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WO2012110860A1 - Composés tricycliques en tant qu'inhibiteurs de mpges-1 - Google Patents

Composés tricycliques en tant qu'inhibiteurs de mpges-1 Download PDF

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Publication number
WO2012110860A1
WO2012110860A1 PCT/IB2011/054031 IB2011054031W WO2012110860A1 WO 2012110860 A1 WO2012110860 A1 WO 2012110860A1 IB 2011054031 W IB2011054031 W IB 2011054031W WO 2012110860 A1 WO2012110860 A1 WO 2012110860A1
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Prior art keywords
dimethyl
chloro
phenyl
imidazole
dihydro
Prior art date
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PCT/IB2011/054031
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English (en)
Inventor
Laxmikant Atmaram Gharat
Jitendra Maganbhai Gajera
Lakshminarayana Narayana
Neelima Khairatkar-Joshi
Vidya Ganapati Kattige
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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Publication of WO2012110860A1 publication Critical patent/WO2012110860A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • the present patent application relates to tricyclic compounds as mPGES-1 inhibitors.
  • 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 prostaglandin J3 ⁇ 4
  • PGF 2 o, PGD 2 , prostacyclin and thromboxane A 2 These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological, activity including pro-inflammatory effects.
  • the COX enzyme exists in two forms, one that is const utive! ⁇ ' expressed in many cells and tissues (COX- 1 ), and other that in most cells and tissues are induced by proinflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).
  • PGE 2 is particularly known to be a strong pro-inflammator mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a vie 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
  • drugs which act by inhibition of COXs are therefore known / suspected to cause adverse biological effects.
  • 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.
  • PGE2 A combination of pharmacological, genetic and neutralizing antibody approaches demonstrates the importance of PGE2 in inflammation.
  • the conversion of PGH2 to PGE2 by prostaglandin E synthases (PGES) may therefore represent a pivotal step in the propagation of inflammatory stimuli.
  • Microsomal prostaglandin E synthase- 1 (mPGES-1) is an inducible PGES after exposure to pro-inflammatory stimuli.
  • mPGES-1 is induced in the periphery and CNS by inflammation and represents therefore a target for acute and chronic inflammatory disorders.
  • PGE2 is a major prostanoid, produced from arachidonic acid liberated by phospholipases (PLAs), which drives the inflammatory processes.
  • PGH synthase cycloxygenase
  • mPGES-1 a substrate for mPGES-1
  • PGH 2 may be transformed to PGE 2 by prostaglandin E synthases (PGES).
  • PGES prostaglandin E synthases
  • mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
  • cPGES cytosolic prostaglandin E 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 likely to be of benefit in the treatment of inflammation.
  • agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma, and COPD.
  • PGE2 is involved in malignant growth. PGE2 facilitates tumor progression by stimulation of cellular proliferation and angiogenesis and by modulation of immunosupression.
  • genetic deletion of mPGES-1 in mice suppress the intestinal tumourogenesis ( akanishi 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 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).
  • mice lacking the mPGES-1 receptor was 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 invention is directed to novel compounds that are inhibitors of the mPGES-1 enzyme and would therefore be useful for the treatment of pain and inflammation in a variety of diseases or conditions.
  • the present patent application is directed to tricyclic compounds with mPGES-1 inhibition.
  • the present invention relates to compound of formula (I):
  • X 1 and X" are independently selected from -CH- and -N-;
  • R 1 is selected from hydrogen, substituted or unsubstituted aryl and heteroaryl
  • R 2 at each occurrence, is independently selected from halogen
  • R 3 and R 4 may be same or different, are independently selected from hydrogen and substituted or unsubstituted alkyl or R 3 and R 4 taken together with the carbon atom to which they are attached may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include heteroatoms selected from O, N or S;
  • R a and R b are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring, and heterocyclylalkyl; or R a and R b may be joined together to form an substituted or unsubstituted 3 to 7 membered saturated, unsaturated or partially saturated cyclic ring, which may optionally include at least two heteroatoms selected from O, N, and S;
  • R p is hydrogen, substituted or unsubstituted alkyl or arylalkyl
  • 'm' is integer selected from 0 to 3, both inclusive;
  • 'n' is integer selected from 0 to 3, both inclusive;
  • the compounds of formula (I) 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.
  • the present application provides the compound of formula (la) or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , R 1 , R 3 , R 4 , and R p are as defined for formula (I);
  • R 2 is selected from halogen, substituted or unsubstituted aryl, herteroaryl and heterocyclic ring; whererin the substitution on the substituted groups are one or more selected from halogen, nitro, cyano, hydroxyl, -OR x , -OC(0)R x , -C(0)OR x , -S0 2 R x , substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl; and
  • R x is selected from hydrogen, substituted or unsubstituted alkyl and haloalkyl
  • the present application provides compound of formula (la') or a pharmaceutically acceptable salt thereof:
  • R 1 is substituted or unsubstituted aryl, wherein the substitution(s) on the substituted group are one or more selected from halogen and cyano;
  • R 2 is selected from halogen, substituted or unsubstituted aryl, herteroaryl and heterocyclic ring; whererin the substitution on the substituted groups are one or more selected from halogen, cyano, -OR x , -S0 2 R x , substituted or unsubstituted alkyl, haloalkyl and cycloalkyl; R x is selected from hydrogen, substituted or unsubstituted alkyl and haloalkyl;
  • the compound of formula (la') wherein R 2 is halogen for e.g. chloro, fluoro, bromo or iodo.
  • substituents are halogen (e.g. chloro, fluoro, bromo or iodo), haloalkyl (for e.g. trifluoromethyl), haloalkoxy (for e.g. trifluoromethoxy, trifluoroethoxy) and methylsulfonyl.
  • the present application provides the compound of formula (la”) or a pharmaceutically acceptable salt thereof:
  • R 1 is substituted or unsubstituted aryl, wherein the substitution(s) on the substituted group are one or more selected halogen and cyano; and R 2 is halogen.
  • substituents are halogen (for e.g. chloro, fluoro, bromo or iodo) and cyano.
  • the compound of formula (la' ') wherein R 2 is halogen for e.g. chloro, fluoro, bromo or iodo.
