drugs
  • coxibs selective COX-2 inhibitors
  • the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
  • Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
  • PGES prostaglandin E synthases
  • mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
  • cPGES cytosolic prostaglandin E synthase
  • mPGES-1 is an inducible PGES after exposure to proinflammatory stimuli.
  • mPGES-1 is induced in the periphery and CNS by inflammation, and represents therefore a target for acute and chronic inflammatory disorders.
  • PGE 2 is a major prostanoid, produced from arachidonic acid liberated by phospholipases (PLAs), which drives the inflammatory processes.
  • PHAs phospholipases
  • Arachidonic acid is transformed by the action of prostaglandin H synthase (PGH synthase, cycloxygenase) into PGH 2 which is a substrate for mPGES-1, the terminal enzyme transforming PGH 2 to the pro-inflammatory PGE 2 .
  • PGH synthase prostaglandin H synthase
  • Agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE 2 are beneficial in the treatment of inflammation. Further, agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also beneficial in the treatment of asthma and COPD.
  • PGE 2 is involved in malignant growth. PGE 2 facilitates tumor progression by stimulation of cellular proliferation and angiogenesis and by modulation of immunosupression.
  • genetic deletion of mPGES-1 in mice suppresses intestinal tumourogenesis (Nakanishi et. al., Cancer Research 2008, 68(9), 3251-9).
  • mPGES-1 is also upregulated in cancers such as colorectal cancer (Schroder Journal of Lipid Research 2006, 47, 1071-80).
  • Myositis is a chronic muscle disorder characterized by muscle weakness and fatigue. Proinflammatory cytokines and prostanoids have been implicated in the development of myositis. In skeletal muscle tissue from patients suffering from myositis an increase in cyclooxygenases and mPGES-1 has been demonstrated, implicating mPGES-1 as a target for treating this condition. (Korotkova Annals of the Rheumatic Diseases 2008, 67, 1596- 1602).
  • Atherosclerosis inflammation of the vasculature leads to atheroma formation that eventually may progress into infarction.
  • carotid atherosclerosis an increase in mPGES-1 in plaque regions has been reported (Gomez-Hernandez Atherosclerosis 2006,187, 139-49).
  • mice lacking the mPGES-1 receptor were found to show a retarded atherogenesis and a concomitant reduction in macrophage-derived foam cells together with an increase in vascular smooth muscle cells (Wang, Proceedings of National Academy of Sciences 2006, 103(39), 14507-12).
  • the present application is directed to compounds that act as inhibitors of the mPGES-1 enzyme and therefore, are useful for the treatment of pain and inflammation in a variety of diseases or conditions.
  • the present invention relates to a compound of formula (I)
  • Q 1 , Q 2 , Q 3 and Q 4 which may be same or different, are independently selected from N, CH and CR 4 ; with a proviso that Q 2 , Q 3 and Q 4 are not N simultaneously;
  • W is selected from Ci -8 alkyl, Ci -8 alkoxyCi -8 alkyl, haloCi -8 alkyl, hydroxyCi. 8alkyl, carboxylCi -8 alkyl, C 3- i 2 cycloalkyl and 3 to 15 membered heterocyclyl;
  • R 1 is selected from Ci -8 alkyl, Ci -8 alkoxyCi -8 alkyl, haloCi -8 alkyl, hydroxyCi. 8 alkyl, carboxylCi -8 alkyl, C 3- i 2 cycloalkyl, C 6 -i 4 ryl, C 6 -i 4 arylCi -8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi -8 alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi -8 alkyl;
  • R 2 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci -8 alkyl, Ci. 8alkoxy, haloCi -8 alkyl, hydroxyCi -8 alkyl, C 3- i 2 cycloalkyl and C 3-8 cycloalkylCi -8 alkyl;
  • R 3 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, Ci -8 alkyl, Ci. 8alkoxy, haloCi -8 alkyl, hydroxyCi -8 alkyl, C 3- i 2 cycloalkyl and C 3-8 cycloalkylCi -8 alkyl; each occurrence of R 4 is independently selected from halogen, nitro, cyano, hydroxyl, Ci -8 alkyl, Ci -8 alkoxy, Ci -8 alkoxyCi -8 alkyl, haloCi -8 alkyl, hydroxyCi -8 alkyl, C 3- i 2 Cycloalkyl and C 3-8 cycloalkylCi -8 alkyl;
  • each occurrence of R x and R y which may be the same or different, are independently selected from hydrogen, Ci -8 alkyl and C 6 -i 4 arylCi -8 alkyl;
  • 'n' is an integer ranging from 1 to 4, both inclusive;
  • dotted line [— ] inside the ring represents an optional bond; with a proviso that when dotted line [— ] inside the ring represents a bond then R 3 is absent.
  • the compounds of formula (I) may involve one or more embodiments.
  • Embodiments of formula (I) include compounds of formula (II)), as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (I) as defined above wherein Q 1 is CH or CR 4 (according to an embodiment defined below), R 2 is hydrogen or methyl (according to another embodiment defined below), R x is hydrogen (according to yet another embodiment defined below) and n is 1 (according to yet another embodiment defined below).
