WO2011114184A1 - Amides de composés hétérocycliques à titre d'inhibiteurs de trpa1 - Google Patents

Amides de composés hétérocycliques à titre d'inhibiteurs de trpa1 Download PDF

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Publication number
WO2011114184A1
WO2011114184A1 PCT/IB2010/002218 IB2010002218W WO2011114184A1 WO 2011114184 A1 WO2011114184 A1 WO 2011114184A1 IB 2010002218 W IB2010002218 W IB 2010002218W WO 2011114184 A1 WO2011114184 A1 WO 2011114184A1
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Prior art keywords
thiazol
acetamide
phenyl
dioxo
dimethyl
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PCT/IB2010/002218
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English (en)
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Sachin Sundarlal Chaudhari
Sukeerthi Kumar
Abraham Thomas
Nisha Parag Patil
Ashok Bhausaheb Kadam
Nayan Taterao Waghmare
Neelima Khairatkar-Joshi
Indranil Mukhopadhyay
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Glenmark Pharmaceuticals S.A.
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Publication of WO2011114184A1 publication Critical patent/WO2011114184A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present patent application relates to amides of heterocyclic compounds with transient receptor potential ankyrinl (TRPA1) activity.
  • TRP channels or receptors are pain receptors. They have been classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin, ANKTM1) and TRPN (NOMPC) families.
  • TRPC canonical
  • TRPV vanilloid
  • TRPM melastatin
  • TRPP polycystin
  • TRPML mucolipin
  • TRPA ankyrin, ANKTM1
  • TRPN nuclear factor-associated TRPN
  • TRPV5 and TRPV6 are more closely related to each other than to TRPV1, TRPV2, TRPV3 or TRPV4.
  • TRPAl is most closely related to TRPV3 and is more closely related to TRPVl and TRPV2 than to TRPV5 and TRPV6.
  • the TRPM family has 8 members.
  • Constituents include the following: the founding member TRPMl (melastatin or LTRPC1), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (TRP-p8 or CMR1), TRPM5 (MTR1 or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4).
  • TRPMl melastatin or LTRPC1
  • TRPM3 KAA1616 or LTRPC3
  • TRPM7 TRP-PLIK, ChaK(l), LTRPC7
  • TRPM6 ChoK2
  • TRPM2 TRPC7 or LTRPC2
  • TRPM8 TRP-p8 or CMR1
  • TRPM5 MTR1 or LTRPC5
  • TRPM4 FLJ20041 or LTRPC4
  • TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have eleven.
  • TRPP2 PPD2
  • TRPP3 PPD2L1
  • TRPP5 PPD2L2
  • TRPPl PPDl, PCI
  • PKD-REJ PKD-REJ
  • PKD-lLl The sole mammalian member of the TRPA family is ANKTM1. It is believed TRPAl is expressed in nociceptive neurons. Nociceptive neurons of the nervous system sense the peripheral damage and transmit pain signals. TRPAl is membrane bound and most likely acts as a heterodimeric voltage gated channel.
  • TRPAl is activated by a variety of noxious stimuli, including cold temperatures (activated at 17°C), pungent natural compounds (e.g., mustard, cinnamon and garlic) and environmental irritants (MacPherson, L. J. et al., Nature, 2007, 445; 541-545). Noxious compounds activate TRPAl ion channels through covalent modification of cysteines to form covalently linked adducts. Variety of endogenous molecules produced during tissue inflammation / injury have been identified as pathological activators of TRPAl receptor.
  • TRPAl is also activated in receptor dependant fashion by Bradykinin (BK) which is released during tissue injury at peripheral terminals
  • TRPAl and other TRP receptors The difference between TRPAl and other TRP receptors is that TRPAl ligand binding persists for hours due to which the physiological response (e.g., pain) is greatly prolonged. Hence to dissociate the electrophile, an effective antagonist is required.
  • WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO 2004/055054 and WO 2005/089206 describe the TRP channels as the targets for the treatment of pain and related conditions.
  • the present invention relates to compounds of the formula (I):
  • Q is a heterocycle selected from the group consisting of
  • U is selected from -(CR x R y ) n -, substituted or unsubstituted aryl, substituted or unsubstituted heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles, 1,2,3-triazoles and 1, 2, 4-triazole, pyrimidine, pyridine and pyridazine;
  • V is selected from hydrogen, cyano, nitro, -NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl
  • R 1 , R 2 and R 3 which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R y ) complicatOR x , COR", COOR x , CONR x R y ,and (CH 2 ) n CHR x R y ;
  • R 4 is halogen
  • R x and R y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyi, heterocyclic ring and heterocyclylalkyl;
  • 'n' is selected from 0 to 2, both inclusive.