  • the present application provides compound of formula (lb) or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , R 1 , R 3 , R 4 , and R p are as defined for formula (I);
  • R a is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl and heterocyclic ring; whererin the substitution on the substituted groups are one or more selected from halogen, nitro, cyano, hydroxyl, -OR x , - OC(0)R x , -C(0)OR x , -S0 2 R x , substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl; and
  • R x is selected from hydrogen, substituted or unsubstituted alkyl and haloalkyl
  • the present application provides compound of formula (lb') or a pharmaceutically acceptable salt thereof:
  • X , X , R , R , and R p are as defined for formula (I);
  • R a is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic ring; whererin the substitution on the substituted groups are one or more selected from halogen, nitro, cyano, hydroxyl, -OR x , -OC(0)R x , -C(0)OR x , - S0 2 R x , substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl; and
  • R x is selected from hydrogen, substituted or unsubstituted alkyl and haloalkyl
  • the compound of formula (lb') wherein X 1 and X 2 is -CH.
  • the compound of formula (lb') wherein R 3 and R 4 are methyl. According to yet another embodiment, the compound of formula (lb') wherein R 3 and R 4 combines together to form substituted or unsubstituted cyclic ring, preferably unsubstituted cyclic ring, more preferably cyclobutyl.
  • the compound of formula (lb') wherein R a is substituted cycloalkyl, preferably substituted cyclohexyl and cyclopentyl, wherein substituent is hydroxy.
  • substituents are halogen (for e.g. chloro, fluoro, bromo or iodo), cyano, alkyl (for e.g. methyl), nitro, C(0)OH, alkyl- C(0)0-, alkoxy (for e.g. methoxy, ethoxy), haloalkyl (for e.g. trifiuoromethyl), hal
  • alkylsulfinyl for e.g. methylsulfinyl
  • aryl for e.g. phenyl
  • heteroaryl for e.g oxadiazole or methylated- oxadiazole
  • heterocyclyl for e.g. pyrrolidin-2-one
  • the compound of formula (lb') wherein R a is unsubstituted heteroaryl, preferably pyridine, pyrimidine or isoquinoline.
  • substituents are halogen (for e.g. chloro, fluoro, bromo or iodo), alkyl (for e.g. methyl) and haloalkyl (for e.g. trifiuoromethyl).
  • the present application provides compound of formula (lb") or a pharmaceutically acceptable salt thereof:
  • R 1 , R 3 , R 4 , and R p are as defined for formula (I);
  • R a is selected from hydrogen and substituted or unsubstituted aryl; whererin the substitution on the substituted groups are one or more selected from halogen, substituted or unsubstituted alkyl and haloalkyl;
  • the present application provides the compound of formula (Ic) or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , R 1 , R 3 , R 4 , and R p are as defined for formula (I);
  • R a is selected from hydrogen, substituted or unsubstituted cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, whererin the substitution on the substituted groups are one or more selected from halogen, nitro, cyano, hydroxyl, - OR x , -OC(0)R x , -C(0)OR x , -S0 2 R x , substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl; and
  • R x is selected from hydrogen, substituted or unsubstituted alkyl and haloalkyl
  • the present application provides the compound of formula (Ic') or a pharmaceutically acceptable salt thereof:
  • R a is selected from substituted or unsubstituted cycloalkyl and arylalkyl, whererin the substitution on the substituted group is haloalkyl;
  • the compound of formula (Ic') wherein R a is substituted arylalkyl, preferably substituted phenylalkyl, wherein substituent is haloalkyl (for e.g. trifluoromethyl).
  • the compound of formula (Ic') wherein R a is unsubstituted or substituted cycloalkyl, preferably cyclopentyl.
  • the present application provides the compound of formula (Id) or a pharmaceutically acceptable salt thereof:
  • R a and R b are independently selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, hetero arylalkyl, heterocyclic ring, and heterocyclylalkyl; whererin the substitution on the substituted groups are one or more selected from halogen, nitro, cyano, hydroxyl, -OR x , -OC(0)R x , -C(0)OR x , -S0 2 R x , substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl; and
  • R x is selected from hydrogen, substituted or unsubstituted alkyl and haloalkyl
  • the present application provides the compound of formula (Id') or a pharmaceutically acceptable salt thereof:
  • R a is selected from substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, whererin the substitution on the substituted groups are one or more selected from halogen, substituted or unsubstituted alkyl and haloalkyl;
  • substituents are halogen (for e.g. fluoro, chloro, bromo or iodo) and haloalkyl (for e.g. trifluoromethyl).
  • the compound of formula (Id') wherein R a is substituted arylalkyl, preferably benzyl, wherein substituent is haloalkyl (for e.g. trifluoromethyl) .
  • the compound of formula (Id') wherein R a is substituted heteroaryl, preferably thiazole and benzthiazole, wherein substituent is alkyl (for e.g. methyl).
  • R a is 6,6-dimethylbicyclo[3.1.1 ]hept-3-yl, 2,6,6-trimethylbicyclo[3.1.1 ]hept-3-yl, cyclohexyl, cyclohexylethyl, cyclopentyl, adamantan-l-yl or 3,3-dimethyl-2-butyl.
  • the present application provides the compound of formula (Ie) or a pharmaceutically acceptable salt thereof:
  • R a is substituted or unsubstituted aryl, whererin the substitution on the substituted group are one or more selected from halogen and haloalkyl;
  • the compound of formula (Ie) wherein R a is substituted aryl, preferably substituted phenyl, wherein substituents are halogen (for e.g. fluoro, chloro, bromo or iodo) and haloalkyl (for e.g. trifluoromethyl).
  • substituents are halogen (for e.g. fluoro, chloro, bromo or iodo) and haloalkyl (for e.g. trifluoromethyl).
  • the present application provides the compound of formula (If) or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , R 1 , R 3 , R 4 , and R p are as defined for formula (I);
  • R b is selected from substituted or unsubstituted aryl and heteroaryl, whererin the substitution on the substituted groups are one or more selected from halogen, nitro, cyano, hydroxyl, -OR x , -OC(0)R x , -C(0)OR x , -S0 2 R x , substituted or unsubstituted alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl;
  • R a and R x are independently selected from hydrogen, substituted or unsubstituted alkyl and haloalkyl.