  • each occurrence of R 4 is independently selected from halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl or ethyl) and haloCi -8 alkyl (e.g. trifluoromethyl or difluoromethyl).
  • halogen e.g. F, CI or Br
  • Ci -4 alkyl e.g. methyl or ethyl
  • haloCi -8 alkyl e.g. trifluoromethyl or difluoromethyl
  • each occurrence of R 4 is independently selected from CH 3 , CF 3 , CHF 2 , CI and F.
  • Q 1 is CH or CR 4
  • Q 2 is CH
  • Q 3 is N or CH
  • Q 4 is CR 4
  • R 4 is CH 3 , CF 3 , CHF 2 , CI or F.
  • R 1 is Ci -8 alkyl (e.g. methyl, ethyl, isopropyl, ie/t-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl).
  • R 1 is Ci -8 alkyl (e.g. methyl, ethyl, isopropyl, ie/t-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl).
  • R 1 is cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), (e.g. methyl) and haloCi -8 alkyl (e.g. trifiuoromethyl).
  • halogen e.g. F, CI or Br
  • haloCi -8 alkyl e.g. trifiuoromethyl
  • R is cyclohexyl optionally substituted with one or more substituents independently selected from CH 3 and CF 3 .
  • R 1 is phenyl optionally substituted with trifiuoromethyl.
  • R 1 is pyridine optionally substituted with trifiuoromethyl.
  • R 1 is Ci -8 alkyl (e.g. methyl, ethyl, isopropyl, ie/t-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl), C 3- i 2 cycloalkyl (e.g.
  • cyclohexyl 4,4-dimethylcyclohexyl, 4- (trifluoromethyl)cyclohexyl or (ls,4s)-4-(trifluoromethyl)cyclohexyl), C6-i 4 ryl (e.g. 4-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl) or 5-14 membered heteroaryl (e.g. 6-(trifluoromethyl)pyridin-3-yl).
  • C6-i 4 ryl e.g. 4-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl
  • 5-14 membered heteroaryl e.g. 6-(trifluoromethyl)pyridin-3-yl.
  • R 1 is isopropyl, ie/t-butyl, 2,4,4-trimethylpentan-2-yl, 3,3- dimethylbutan-2-yl, ( ?)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl.
  • R 2 is hydrogen or (e.g. methyl).
  • R 3 is hydrogen, Ci -4 alkyl (e.g. methyl) or absent.
  • W is Ci-salkyl (e.g. methyl, ethyl, isopropyl or tert-buty ⁇ ) or haloCi-salkyl (e.g. l-fluoro-2-methylpropan-2-yl).
  • Ci-salkyl e.g. methyl, ethyl, isopropyl or tert-buty ⁇
  • haloCi-salkyl e.g. l-fluoro-2-methylpropan-2-yl
  • Q 1 is CH or CR 4 ;
  • Q 2 is CH;
  • Q 3 is N or CH;
  • Q 4 is CR 4 ;
  • R 1 is Ci-salkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3-dimethylbutan-2-yl), C3-i 2 cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, 4-
  • R 3 is hydrogen, Ci -4 alkyl (e.g. methyl) or absent;
  • each occurrence of R 4 is independently halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl or ethyl) or haloCi-salkyl (e.g. trifluoromethyl or difluoromethyl);
  • halogen e.g. F, CI or Br
  • Ci -4 alkyl e.g. methyl or ethyl
  • haloCi-salkyl e.g. trifluoromethyl or difluoromethyl
  • n 1 ;
  • R x is hydrogen
  • R y is hydrogen
  • W is Ci-salkyl (e.g. methyl, ethyl, isopropyl or ie/ -butyl) or haloCi-salkyl (e.g. 1- fluoro-2-methylpropan-2-yl).
  • Ci-salkyl e.g. methyl, ethyl, isopropyl or ie/ -butyl
  • haloCi-salkyl e.g. 1- fluoro-2-methylpropan-2-yl
  • Q 1 is CH or CR 4 ;
  • Q 3 is N or CH
  • Q 4 is CR 4 ;
  • R 1 is isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (R)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4- dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4-
  • R 2 is hydrogen or methyl
  • R 3 is methyl or absent
  • each occurrence of R 4 is independently CH 3 , CF 3 , CHF 2 , CI or F;
  • n 1 ;
  • R x is hydrogen
  • R y is hydrogen
  • W is isopropyl, ie/ -butyl or l-fluoro-2-methylpropan-2-yl.
  • compounds of formula (I) that exhibit an IC50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to mPGES-1 inhibition.
  • the invention also provides a compound of formula (II) which is an embodiment of a compound of formula (I).
  • Q 1 , Q 2 , Q 3 and Q 4 which may be same or different, are independently selected from N, CH and CR 4 ; with a proviso that Q 2 , Q 3 and Q 4 are not N simultaneously;
  • W is selected from Ci -8 alkyl, Ci -8 alkoxyCi -8 alkyl, haloCi -8 alkyl, hydroxyCi.