  • R 1 , U and V are as defined above in formula (I)
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), haloalkoxy (for example OCHF 2 , OCH 2 CF 3j or OCH 2 CH 2 CF 3 ), cycloalkylalkoxy (for example cyclobutylmethoxy) and cycloalkyl (for example cyclohexyl).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • haloalkoxy for example OCHF 2 , OCH 2 CF 3j or OCH 2 CH 2 CF 3
  • cycloalkylalkoxy for example cyclobutylmethoxy
  • cycloalkyl for example cyclohexyl
  • R 1 , U and V are as defined above in formula (I).
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), alkoxy (for example OCH 2 C(CH 3 ) 3 ) and haloalkoxy (for example OCH 2 CF 3 ).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • alkoxy for example OCH 2 C(CH 3 ) 3
  • haloalkoxy for example OCH 2 CF 3
  • R 1 , R 2 , U and V are as defined above in formula (I). According to another embodiment, specifically provided are compounds of the formula (Ic) wherein R 1 and R 2 are alkyl preferably methyl.
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), alkoxy (for example OCH 2 C(CH 3 ) 3 ) and haloalkoxy (for example OCF 3 or OCH 2 CF 3 ).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • alkoxy for example OCH 2 C(CH 3 ) 3
  • haloalkoxy for example OCF 3 or OCH 2 CF 3
  • R 1 , R 2 , R 3 , U and V are as defined above in formula (I).
  • R 1 and R 2 are alkyl preferably methyl.
  • R 3 is alkyl, preferably (C 1 -C4) alkyl.
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), alkoxy (for example OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OCH 2 C(CH 3 ) 3 or OCH 2 CH 2 CH(CH 3 ) 2 ), haloalkoxy (for example OCHF 2 , OCF 3 , OCH 2 CF 3> or OCH 2 CH 2 CF 3 ) and cycloalkylalkoxy (for example cyclopropylmethoxy or cyclobutylmethoxy).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • alkoxy for example OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , OCH
  • R 1 , R 2 , R 4 , U and V are as defined above in formula (I).
  • R 4 is halogen preferably fluorine, chlorine or bromine.
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), dialkylamino (for example diethylamino), and haloalkoxy (for example OCF 3 ).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • dialkylamino for example diethylamino
  • haloalkoxy for example OCF 3
  • R 1 , R 2 , U and V are as defined above in formula (I).
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), alkyl [for example CH 2 CH(CH 3 )2], haloalkyl (for example CF 3 ), alkoxy (for example OCH 3 ) and haloalkoxy (for example OCF 3 or OCH 2 CF 3 ).
  • halogen for example F, CI or Br
  • alkyl for example CH 2 CH(CH 3 )2
  • haloalkyl for example CF 3
  • alkoxy for example OCH 3
  • haloalkoxy for example OCF 3 or OCH 2 CF 3
  • R 1 , R 2 , U and V are as defined above in formula (I).
  • R 1 and R 2 are alkyl preferably methyl.
  • 'LP is substituted or unsubstituted aryl, preferably phenyl.
  • substituent on phenyl is halogen (for example F)
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), alkyl (for example wo-propyl) haloalkyl (for example CF 3 ), haloalkoxy (for example OCF 3 ) and optionally substituted aryloxy (for example methylphenoxy).
  • halogen for example F, CI or Br
  • alkyl for example wo-propyl
  • haloalkyl for example CF 3
  • haloalkoxy for example OCF 3
  • optionally substituted aryloxy for example methylphenoxy
  • Another preferred embodiment is compounds of formula (Ha) to (Ilg):
  • R ⁇ R 2 and R 3 which may be the same or different, are independently selected from hydrogen or substituted or unsubstituted alkyl;
  • R 4 is halogen selected from F, CI, Br or I; at each occurrence, R 5 is selected from hydrogen, halogen or substituted or unsubstituted alkyl;
  • R 6 is selected from hydrogen, cyano, nitro, -NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(0)OR x , -OR x , -C(0)NR x R y and -C(0)R x ;
  • 'm' is selected from 0 to 5, both inclusive.