  • the present application provides the compound of formula (If) or pharmaceutically acceptable salt thereof:
  • R b is selected from substituted or unsubstituted aryl, whererin the substitution on the substituted group are one or more selected from halogen and haloalkyl.
  • substituents are halogen (e.g. chloro, fluoro, bromo or iodo) and haloalkyl (for e.g. trifluoromethyl).
  • the present invention 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 in the present patent application 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 believed to be related to a variety of disease states.
  • the compounds of the present invention exhibit an IC 50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 250 nM, with respect to mPGES-1 activity in cell based assay as measured by the method described in the present application.
  • the present patent application 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 the amount effective to cause inhibition of such receptor.
  • halogen or halo means fluorine, chlorine, bromine, or iodine
  • 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, 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, n-pentyl, and 1 ,1- dimethylethyl (t-butyl).
  • C 1-6 alkyl refers to an alkyl chain having 1 to 6 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 and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), /so-propenyl, 2-methyl-l- 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).
  • Non- limiting examples of 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. 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.
  • haloalkyl and haloalkoxy means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms, where alkyl and alkoxy groups are as defined above.
  • halo is used herein interchangeably with the term “halogen” means F, CI, Br, or I.
  • haloalkyl examples include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl 4,4,4-trifluorobutyl, 4,4-difluorocyclohexyl, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl, and the like.
  • haloalkoxy examples include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy, 1-bromoethoxy and the like.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • 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 cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms, 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.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H4C6H5. 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 which consists of carbon atoms and from one to five heteroatoms 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 oleflnic 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
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. 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.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • 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, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indoli
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • 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” will 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).
  • the compound described in the present patent application may form salts.
  • Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • 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 patent application extends to these stereoisomeric forms and to mixtures thereof.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well 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, solvents and the like.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, 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, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinyl pyrrolidone.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, , buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • the pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, 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, pulmonary, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • 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. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch and/or potato starch. A syrup or elixir is used in cases where a sweetened vehicle is employed.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the pharmaceutical forms suitable for injectable or infusing use include sterile aqueous solutions, suspensions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable or infusing solutions, suspension or dispersions.
  • 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 selectively inhibit the activity of prostaglandin E synthases ⁇ and particularly microsomal prostaglandin E synthase-1 (mPGES-1) ⁇ , i.e. they prevent 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.
  • Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
  • 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, invasion of the affected area by white.
  • 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, pain, 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 or dental procedures, 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 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 disease with an inflammatory
  • 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 of Formula I 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 and dental procedures as well as the preemptive treatment of surgical pain.
  • Such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
  • Compounds of Formula I may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.
  • Compounds of Formula I 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.
  • the compound of the present invention may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
  • Compounds of the 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.
  • the compounds of formula (la) and (lb) are prepared according to the sequence depicted in Scheme 1.
  • the compound of formula (1) can be converted to a compound of formula (3), by reacting it with a compound of formula (2) in presence of an organic base (for e.g., piperidine, pyrrolidine, morpholine etc,) or inorganic base (for e.g., alkali metal carbonate, alkali metal hydroxide, alkali metal hydride etc).
  • an organic base for e.g., piperidine, pyrrolidine, morpholine etc,
  • inorganic base for e.g., alkali metal carbonate, alkali metal hydroxide, alkali metal hydride etc.
  • the compound of formula (3) can be converted to a compound of formula (4) in presence of oxidizing agent like isoamyl nitrite (J. Heterocyclic chem., 1988, 26, 1013-1021) or selenium dioxide by following procedure known in the art of organic synthesis.
  • the compound of formula (4) can be converted to a compound of formula (6) by reacting with a compound of formula (5) in presence of in situ generated ammonia using ammonium acetate or ammonium chloride in solvents such as acetic acid or propionic acid.
  • Compound of formula (6) can be converted to compound of formula (la), wherein substituted or unsubstituted monocyclic or bicyclic aryl, heteroaryl substituent, is introduced by a sequence of transformations such as transition metal catalyzed reactions.
  • Compound of formula (6) can be converted to compound of formula (lb), which is a substituted or unsubstituted alkynyl derivative, by a sequence of transformations such as transition metal catalyzed reactions (for example Suzuki-Miyaura coupling or Sonogashira coupling).
  • a sequence of transformations such as transition metal catalyzed reactions (for example Suzuki-Miyaura coupling or Sonogashira coupling).
  • alkynyl or aryl/heteroaryl moiety may be introduced initially to the compound of formula (3) before converting it to compound of formula (4).
  • the compound of formula (4) is converted to compound of formula (la) or (lb).
  • Scheme 2 depicts another approach for the preparation of compound of formula (la), wherein X 1 , X z , R , R , R , R a are as defined above, while 'Hal' is halogen.
  • the compound of formula (3) can be converted to alkyne derivative of formula (7) by reacting with trialkylacetylene compound, such as silyl acetylene derivative, in the presence of a catalyst (for example a palladium catalyst).
  • the compound of formula (7) can be de- silylated for example in the presence of tertiary butyl ammnoum fluoride in the suitable solvent such as dichloromethane to get compound of formula (8).
  • the compound of formula (8) can be converted to a compound of formula (9) in presence of oxidizing agent like isoamyl nitrite (J. Heterocyclic chem., 1988, 26, 1013-1021) or selenium dioxide following procedure known in the art of organic synthesis.
  • oxidizing agent like isoamyl nitrite (J. Heterocyclic chem., 1988, 26, 1013-1021) or selenium dioxide following procedure known in the art of organic synthesis.
  • the compound of formula (9) can be converted to a compound of formula (10) by reacting with an appropriate aldehyde in the presence of in situ generated ammonia using ammonium acetate or ammonium chloride in the presence of solvent such as acetic acid or propionic acid.
  • the compound of formula (10) can be converted to compound of formula (lb) wherein substituted or unsubstituted monocyclic or bicyclic aryl, heteroaryl substituent is introduced by a sequence of transformations such as transition metal catalyzed reactions.