  • R 1 is selected from Ci -8 alkyl, Ci -8 alkoxyCi -8 alkyl, haloCi -8 alkyl, hydroxyCi. 8 alkyl, carboxylCi -8 alkyl, C 3- i 2 cycloalkyl, C 6- i 4 aryl, C 6- i 4 arylCi -8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi -8 alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi -8 alkyl;
  • R 2 is selected from hydrogen, and Ci -8 alkyl
  • R 3 is selected from hydrogen and Ci -8 alkyl
  • each occurrence of R 4 is independently selected from halogen, nitro, cyano, hydroxyl, Ci -8 alkyl, Ci -8 alkoxy, Ci -8 alkoxyCi -8 alkyl, haloCi -8 alkyl, hydroxyCi -8 alkyl, C 3- i 2 cycloalkyl and C 3-8 cycloalkylCi -8 alkyl.
  • the compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
  • the invention provides compounds of formula (II) as defined above wherein Q 1 is CH or CR 4 (according to an embodiment defined below), Q 2 is CH or CR 4 (according to another embodiment defined below), Q 3 is N or CH (according to yet another embodiment defined below) and R 2 and R 3 are methyl (according to yet another embodiment defined below).
  • each occurrence of R 4 is independently selected from halogen (e.g. F, CI or Br), (e.g. methyl or ethyl) and haloCi-salkyl (e.g. trifiuoromethyl or difluoromethyl).
  • halogen e.g. F, CI or Br
  • haloCi-salkyl e.g. trifiuoromethyl or difluoromethyl
  • each occurrence of R 4 is independently selected from CH 3 , CF 3 , CHF 2 , CI and F.
  • Q 1 is CH or CR 4
  • Q 2 is CH
  • Q 3 is N or CH
  • Q 4 is CR 4
  • R 4 is CH 3 , CF 3 , CHF 2 , CI or F.
  • R 1 is Ci-salkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl).
  • Ci-salkyl e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl.
  • R 1 is C 3- i 2 cycloalkyl, preferably C 3-6 Cycloalkyl, and more preferably substituted or unsubstituted cyclohexyl.
  • substituent(s) on C 3 -i 2 cycloalkyl, C 3 - 6 cycloalkyl or cyclohexyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl) and haloCi-salkyl (e.g. trifluoromethyl).
  • R 1 is cyclohexyl optionally substituted with one or more substituents independently selected from halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl) and haloCi -8 alkyl (e.g. trifluoromethyl).
  • halogen e.g. F, CI or Br
  • Ci -4 alkyl e.g. methyl
  • haloCi -8 alkyl e.g. trifluoromethyl
  • R 1 is cyclohexyl optionally substituted with one or more substituents independently selected from CH 3 and CF 3 .
  • R 1 is C 6 -i 4 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.
  • substituent(s) on C 6 -i 4 ryl or phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl, isopropyl) and haloCi -8 alkyl (e.g. trifluoromethyl).
  • R 1 is 5-14 membered heteroaryl, preferably substituted or unsubstituted pyridine, more preferably substituted pyridine.
  • substituent(s) on 5-14 membered heteroaryl or pyridine may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci -4 alkyl (e.g. methyl, isopropyl) and haloCi -8 alkyl (e.g. trifluoromethyl).
  • R 1 is pyridine optionally substituted with trifluoromethyl.
  • R 1 is Ci -8 alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4- trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3- dimethylbutan-2-yl), C 3- i 2 cycloalkyl (e.g.
  • cyclohexyl 4,4-dimethylcyclohexyl, 4- (trifluoromethyl)cyclohexyl or (ls,4s)-4-(trifluoromethyl)cyclohexyl), C 6- i 4 aryl (e.g. 4-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl) or 5-14 membered heteroaryl (e.g. 6-(trifluoromethyl)pyridin-3-yl).
  • R 1 is isopropyl, ie/ -butyl, 2,4,4-trimethylpentan-2-yl, 3,3- dimethylbutan-2-yl, ( ?)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4-dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4- (trifluoromethyl)cyclohexyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl or 6-(trifluoromethyl)pyridin-3-yl.
  • R 2 is hydrogen or Ci -4 alkyl (e.g. methyl).
  • R 3 is hydrogen or Ci -4 alkyl (e.g. methyl).
  • W is Ci -8 alkyl (e.g. methyl, ethyl, isopropyl or tert-buty ⁇ ) or haloCi -8 alkyl (e.g. l-fluoro-2-methylpropan-2-yl).
  • Q 1 is CH or CR 4 ;
  • Q 2 is CH;
  • Q 3 is N or CH;
  • Q 4 is CR 4 ;
  • R 1 is Ci -8 alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (7?)-3,3-dimethylbutan-2-yl or (S)-3,3-dimethylbutan-2-yl), C3-i 2 cycloalkyl (e.g. cyclohexyl, 4,4-dimethylcyclohexyl, 4-
  • R 2 is hydrogen or Ci -4 alkyl (e.g. methyl);
  • R 3 is hydrogen or Ci -4 alkyl (e.g. methyl); each occurrence of R 4 is independently halogen (e.g. F, CI or Br), (e.g. methyl or ethyl) or haloCi -8 alkyl (e.g. trifluoromethyl or difluoromethyl); and
  • W is Ci -8 alkyl (e.g. methyl, ethyl, isopropyl or ie/ -butyl) or haloCi -8 alkyl (e.g. 1- fluoro-2-methylpropan-2-yl).