  • the compound of formula (Ic) can be prepared following the synthetic route as depicted in scheme 3, wherein X 1 , X 2 , R p , R 1 , R 3 , R 4 , and R a are as defined above and PG is a protecting group.
  • Scheme 3 primarily describes one of the ways to introduce the substituent -OR a .
  • the hydro xyl group of the compound of formula (11) can be masked using a suitable protecting group to obtain the compound of formula (12).
  • the compound of formula (12) can be converted to compound of formula (13) by reacting with compound of formula (2) in the presence of organic or inorganic base.
  • the protection of the hydroxyl group may be removed under suitable conditions to obtain compound of formula (14) and desired OR a substituent may be introduced under suitable condition, for example a halogen derivative may be reacted with compound of formula (14) in the presence of suitable solvent and suitable base to obtain the compound of formula (15).
  • the further transformations of compound of formula (15) to compound of formula (lc) can be achieved by following the reaction conditions/reagents described for similar steps in the scheme 1 or scheme 2.
  • the compound of formula (Id) can be prepared following the synthetic route as depicted in scheme 4, wherein X 1 , X 2 , R P , R 1 , R 3 , R 4 , R a ' R b and R x are as defined above while R may be alkyl.
  • the scheme 4 primarily depicts the introduction of amide moiety to the basic scaffold of compound of formula (I). The other transformations are previously described in the scheme 1 and scheme 2.
  • the compound of formula (21) which is a carboxylic acid derivative may be treated with an appropriate amine (compound of formula 22) under suitable conditions to get compound of formula (Id) or compound of formula (24) depending on the nature of amine utilized for the reaction.
  • the compound of formula (If) can be prepared following the synthetic route as depicted in scheme 5, wherein X 1 , X 2 , R p , R 1 , R 3 , R 4 , R a and R b are as defined above, while 'Hal' is halogen.
  • the compound of formula (3) can be converted to compound of formula (25) by treating it with amide derivative such as substituted or unsubstituted benzamides.
  • the reaction may be catalyzed by transition metal catalyst such as palladium catalyst.
  • transition metal catalyst such as palladium catalyst.
  • the compound of formula (lb'), which is imidazolo-pyrano-pyridine derivative, may be prepared following the synthetic scheme depicted in scheme 6, wherein X 1 , X 2 , R r , R , R , R d are as defined above while 'Hal' is halogen.
  • the pyridine aldehyde of formula (27) may be oxidized to its carboxylic acid derivative of formula (28) under standard acidic conditions in a suitable solvent.
  • the acid derivative of formula (28) may be converted to compound of formula (29) by treating with a suitable ester derivative under suitable conditions.
  • the keto group of compound of formula (29) may be selectively reduced to hydroxyl group using suitable reducing agent such as sodium borohydride to give compound of formula (30).
  • suitable reducing agent such as sodium borohydride
  • the compound of formula (30) may be further treated with methyl magnesium halide under Grignard reaction conditions to obtain tertiary alcohol of formula (31).
  • the secondary alcohol group of diol compound of formula (31) may be selectively oxidized to compound of formula (32) using suitable oxidizing reagent such as pyridinium chlorochromate.
  • the obtained compound of formula (32) may under go cyclization for example in the presence of hydrobromic acid in acetic acid under appropriate reaction conditions.
  • the obtained compound of formula (33) may be converted to compound of formula (35) via preparation of intermediate compound of formula (34) following the reaction sequence described in the scheme 1 or scheme 2.
  • the obtained compound of formula (35) may be converted to compound of formula (lb') following the reaction sequence as described in the scheme 1.
  • Step-1 Preparation of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-
  • Step-2 - Preparation of 6-bromo-2,2-dimethyl-2H-chromene-3,4-dione:-
  • Step-1 Preparation of 7-chloro-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-
  • Step-2 Preparation of 7-chloro-2,2-dimethyl-2H-chromene-3,4-dione:- The title compound was prepared according the procedure described in step-2 of
  • Step-1 Preparation of 7-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-
  • Step-2 - Preparation of 7-bromo-2,2-dimethyl-2H-chromene-3,4-dione:-
  • Step-1 - Preparation of 3-iodophenyl acetate: r ⁇ "ococH 3
  • Step-2 Preparation of l-(2-hydroxy-4-iodophenyl)ethanone:- A mixture of 3-iodophenyl acetate (10 g, 0.030 mol) and anhydrous aluminium chloride (15.17 g, 0.114 mol) was stirred at 100°C. The reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was concentrated to afford 3 g of desired product. ! HNMR (CDC1 3 ): ⁇ 2.60 (s, 3H), 7.24-7.27 (m, 1H), 7.39-7.48 (m, 2H), 12.25 (s, 1H).
  • Step-3 - Preparation of 7-iodo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-
  • Step-1 Preparation of 2-(2-chloro-6-fiuoro-phenyl)-4,4-dimethyl-7- trimethylsilanylethynyl-l ,4-dihydro-chromeno[3,4-d]imidazole:-
  • Trimethylsilylacetylene (0.032 g, 0.329 mmol) was added to the reaction mixture and the reaction mixture was stirred at 90- 100°C for 12 hours.
  • the reaction mixture was filtered through celite bed. The filtrate was quenched in water and extracted with ethyl acetate. The organic layer was concentrated to afford 0.05 g of desired product.
  • 'HNMR (DMSO-de) ⁇ 0.22 (s, 9H), 1.58 (s, 6H), 6.89- 6.91 (m, 1H), 7.04-7.08 (m, 2H), 7.35-7.59 (m, 3H), 13.14 (s, 1H); MS [M+H] + : 425.30.
  • Step-2 Preparation of 2-(2-chloro-6-fiuoro-phenyl)-7-ethynyl-4,4-dimethyl-l,4-dihydro- chromeno [3 ,4-d] imidazole : -
  • Step-1 Preparation of 2,2-dimethyl-7-trimethylsilanylethynyl-chroman-4-one
  • step-3 of Intermediate- 4 (25.0 g, 0.083 mol), copper iodide (0.630 g, 0.0033 mol), dichloro- bis(triphenylphosphine)palladium (II) (1.16 g, 0.0016 mol), triethyl amine (20.0 mL) and trimethylsilylacetylene (12.0 g, 0.124 mol) in DMSO (20 mL) to afford 22.0 g of desired product.
  • Step-2 - Preparation of 7-ethynyl-2,2-dimethyl-chroman-4-one:-
  • Step 3 Preparation of 7-ethynyl-2,2-dimethyl-chroman-3,4-dione:-
  • the title compound was prepared by following the same procedure as described for step- 2 of Intermediate- 1 by using 7-ethynyl-2,2-dimethyl-chroman-4-one (10.0 g, 0.046 mol) and Isoamyl nitrite (10 mL) in HC1 (6 mL) to afford 6.0 g of desired product.
  • Step 4 - Preparation of 2-(2,6-Dibromo-phenyl)-7-ethynyl-4,4-dimethyl-l,4-dihydro- chromeno [3 ,4-d] imidazole : -
  • Step 5 Preparation of 7-(2-chloro-5-trifluoromethyl-phenylethynyl)-2-(2,6-dibromo- phenyl)-4,4-dimethyl-l,4-dihydro-chromeno[3,4-d]imidazole:-
  • step-4 of Intermediate-7 0.500 g, 109 mol
  • dichloro bis (triphenyl phosphine)palladium (II) 0.022 g, 0.032 mol
  • tetra butyl ammonium fluoride 0.855 g, 3.27 mol
  • 2,5-dichloro-iodobenzene 0.447 g, 1.63 mol
  • step-4 of Intermediate-7 0.500 g, 2.18 mmol
  • dichloro bis (triphenyl phosphine)palladium (II) catalytic amount
  • tetra butyl ammonium fluoride 2.06 g, 6.55 mmol
  • l-iodo-2-trifluoromethyl-benzene 0.90 g, 3.27 mmol
  • Step-1 -Preperation of 2-iodo-4,5-dimethyl-thiazole:-
  • Step-1 -Preperation of 4-methoxy-l-nitro-2-trifluoromethyl-benzene:-
  • Step-2 -Preperation of 4-methoxy-2-trifluoromethyl-phenylamine:-
  • Step-3 Preparation of l-iodo-4-methoxy-2-trifluoromethyl-benzene:-
  • the title compound was prepared by following the same procedure as described for Intermediate- 1 1 by using 4-methoxy-2-trifluoromethyl-phenylamine (0.400 g, 2.09 mmol), cone HC1 (0.877 g, 5.09 mmol), sodium nitrite (0.213 g, 2.36 mmol) and potassium iodide (0.416 g, 2.50 mmol) to afford 0.300 g of desired product.
  • Step-1 Preparation of 4-chloro-2,6-difluoro-phenylamine:-
  • Step-2 Preparation of 5-chloro-l ,3-difluoro-2-iodo-benzene:-
  • Step-1 -Preperation of 2,5-dichloro-4-fluoro-phenylamine:-
  • Step-2 Preparation of l ,4-dichloro-2-fluoro-5-iodo-benzene:-
  • Step-l - Preparation of 2-(3,5-dibromo-pyridin-4-yl)-7-ethynyl-4,4-dimethyl-l,4- dihydro-chromeno [3 ,4-d] imi
  • Step-2 Preparation of 2-(3,5-dibromo-pyridin-4-yl)-4,4-dimethyl-7-(2-trifluoromethyl- phenylethynyl)-l ,4-dihydrohromeno[3,4-d]imidazole:-
  • step-2 of Intermediate-6 0.150 g, 0.426 mmol
  • dichloro bis (triphenyl phosphine)palladium (II) 0.022 g, 0.0327 mol
  • methyl-2-iodo benzoate 0.133 g, 0.51 1 mmol
  • tetra butyl ammonium fluoride 0.402 g, 1 mmol
  • Step-2 - Preperation of 2-(2-iodophenyl)-l,3,4-oxadiazole:-
  • step-4 of intermediate-7 0.500 g, 1.09 mmol
  • dichloro bis (triphenyl phosphine)palladium (II) catalytic acmount
  • l ,3-dichloro-2- iodobenzene intermediate-39, 0.357 g, 1.31 mmol
  • tetra butyl ammonium fluoride (1.03 g, 3.27 mmol)
  • step-4 of Inermediate-7 0.500 g, 1.09 mmol
  • dichloro bis (triphenyl phosphine)palladium (II) catalytic ampunt
  • 1 -(difluoromethoxy)- 2-iodobenzenedifluoromethyl 2-iodophenyl ether 0.53 g, 1.31 mmol
  • tetra butyl ammonium fluoride 1.03 g, 3.27 mmol
  • Step-1 Preperation of 4-bromo- -(2-iodophenyl)butanamide:-
  • Step-2 Preperation of l -(2-iodophenyl)pyrrolidin-2-one:-
  • Step-1 Preparation of 2,2-dimethyl-7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-2 - Preperation of 7-(cyclopentyloxy)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one
  • Step-3 - Preperation of 7-(cyclopentyloxy)-2,2-dimethyl-2H-chromene-3,4-dione
  • Step-1 Preparation of 7-hydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-
  • step-2 of Intermediate-46 A mixture of 7-(cyclopentyloxy)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (step-2 of Intermediate-46, 2.0 g, 7.69 mmol) in a mixture of acetic acid and 48% HBr (10 mL) in a ratio of 2:3, was stirred for 4-5 hours at 100°C. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was concentrated to afford 1.5 g of desired product.