  • Q 1 is CH or CR 4 ;
  • Q 3 is N or CH
  • Q 4 is CR 4 ;
  • R 1 is isopropyl, tert-butyl, 2,4,4-trimethylpentan-2-yl, 3,3-dimethylbutan-2-yl, (R)-3,3-dimethylbutan-2-yl, (S)-3,3-dimethylbutan-2-yl, cyclohexyl, 4,4- dimethylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, (ls,4s)-4-
  • R 2 is methyl
  • R 3 is methyl
  • each occurrence of R 4 is independently CH 3 , CF 3 , CHF 2 , CI or F;
  • W is isopropyl, ie/ -butyl or l-fluoro-2-methylpropan-2-yl.
  • compounds of formula (II) which exhibit an IC 50 value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to mPGES-1 inhibition.
  • the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of mPGES-1, which is related to a variety of disease states.
  • the present invention further provides a method of inhibiting mPGES-1 in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.
  • halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci -8 alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n- butyl, ft-pentyl and 1, 1-dimethylethyl (i-butyl).
  • Ci -8 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • the term refers to an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2-ioalkenyl) and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), z ' so-propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon- carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred i.e. C 2- ioalkynyl).
  • alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci -8 alkoxy). Representative examples of such groups are -OCH 3 and -OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e. Ci. 8 alkoxyCi -8 alkyl or Ci -8 alkyloxyCi -8 alkyl).
  • alkoxyalkyl moiety includes, but are not limited to, -CH 2 OCH 3 and -CH 2 OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e. haloCi -8 alkyl).
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi -8 alkoxy).
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxyalkyl refers to haloalkoxy group as defined above directly bonded to an alkyl group as defined above (i.e. haloCi -8 alkoxyCi -8 alkyl).
  • alkyl group as defined above (i.e. haloCi -8 alkoxyCi -8 alkyl).
  • haloCi -8 alkoxyCi -8 alkyl include but are not limited to (2,2,2- trifluoroethoxy )m ethyl or (2,2-difluoroethoxy)m ethyl. Unless set forth or recited to the contrary, all haloalkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi -8 alkyl).
  • hydroxyalkyl moieties include, but are not limited to -CH 2 OH, -C 2 H 4 OH and -CH(OH)C 2 H 4 OH. Unless set forth or recited to the contrary, all hydroxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • carboxyl means the group -COOH.
  • carboxylalkyl refers to an Ci -8 alkyl group as defined above wherein at least one of the hydrogen atoms of the Ci -8 alkyl group is replaced by a carboxyl group (i.e. "carboxylCi -8 alkyl”).
  • carboxylalkyl moieties include, but are not limited to carboxylmethyl (-CH 2 -COOH), carboxylethyl (-CH 2 - CH 2 -COOH), carboxylisopropyl (-C(CH 3 ) 2 -COOH) and carboxyltertbutyl (- C(CH 3 ) 2 CH 2 -COOH). Unless set forth or recited to the contrary, all carboxylalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e. C 3- i 2 cycloalkyl).
  • monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
  • C 3-6 Cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a non-aromatic cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group (i.e. C 3- 8 cycloalkylCi -8 alkyl).
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a ccyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, (i.e. C 3- 8 cycloalkenyl).
  • Examples of “cycloalkenyl” include but are not limited to cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenylalkyl refers to a non-aromatic cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, (i.e. Cs-scycloalkenylCi-salkyl). Unless set forth or recited to the contrary, all cycloalkenylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C 6- i 4 aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. C 6 -i 4 aryloxy).
  • aryloxy moieties include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. such as -CH 2 C 6 H 5 and - C 2 H 4 C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e. 3 to 15 membered heterocyclyl) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylCi-salkyl). Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S (i.e. 5 to 14 membered heteroaryl).
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazol
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group (i.e. 5 to 14 membered heterarylCi-salkyl). Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sul
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non- domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” may vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • Nociceptors are primary sensory afferent (C and ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH ⁇ 6) modalities.
  • Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.
  • chronic pain usually refers to pain which persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life.
  • Chronic pain can be classified as either nociceptive or neuropathic.
  • Nociceptive pain includes tissue injury -induced pain and inflammatory pain such as that associated with arthritis.
  • Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant, and often with an aching or throbbing quality.
  • Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized.
  • Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).
  • Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I), the present invention extends to all these stereoisomeric forms and to mixtures thereof.
  • the different stereoisomeric forms of the compounds described herein may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated. It is also to be understood that compounds described herein may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, and solvents.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • Compounds of the present invention are particularly useful because they may inhibit the activity of prostaglandin E synthases ⁇ and particularly microsomal prostaglandin E synthase- 1 (mPGES-1) ⁇ , i.e., they prevent, inhibit, or suppress the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit mPGES-1 modulating effect.
  • mPGES-1 microsomal prostaglandin E synthase- 1
  • inflammation will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow.
  • inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
  • the compounds of the present invention may also be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical procedures, dental procedures or condition (e.g. dental surgery, tooth removal, toothache, dental pain or postsurgical dental pain), malignancies (e.g.
  • hyperprostaglandin E syndrome classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other
  • Compounds of the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject.
  • Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.
  • the compounds are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) procedure and dental procedures or conditions such as dental surgery, tooth removal, toothache, dental pain or postsurgical dental pain as well as the preemptive treatment of surgical pain.
  • rheumatic fever symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, migraine (a
  • the pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy - induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy & chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease such as multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neuro
  • Compounds of the present invention will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma.
  • cancer includes Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adolescents Cancer, Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Astrocytomas, Atypical Teratoid, Basal Cell Carcinoma, Bile Duct Cancer, Extrahepatic, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Central Nervous System tumors, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic
  • the compounds of the present invention may be useful in the treatment of disease, disorder, syndrome or condition selected from the group consisting of inflammation, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections, influenza, common cold, herpes zoster, hepatitis C, AIDS, bacterial infections, fungal infections, dysmenorrhea, burns, pains assoicted with surgical and dental procedures, dental pain, malignancies hyperprostaglandin E syndrome, classic Bartter syndrome, synovitis, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic
  • the compounds of the present invention may be useful in the treatment of pain, chronic pain, acute pain, rheumatoid arthritic pain, osteoarthritic pain or dental pain.
  • the compounds of the present invention may be useful in the treatment of pain.
  • the compounds of the present invention may be useful in the treatment of chronic pain or acute pain.
  • the compounds of the present invention may be useful in the treatment of rheumatoid arthritic pain, osteoarthritic pain or dental pain.
  • the compounds of the present invention may be useful in the treatment of pain associated with dental procedures or condition selected from dental surgery, tooth removal, toothache, dental pain and postsurgical dental pain. In yet another embodiment, the compounds of the present invention may be useful in the treatment of toothache, dental pain, postsurgical dental pain, dental surgery or tooth removal.
  • the compounds of the present invention may be useful in the treatment of inflammation, asthma or chronic obstructive pulmonary disease.
  • the compounds of the present invention may be useful in the treatment of neurodegenerative disorders selected from Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.
  • the compounds of the present invention may be useful in the treatment prevention or management of the cancer.
  • Compounds of the present invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.
  • (II) may be prepared using techniques known to one skilled in the art through the reaction sequences depicted in schemes provided below, as well as by other methods. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained by using the general reaction sequences may be of insufficient purity.
  • the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N- diisoporpylethylamine (DIPEA).
  • a suitable coupling reagent known to those skilled in the art for example, (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP) in a suitable solvent such as dimethylformamide (DMF) or tetrahydrofuran (THF) in the temperature range of 0-120°C, optionally in the presence of a suitable base such as N,N- diisop
  • the reaction can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
  • a suitable solvent such as DMF or THF in the temperature range of 0-120°C, optionally in the presence of a suitable base such as DIPEA.
  • the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • a compound of formula (3) is reacted with a compound of formula (4) using a suitable coupling reagent for example, (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP) in a suitable solvent such as DCM, dimethylformamide (DMF) or tetrahydrofuran (THF) optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • a suitable coupling reagent for example, (benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate) (PyBOP) in a suitable solvent such as DCM, dimethylformamide (DMF) or tetrahydrofuran (THF) optionally in the presence of a suitable base such as N,N-diisoporpylethylamine (DIPEA).
  • a compound of formula (3) is reacted with a compound of formula (4) using PyBOP (benzotriazol- l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate and DIPEA in DMF.
  • the reaction of a compound of formula (3) with a compound of formula (4) can be performed using a suitable reagent such as isobutyl chloroformate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA or Et 3 N.
  • the reaction of a compound of formula (3) with a compound of formula (4) can be performed in a suitable solvent such as DMF or THF in the temperature range of 0-120°C, optionally in the presence of a suitable base such as DIPEA.
  • a suitable solvent such as DMF or THF
  • a suitable base such as DIPEA
  • the reaction of a compound of formula (3) with a compound of formula (4) can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate (Na 2 S0 4 ), filtration and evaporation of the solvent under reduced pressure.
  • Purification includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase.