  • Step-2 Preparation of 2,2-dimethyl-7- ⁇ [2-(trifluoromethyl)benzyl]oxy ⁇ -2,3-dihydro- 4H-chromen-4-one:-
  • Step-3 Preparation of 2,2-dimethyl-7- ⁇ [2-(trifiuoromethyl)benzyl]oxy ⁇ -2H-chromene- 3,4-dione:-
  • Step-1 Preparation of 2,2-dimethyl-7- ⁇ [3-(trifluoromethyl)benzyl]oxy ⁇ -2,3-dihydro- 4H-chromen-4-one:-
  • Step-2 Preparation of 2,2-dimethyl-7- ⁇ [3-(trifiuoromethyl)benzyl]oxy ⁇ -2H-chromene- 3,4-dione:-
  • Step-1 Preparation of 2,2-dimethyl-7- ⁇ [4-(trifluoromethyl)benzyl]oxy ⁇ -2,3-dihydro- 4H-chromen-4-one:-
  • step- 1 of Intermediate-47 1.0 g, 5.208 mmol
  • DMF 10 mL
  • potassium carbonate 1.078 g, 7.81 mmol
  • l-(bromomethyl)-4-(trifluoromethyl)benzene 1.67 g, 7.81 1 mmol
  • Step-2 - Preparation of 2,2-dimethyl-7- ⁇ [4-(trifiuoromethyl)benzyl]oxy ⁇ -2H-chromene- 3,4-dione
  • Step-1 Preparation of 7-iodospiro[chromene-2,l'-cyclobutan]-4(3H)-one:-
  • Step-2 - Preparation of 7-iodospiro[chromene-2,l'-cyclobutane]-3,4-dione:-
  • Step-3 Preparation of 2-(2-chloro-6-fluorophenyl)-7-iodo-lH-spiro[chromeno[3,4- JJimidazole-4, 1 '-cyclobutane] :-
  • Step-4 - Preparation of 2-(2-chloro-6-fluorophenyl)-7-[(trimethylsilyl)ethynyl]-lH- spiro[chromeno[3,4-JJimidazole-4,l'-cyclobutane]:-
  • Step-5 - Preparation of 2-(2-chloro-6-fluorophenyl)-7-ethynyl-lH-spiro[chromeno[3,4- JJimidazole-4, 1 '-cyclobutane] :-
  • Step-1 Preparation of 2,2-dimethyl-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[4-(trifluoromethoxy)phenyl]-2H-chromene-3,4- dione:-
  • Step-1 Preparation of 2,2-dimethyl-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[4-(trifluoromethoxy)phenyl]-2H-chromene-3,4- dione:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-3 - Preparation of 2,2-dimethyl-7-[3-(2,2,2-trifluoroethoxy)phenyl]-2H-chromene- 3,4-dione:-
  • Step-4 - Preparation of 2-(2,6-dibromophenyl)-4,4-dimethyl-7-[3-(2,2,2- trifluoroethoxy)phenyl]-l ,4-dihydrochromeno[3,4-JJimidazole:-
  • Step-1 Preparation of 2,2-dimethyl-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[3-(trifluoromethoxy)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-1 Preparation of 2,2-dimethyl-7-[3-(trifluoromethoxy)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[3-(trifluoromethoxy)phenyl]-2H-chromene-3,4- dione:-
  • Step-2 - Preparation of 6-iodo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-
  • Step-3 - Preparation of 6-bromo-2,2-dimethyl-2H-chromene-3,4-dione:-
  • Step-4 - Preparation of 2-(2-chloro-6-fluoro-phenyl)-8-iodo-4,4-dimethyl-l ,4-dihydro- chromeno [3 ,4-d] imidazole : -
  • Step-5 Preparation of 2-(2-chloro-6-fluoro-phenyl)-4,4-dimethyl-8- trimethylsilanylethynyl-l ,4-dihydro-chromeno[3,4-d]imidazole:-
  • Step-6 Preparation of 2-(2-chloro-6-fiuoro-phenyl)-7-ethynyl-4,4-dimethyl-l,4-dihydro- chromeno [3 ,4-d] imidazole : -
  • Step-1 Preparation of 4-acetyl-3-hydroxybenzoic acid:-
  • Step-2 Preparation of ethyl 4-acetyl-3-hydroxybenzoate:-
  • Step-3 Preparation of ethyl 2,2-dimethyl-4-oxochromane-7-carboxylate:-
  • Step-4 Preparation of ethyl 2,2-dimethyl-3,4-dioxochromane-7-carboxylate:-
  • Step-5 - Preparation of ethyl 2-(2-chloro-6-fluorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[3,4-JJimidazole-7-carboxylate
  • Step-6 - Preparation of 2-(2-chloro-6-fiuorophenyl)-4,4-dimethyl- l ,4- dihydrochromeno[3,4-JJimidazole-7-carboxylic acid
  • Step-2 Preparation of l-(2-hydroxy-4-iodophenyl)ethanone:-
  • reaction mixture (15.17 g, 0.1 14 mol). The reaction mixture was stirred at 100°C. After the completion of reaction, the reaction mixture was quenched in water and extracted with ethyl acetate.
  • Step-3 - Preparation of 7-iodo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one:-
  • Step-1 Preparation of 4-bromo-N-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-7- yl)benzamide:-
  • Step-2 - Preparation of 4-bromo-N-(2,2-dimethyl-3,4-dioxo-3,4-dihydro-2H-chromen-7- yl)benzamide:-
  • Step-1 - Preparation of N-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-7-yl)-2- (trifluoromethyl)benzamide: -
  • Step-2 Preparation of N-(2,2-dimethyl-3,4-dioxo-3,4-dihydro-2H-chromen-7-yl)-2- (trifluoromethyl)benzamide: -
  • Step-1 Preparation of 2-chloro-N-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-7-yl)- 6-fluorobenzamide:-
  • Step-1 Preparation of 6-chloro-2-methoxypyridine-3-carbaldehyde:-
  • Step-2 Preparation of 6-chloro-2-methoxypyridine-3-carboxylic acid:-
  • Step-3 Preparation of ethyl 3-(6-chloro-2-methoxypyridin-3-yl)-3-oxopropanoate:-
  • reaction mass was stirred at 0°C for 1 hour followed by stirring at room tempreture for 5-6 hours.
  • the above prepared solution was added to it and again continued stiring fori 2- 15 hours.
  • the reaction mass was quenched in water and adjusted pH -5-6 by acetic acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 45.0 g of desired product. !