  • DMSO-i Hexadeuterodimethyl sulfoxide
  • CDC1 3 deuterated chloroform
  • DMSO dimethyl sulfoxide
  • DMF N,N- Dimethylformamide
  • DCM dichloromethane
  • DIPEA N,N-diisopropylethylamine
  • EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide)
  • HOBt hydroxybenzotriazole
  • BOP Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafiuorophosphate
  • PyBOP Benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafiuorophosphate
  • Boc/BOC ie/t-Butoxycarbonyl
  • BOC anhydride: Di-ie/t-butyl
  • Step 1 Preparation of 2-bromo- -cyclohexyl-5-nitrobenzamide
  • 2-bromo-5-nitrobenzoic acid 1.0 g, 4.06 mmol
  • C3 ⁇ 4CN 10 mL
  • N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5- ⁇ ]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (1.54 g, 4.06 mmol)
  • cyclohexylamine (442 mg, 4.47 mmol)
  • DIPEA 1.57 g, 12.18 mmol
  • Step 3 Preparation of 2-cyclohexyl-4,4-dimethyl-7-nitro-3,4-dihydroisoquinolin- l(2H)-one
  • Step 4 Preparation of 7-amino-2-cyclohexyl-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one
  • Step 1 Preparation of 2-chloro- - ⁇ [(trifluoroacetyl)amino]methyl ⁇ benzoic acid
  • Step 1 Preparation of 2-bro -N-(4,4-dimethylcyclohexyl)-5-nitrobenzamide
  • Step 3 Preparation of 2-(4,4-dimethylcyclohexyl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-on
  • Step 1 Preparation of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate
  • Step 2 Preparation of ethyl -chloro-2-fluoro-3-(isobutyramidomethyl)benzoate
  • Step 3 Preparation of 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid
  • the title compound was prepared following the procedure described in step-6 of Intermediate-2 using ethyl 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoate (1.00 g, 3.31 mmol) and NaOH (530 mg, 13.26 mmol) in THF:MeOH:H 2 0 (3 :2: 1; 12 mL) to afford 800 mg of the title product.
  • Step 1 Preparation of (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate
  • Step 2 Preparation of ethyl 5-cyano-2-(difluoromethyl)nicotinate
  • Step 3 Preparation of ethyl 5-(((tert-butoxycarbonyl)amino)methyl)-2- (difluoromethyl)nicotinate
  • Step 4 Preparation of ethyl -(difluoromethyl)-5-(isobutyramidomethyl)nicotinate
  • Step 5 Preparation of 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid
  • ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinate 200 mg, 0.66 mmol
  • 1,4-Dioxane 2 mL
  • Li OH 70 mg, 1.66 mmol
  • H 2 0 0.5 mL
  • Step 1 Preparation of ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2- dimethylpropanamido)methyl)benzoate
  • Step 4 Preparation of ethyl 5-(isobutyramidomethyl)-2-methylnicotinate
  • Step 3 Preparation of 2-(ieri-butyl)-4,4-dimethyl-7-nitro-3,4-dihydroisoquinolin- l(2H)-one
  • Step 4 Preparation of 7-amino-2-(ieri-butyl)-4,4-dimethyl-3,4-dihydroisoquinolin- l(2H)-one
  • step-4 using 2-(ieri-butyl)-4,4-dimethyl-7-nitro-3,4-dihydroisoquinolin-l(2H)-one (90 mg, 0.33 mmol), iron powder (185 mg, 3.30 mmol), and H 4 Cl (143 mg, 2.64 mmol) in EtOH:H 2 0 (2: 1, 6 mL) to afford 70 mg of the title product.
  • Step 1 Preparation of 2-(2,4-dimethoxybenzyl)-7-nitroisoquinolin-l(2H)-one
  • Step 3 Preparation of 2-(4,4-dimethylcyclohexyl)-7-nitroisoquinolin-l(2H)-one
  • Step 4 Preparation of 7-amino-2-(4,4-dimethylcyclohexyl)isoquinolin-l(2H)-one
  • the title compound was prepared following the procedure described in Intermediate- 1, step-4 using 2-(4,4-dimethylcyclohexyl)-7-nitroisoquinolin-l(2H)-one (100 mg, 0.33 mmol), iron powder (185 mg, 3.30 mmol), and H 4 CI (143 mg, 2.65 mmol) in EtOH:H 2 0 (2: 1, 3 mL) to afford 30 mg of the title product.
  • Step 1 Preparation of 2-isoprop -7-nitroisoquinolin-l(2H)-one
  • Step 2 Preparation of 7-amino-2-(ie/ -butyl)isoquinolin-l(2H)-one
  • Step 1 Preparation of 2-bro -5-nitro-N-(3-(trifluoromethyl)phenyl)benzamide
  • Step 3 Preparation of 4,4-dimethyl-7-nitro-2-(3-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-o
  • Step 4 Preparation of 7-amino-4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one
  • the title compound was prepared following the procedure described in Intermediate- 1, step-4 using 4,4-dimethyl-7-nitro-2-(3-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one (120 mg, 0.33 mmol), iron powder (185 mg, 3.30 mmol), and H 4 C1 (143 mg, 2.64 mmol) in EtOH: H 2 0 (2: 1, 6 mL) to afford 90 mg of the title product.