  • Step-4 Preparation of ethyl 3-(6-chloro-2-methoxypyridin-3-yl)-3-hydroxypropanoate:-
  • Step-5 Preparation of l-(6-chloro-2-methoxypyridin-3-yl)-3-methylbutane-l,3-diol:-
  • Step-6 Preparation of l-(6-chloro-2-methoxypyridin-3-yl)-3-hydroxy-3-methylbutan-l- one:-
  • Step-7 - Preparation of 7-chloro-2,2-dimethyl-2,3-dihydro-4H-pyrano[2,3-&]pyridin-4- one:-
  • Step-8 - Preparation of 7-chloro-2,2-dimethyl-2H-pyrano[2,3-&]pyridine-3,4-dione:-
  • Step-9 Preparation of 7-chloro-2-(2-chloro-6-fiuorophenyl)-4,4-dimethyl-l ,4- dihydroimidazo[4',5':4,5]pyrano[2,3-&]pyridine:-
  • Step-2 Preparation of 2,2-dimethyl-7-[(trimethylsilyl)ethynyl]-2,3-dihydro-4H- pyrano[2,3-£>]pyridin-4-one:-
  • Step-4 - Preparation of 2,2-dimethyl-7- ⁇ [2-(trifluoromethyl)phenyl]ethynyl ⁇ -2,3- dihydro-4H-pyrano[2,3-£>]pyridin-4-one:-
  • Step-1 Preparation of 7- ⁇ [2-fluoro-6-(trifluoromethyl)phenyl]ethynyl ⁇ -2,2-dimethyl- 2,3-dihydro-4H-pyrano[2,3-£>]pyridin-4-one:-
  • Step-2 Preparation of 7- ⁇ [2-fluoro-6-(trifluoromethyl)phenyl]ethynyl ⁇ -2,2-dimethyl- 2H-pyrano [2 ,3-£>]pyridine-3 ,4-dione : -
  • the title compound was prepared according the same procedure as described in step-2 of Intermediate- 1 by using 7- ⁇ [2-fluoro-6-(trifluoromethyl)phenyl]ethynyl ⁇ -2,2-dimethyl- 2,3-dihydro-4H-pyrano[2,3-£>]pyridin-4-one (0.100 g, 0.275 mmol), ethanol (2 mL), hydrochloric acid (1.0 mL) and isoamyl nitrite (1.0 mL) to afford 0.100 g of desired product.
  • Step-2 Preparation of 7- ⁇ [2-chloro-5-(trifluoromethyl)phenyl]ethynyl ⁇ -2,2-dimethyl- 2H-pyrano [2 ,3-£>]pyridine-3 ,4-dione : -
  • Step-1 Preparation of 2,2-dimethyl-7-[3-(methylsulfonyl)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-1 Preparation of 2,2-dimethyl-7-[4-(methylsulfonyl)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[4-(methylsulfonyl)phenyl]-2H-chromene-3,4- dione:-
  • Step-1 Preparation of 2,2-dimethyl-7-[2-(methylsulfonyl)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-1 Preparation of 2,2-dimethyl-7-[2-(trifluoromethoxy)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[2-(trifluoromethoxy)phenyl]-2H-chromene-3,4- dione:-
  • Step-3 Preparation of 2-(2,6-dibromophenyl)-4,4-dimethyl-7-[2-( trifluoromethoxy)phenyl]-l ,4-dihydrochromeno[3,4-(i]imidazole:-
  • the title compound was prepared by following the same procedure as described for Intermediate-5 by using 2,2-dimethyl-7-[2-(trifluoromethoxy)phenyl]-2H-chromene-3,4- dione (0.350 g, 1.14 mmol), 2,6-di bromo benzaldehyde (0.452 g, 1.71 mmol), ammonium acetate (0.438 g, 5.7 mmol) and acetic acid (4 mL).
  • Step-1 Preparation of 7-(2-hydroxyphenyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4- one:-
  • Step-2 - Preparation of 2,2-dimethyl-7-[2-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-4H- chromen-4-one:-
  • Step-3 Preparation of 2,2-dimethyl-7-[2-(2,2,2-trifluoroethoxy)phenyl]-2H-chromene- 3,4-dione:-
  • Step-4 - Preparation of 2-(2,6-dibromophenyl)-4,4-dimethyl-7-[2-(2,2,2- trifluoroethoxy)phenyl]-l ,4-dihydrochromeno[3,4-JJimidazole:-
  • Step-2 Preparation of methyl 4,6-dichloropyridine-3-carboxylate:-
  • Step-3 Preparation of methyl 6-chloro-4-methoxypyridine-3-carboxylate:-
  • Step-4 Preparation of methyl 6-chloro-4-methoxypyridine-3-carboxylic acid:-
  • Step-5 Preparation of ethyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropanoate:-
  • Step-6 Preparation of ethyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-hydroxypropanoate:-
  • Step-7 Preparation of l-(6-chlor -4-methoxypyridin-3-yl)-3-methylbutane-l,3-diol:-
  • Step-8 Preparation of l-(6-chloro-4-methoxypyridin-3-yl)-3-hydroxy-3-methylbutan-l- one:-
  • Step-9 Preparation of 7-chloro-2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-c]pyridin-4- one:-
  • Step- 10 Preparation of 7-iodo-2,2-dimethyl-2,3-dihydro-4H-pyrano[3,2-c]pyridin-4- one:-
  • Step-l 1 - Preparation of 7-iodo-2,2 [3,2-c]pyridine-3,4-dione:-
  • Step- 12 - Preparation of 2-(2-chloro-6-fluorophenyl)-7-iodo-4,4-dimethyl-l ,4- dihydroimidazo [4',5':4,5]pyrano[3,2-c]pyridine:-
  • Step-2 Preparation of methyl 3-acetyl-5-chloro-2-hydroxybenzoate:-
  • Step-3 Preparation of methyl 6-chloro-2,2-dimethyl-4-oxochroman-8-carboxylate:-
  • Step 4 Preparation of methyl 6-chloro-2,2-dimethyl-3,4-dioxochroman-8-carboxylate:-
  • Step-5 Preparation of methyl 8-chloro-2-(2-chloro-6-fluorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[3,4-d]imidazol -6-carboxylate:-
  • Step-5 Preparation of 8-chloro-2-(2-chloro-6-fiuorophenyl)-4,4-dimethyl-l,4- dihydrochromeno[3,4-d]imidazole-6-carboxylic acid :-
  • Step 1 2-(2,6-Dibromophenyl)-4,4-dimethyl-7-(phenylethynyl)-l ,4- dihydrochromeno [3 ,4-d] imi
  • Step 2 2-[4,4-Dimethyl-7-(phenylethynyl)- l ,4-dihydrochromeno[3,4- ⁇ i]imidazol-2- yl] isophthalonitrile: To the solution of 2-(2,6-dibromophenyl)-4,4-dimethyl-7-(phenylethynyl)-l ,4- dihydrochromeno[3,4-d]imidazole (0.250 g, 0.469 mmol) in N-methyl-2-pyrrolidinone (5 mL) was added copper cyanide (0.115 g, 1.279 mmol) and the reaction mixture was stirred at 100-1 10°C for 12-14 hours.
  • Step 2 Preparation of 7-(3 -hydro xy-3-methylbut- l -yn- l-yl)-2, 2-dimethyl-2H- chromene-3 ,4-dione: -
  • Step 3 - Preparation of 4-[2-(2-chloro-6-fluorophenyl)-4,4-dimethyl-l ,4- dihydrochromeno[3,4-JJimidazol-7-yl]-2-methylbut-3-yn-2-ol:-
  • step 3 of Intermediate-4 0.500 g, 1.661 mmol
  • copper iodide catalytic amount
  • dichloro- bis(triphenylphosphine)palladium (catalytic amount)
  • triethyl amine (1 mL
  • phenyl acetylene (0.187 g, 1.82 mmol)
  • ⁇ , ⁇ -dimethyl formamide 5 mL
  • Step 2 - Preparation of 2,2-dimethyl-7-(phenylethynyl)-2H-chromene-3,4-dione:-
  • Step 3 Preparation of 2-(2-chloro-6-fluorophenyl)-4,4-dimethyl-7-(phenylethynyl)-l ,4- dihydro chromeno [3 ,4-JJ imidazole : -
  • Step 1 -Preparation of 2-(2-chloro-6-fluoro-phenyl)-4,4-dimethyl-7-(4-nitro- phenylethynyl)-4H-chromeno[3,4-d]imidazole-l-carboxylic acid tert-butyl ester:-
  • Step 2 Preparation of 2-(2-chloro-6-fluoro-phenyl)-4,4-dimethyl-7-(4-nitro- phenylethynyl)-l ,4-dihydro-chromeno[3,4-d]imidazole:-

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Abstract

La présente invention concerne des composés tricycliques de formule (I), ou un sel pharmaceutiquement acceptable de ceux-ci, en tant qu'inhibiteurs de mPGES-1. Ces composés sont des inhibiteurs de l'enzyme prostaglandine E synthase- 1 microsomale (mPGES-1) et sont, par conséquent, utiles dans le traitement de la douleur et/ou de l'inflammation provenant d'une variété de maladies ou d'états pathologiques, tels que l'asthme, l'arthrose, la polyarthrite rhumatoïde, la douleur aiguë ou chronique et des maladies neurodégénératives. (I).
PCT/IB2011/054031 2011-02-17 2011-09-15 Composés tricycliques en tant qu'inhibiteurs de mpges-1 Ceased WO2012110860A1 (fr)

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WO2013186692A1 (fr) 2012-06-15 2013-12-19 Glenmark Pharmaceuticals S.A. Composés triazolone utilisés comme inhibiteurs de la mpges-1
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WO2014172190A1 (fr) 2013-04-15 2014-10-23 E. I. Du Pont De Nemours And Company Amides fongicides
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WO2015059618A1 (fr) 2013-10-22 2015-04-30 Glenmark Pharmaceuticals S.A. Composés de pyrimidine substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2016016861A1 (fr) 2014-08-01 2016-02-04 Glenmark Pharmaceuticals S.A. Formulation nanoparticulaire comprenant un inhibiteur de mpges -1
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US9006257B2 (en) 2012-02-09 2015-04-14 Glenmark Pharmaceuticals S.A. Bicyclic compounds as mPGES-1 inhibitors
WO2013153535A1 (fr) 2012-04-13 2013-10-17 Glenmark Pharmaceuticals S.A. Composés tricycliques à titre d'inhibiteurs de la mpges-1
US9439890B2 (en) 2012-06-15 2016-09-13 Glenmark Pharmaceuticals S.A. Triazolone compounds as mPGES-1 inhibitors
WO2013186692A1 (fr) 2012-06-15 2013-12-19 Glenmark Pharmaceuticals S.A. Composés triazolone utilisés comme inhibiteurs de la mpges-1
US10391083B2 (en) 2012-06-15 2019-08-27 Glenmark Pharmaceuticals S.A Triazolone compounds as MPGES-1 inhibitors
US10821100B2 (en) 2012-06-15 2020-11-03 Ichnos Sciences SA Triazolone compounds as mPGES-1 inhibitors
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US9096545B2 (en) 2012-06-15 2015-08-04 Glenmark Pharmaceuticals S.A. Triazolone compounds as mPGES-1 inhibitors
WO2014130258A1 (fr) * 2013-02-22 2014-08-28 Bristol-Myers Squibb Company 5h-chromeno[3,4-c]pyridines utilisés en tant qu'inhibiteurs de la kinase 1 associée à un adaptateur (aak1)
WO2014167444A1 (fr) 2013-04-08 2014-10-16 Glenmark Pharmaceuticals S.A. Composés bicycliques substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2014172190A1 (fr) 2013-04-15 2014-10-23 E. I. Du Pont De Nemours And Company Amides fongicides
WO2015059618A1 (fr) 2013-10-22 2015-04-30 Glenmark Pharmaceuticals S.A. Composés de pyrimidine substitués utilisés en tant qu'inhibiteurs de mpges-1
WO2016016861A1 (fr) 2014-08-01 2016-02-04 Glenmark Pharmaceuticals S.A. Formulation nanoparticulaire comprenant un inhibiteur de mpges -1
EP3517104A1 (fr) 2014-08-01 2019-07-31 Glenmark Pharmaceuticals S.A. Formulation nanoparticulaire comprenant un inhibiteur de mpges -1
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