  • Step 1 Preparation of ethyl 2-bromo-4,4,4-trifluoro-3-oxobutanoate
  • Step 2 Preparation of ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate
  • Step 3 Preparation of ethyl 2-bro -4-(trifluoromethyl)thiazole-5-carboxylate
  • Step 4 Preparation of ethyl 2-carbamoyl-4-(trifluoromethyl)thiazole-5-carboxylate
  • Step 5 Preparation of ethyl 2-cyan -4-(trifluoromethyl)thiazole-5-carboxylate
  • Step 6 Preparation of ethyl 2-(((ieri-butoxycarbonyl)amino)methyl)-4- (trifluoromethyl)thiazole-5-carboxylate
  • Step 7 Preparation of ethyl 2-(isobutyramidomethyl)-4-(trifluoromethyl)thiazole-5- carboxylate
  • Step 8 Preparation of 2-(isobutyramidomethyl)-4-(trifluoromethyl)thiazole-5- carboxylic acid
  • Step 1 Preparation of 2-brom -5-nitro-N-(2,4,4-trimethylpentan-2-yl)benzamide
  • Step 3 Preparation of 4,4-dimethyl-7-nitro-2-(2,4,4-trimethylpentan-2-yl)-3,4- dihydroisoquinolin-l(2H)-on
  • Step 4 Preparation of 7-amino-4,4-dimethyl-2-(2,4,4-trimethylpentan-2-yl)-3,4- dihydroisoquinolin-l(2H)-one
  • Step 1 Preparation of 2-bromo-5-nitro-/V-((l5,45)-4- (trifluoromethyl)cyclohexyl)benzamide
  • Step 3 Preparation of 4,4-dimethyl-7-nitro-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)- 3 ,4-dihydroisoquinolin- 1 (2 -one
  • Step 4 Preparation of 7-amino-4,4-dimethyl-2-((l5,45)-4- (trifluoromethyl)cyclohexyl)-3,4-dihydroisoquinolin-l(2H)-one
  • Step 1 Preparation of 2-bro -5-nitro-N-(4-(trifluoromethyl)phenyl)benzamide
  • Step 3 Preparation of 4,4-dimethyl-7-nitro-2-(4-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-o
  • Step 4 Preparation of 7-amino-4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one
  • Step 1 Preparation of ethyl 2-bromo-4,4-difluoro-3-oxobutanoate
  • Step 2 Preparation of ethyl 2-amino-4-(difluoromethyl)thiazole-5-carboxylate
  • Step 3 Preparation of ethyl 2-bromo-4-(difluoromethyl)thiazole-5-carboxylate
  • Step 4 Preparation of ethyl 2-carbamoyl-4-(difluoromethyl)thiazole-5-carboxylate
  • Step 5 Preparation of ethyl 2-cyano-4-(difluoromethyl)thiazole-5-carboxylate
  • Step 6 Preparation of ethyl 2-(((ieri-butoxycarbonyl)amino)methyl)-4- (difluoromethy l)thi azol e- 5 -carb oxy 1 ate
  • Step 7 Preparation of ethyl 2-(isobutyramidomethyl)-4-(difluoromethyl)thiazole-5- carb oxy late
  • Step 8 Preparation of 2-(isobutyramidomethyl)-4-(difluoromethyl)thiazole-5- carboxylic acid
  • Step 1 Preparation of ( ?)-2-bromo-/V-(3,3-dimethylbutan-2-yl)-5-nitrobenzamide
  • Step 2 Preparation of ( ?)-2-bromo-N-(3,3-dimethylbutan-2-yl)-N-(2-methylallyl)-5- nitrobenzamide
  • Step 3 Preparation of ( ?)-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-one
  • Step 4 Preparation of ( ?)-7-amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4- dihydroisoquinolin-l(2H)-one
  • Step 1 Preparation of 2-bro -5-nitro-N-(6-(trifluoromethyl)pyridin-3-yl)benzamide
  • Step 4 Preparation of 7-amino-4,4-dimethyl-2-(6-(trifluoromethyl)pyridin-3-yl)-3,4- dihydroisoquinolin-l(2H)-one
  • Step 1 Preparation of (S)-2-bromo-/V-(3,3-dimethylbutan-2-yl)-5-nitrobenzamide
  • Step 3 Preparation of (S)-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-7-nitro-3,4- dihydroisoquinolin-l(2H)-one
  • Step 4 Preparation of (S)-7-amino-2-(3,3-dimethylbutan-2-yl)-4,4-dimethyl-3,4- dihydroisoquinolin-l(2H)-one
  • Step 5 Preparation of (l5,45)-N-(2-bromo-5-nitrobenzyl)-N-(2-methylallyl)-4- (trifluoromethyl)cyclohexanamine
  • Step 6 Preparation of 4,4-dimethyl-7-nitro-2-((l5,45)-4-(trifluoromethyl)cyclohexyl)- 1,2,3,4-tetrahydroisoquinoli
  • the title compound was prepared following the procedure described in Example- 1 using 7-amino-2-(4,4-dimethylcyclohexyl)isoquinolin-l(2H)-one (Intermediate- 10, 30 mg, 0.1 1 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-2, 45 mg, 0.16 mmol), DIPEA (43 mg, 0.33 mmol), thionyl chloride (0.5 mL) and THF (1 mL) to afford 15 mg of the title product.
  • the title compound was prepared following the procedure described in Example- 1 using 7-amino-2-isopropylisoquinolin-l(2H)-one (Intermediate- 1 1, 50 mg, 0.25 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-2, 99 mg, 0.37 mmol), DIPEA (94 mg, 0.73 mmol), thionyl chloride (1 mL) and THF (2 mL) to afford 38 mg of the title product.
  • the title compound was prepared following the procedure described in Example-5 using 7-amino-2-(tert-butyl)isoquinolin-l(2H)-one (Intermediate- 12, 250 mg, 1.16 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-2, 400 mg, 1.48 mmol), DIPEA (449 mg, 3.48 mmol), oxalyl chloride (224 mg, 1.78 mmol) and THF (5 mL) to afford 60 mg of the title product.
  • mPGES-1 microsomal prostaglandin E synthase-1
  • PGH 2 prostaglandin H 2
  • product PGE 2 prostaglandin E 2
  • GSH reduced glutathione
  • mPGES-1 inhibitors were screened by assessing their ability to inhibit formation of PGE 2 from PGH 2 in the presence of mPGES-1 using an anti-PGE 2 antibody based detection method.
  • Recombinant human mPGES-1 was generated in-house by expression in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489 - 495).
  • the assay was set up using crude microsomal fractions at protein concentration of 40-60 ⁇ g/mL.
  • Test compounds were prepared in 100 % dimethyl sulfoxide (DMSO) to obtain 20 mM stock solution and then diluted using assay buffer comprising 0.1 M Potassium phosphate buffer with 2 mM EDTA. The final concentration of DMSO in the reaction was 0.5 % (v/v).
  • Negative controls were comprised of all assay reagents except the enzyme. Positive controls were comprised of the enzyme reaction in the absence of any inhibitor.
  • Test compounds were incubated for 10 minutes in assay buffer containing 2.5 mM GSH and mPGES-1 enzyme followed by addition of PGH 2 at a concentration of 15 ⁇ for 1 minute.
  • Inhibition of mPGES-1 enzyme activity was measured using the percent of reaction occurring in the positive control. Concentration response curves were plotted using percent inhibition of maximum enzyme reaction. The IC 50 value was calculated from the concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
  • the compounds prepared were tested using the above assay procedure and the results obtained are given in Table 1. Percentage inhibition at concentrations of 1.0 ⁇ and 10.0 ⁇ are given in the table along with IC 50 (nM) details for selected examples.
  • the compounds prepared were tested using the above assay procedure and were found to have IC 50 less than 200nM, preferably less than ⁇ , more preferably less than 50nM or most preferably less than 20nM.
  • IC 50 (nM) values of some of the compounds are set forth in Table 1 wherein "A” refers to an IC 50 value of less than 50 nM, “B” refers to IC 50 value in range of 50.01 to 100.0 nM and “C” refers to IC 50 values more than 100 nM.
  • A549 cell line was monitored as inhibition of IL- ⁇ induced PGE 2 release.
  • A549 cells were maintained in DMEM medium with 10% FBS and 1% Penicillin-Streptomycin Solution in 5% C0 2 at 37°C. Cells were seeded 24 h prior to the assay in 96 well plates in DMEM containing 1% Penicillin-Streptomycin and 2% FBS so as to get ⁇ 40,000 cells per well on the day of experiment. The assay was carried out in a total volume of 200 ⁇ . Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and then diluted using plain DMEM.
  • DMSO dimethyl sulfoxide
  • the final concentration of DMSO in the reaction was 0.55% (v/v).
  • Cells were treated with test compounds for 30 minutes followed by addition of IL- ⁇ at a final concentration of 10 ng/mL for 16-20 h. Plates were then centrifuged at 1000 rpm for 10 min at 4°C. Supernatants were collected and analyzed by the addition of PGE 2 -D2 and anti-PGE 2 cryptate conjugate supplied by the CisBio HTRF kit in a 96 well half area blackwell EIA/RIA plate. The assay plate was incubated overnight at 4-5° C before being read in an Artemis (K-101) (Japan) HTRF plate reader and levels of PGE 2 calculated by extrapolation from the standard curve.
  • Artemis K-101 (Japan) HTRF plate reader
  • concentration response curves were plotted as a percentage (%) of maximal response obtained in the absence of test antagonist.
  • the IC 50 value was calculated from the concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

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Abstract

La présente invention concerne des composés de formule (I), et des sels pharmaceutiquement acceptables de ceux-ci, utilisés en tant qu'inhibiteurs de mPGES-1. Ces composés sont des inhibiteurs de l'enzyme microsomale de prostaglandine E synthase-1 (mPGES-1) et sont, par conséquent, utiles dans le traitement de la douleur et/ou de l'inflammation provoquées par une variété de maladies ou d'états, tels que l'asthme, l'ostéoarthrite, la polyarthrite rhumatoïde, la douleur chronique ou aiguë et les maladies neurodégénératives.
PCT/IB2014/060122 2013-04-08 2014-03-25 Composés bicycliques substitués utilisés en tant qu'inhibiteurs de mpges-1 WO2014167444A1 (fr)

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