  • Particularly contemplated are compounds of the formulas (I), (Ia)-(Ig) and (Ila)- (Ilg), which possess IC 5 o of less than 250 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to TRPAl activity as measured by method as described in the present patent application.
  • the present patent application 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 of the present invention can be administered as pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be the doctor's discretion.
  • Compounds of the present invention may be used in the manufacture of medicaments for the treatment of any diseases disclosed herein.
  • the compounds and pharmaceutical compositions described herein are useful for modulating TRPA1 receptors, wherein modulation is believed to be related to a variety of disease states.
  • the compound of the present invention can be administered alone or in combination with other therapeutic agents.
  • the TRPA1 modulator is administered conjointly with one or more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, antifungal agent, anti-viral agent, anti-septic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor
  • the present patent application further provides a method of inhibiting TRPA1 receptors 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 includes fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, 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 (tert-butyl).
  • Ci ⁇ alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • alkyl groups described herein may be straight chain or branched, substituted or unsubstituted
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl and 2-butenyl.
  • alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a straight or branched chain 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) e.g., ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy refers to a straight or branched, saturated aliphatic hydrocarbon radical bonded to an oxygen atom that is attached to a core structure.
  • alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described 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 include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl 4,4,4-trifluorobutyl, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl and the like.
  • haloalkoxy examples include but are not limited to fluoromethoxy, difiuoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy, 1-bromoethoxy and the like. Unless set forth or recited to the contrary, all "haloalkyl” and “haloalkoxy” 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, 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 sprirobicyclic groups, e.g., spiro(4,4) non-2-yl. Unless set forth or recited to the contrary, all cycloalkyi groups described 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 herein may be substituted or unsubstituted.
  • cycloalkylalkoxy is used to denote alkoxy substituted with cycloalkyi, wherein 'alkoxy' and 'cycloalkyi' are as defined above (either in the broadest aspect or a preferred aspect). Examples of 'cycloalkylalkoxy' groups is
  • all cycloalkylalkoxy groups described 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 herein may be substituted or unsubstituted.
  • aryl means a carbocyclic aromatic system containing one, two or three fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc). If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated.
  • fused means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. The term “fused” is equivalent to the term “condensed”.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Unless set forth or recited to the contrary, all aryl 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, e.g., -CH 2 C 6 H 5 or -C 2 H4C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.
  • aryloxy means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • heterocyclic ring refers to a stable 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 monocyclic, bicyclic 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.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoqinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl
  • 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 heterocyclic ring described 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 herein may be substituted or unsubstituted.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • 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. Unless set forth or recited to the contrary, all heteroaryl groups described herein may be substituted or unsubstituted.
  • 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. Unless set forth or recited to the contrary, all heteroarylalkyl groups described 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.
  • IC50 refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity.
  • 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 the present invention including compounds of formula (I), (Ia)-(Ig) and (Ila)-(IIg) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers).
  • the present invention includes these stereoisomeric forms (including diastereomers and enantiomers) and mixtures thereof.
  • the various stereoisomeric forms of the compounds of the present invention may be separated from one another by 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.
  • the pharmaceutical composition of the present patent application 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 includes the compound(s) described herein in an amount sufficient to inhibit TRPAl in a subject (e.g., a human).
  • the inhibitory activity of compounds falling within the formulas (I), (Ia)-(Ig) and (Ila)-(IIg) may be measured by an assay provided below.
  • the compound of the present invention 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.
  • a pharmaceutically acceptable excipient such as a carrier or a diluent
  • the pharmaceutical compositions may be prepared by techniques known in the art.
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the compounds and pharmaceutical compositions of the present invention can be administered to treat any disorder, condition, or disease treatable by inhibition of TRPAl.
  • the compounds and pharmaceutical compositions of the present invention are suitable for treatment or prophylaxis of the following diseases, conditions and disorders mediated or associated with the activity of TRPAl receptors: pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, chemotherapy - induced neuropathies, eye - irritation, bronchial - irritation, skin - irritation (atopic dermatitis), Frost - bites (cold - bite), spasticity, catatonia, catalepsy, parkinsons, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain,
  • the sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors".
  • 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.
  • 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).
  • carboxylic acid ester of formula (1) [when R a is alkyl] can be coupled with amines of general formula (2) by using suitable base (e.g., sodium hydride) and in suitable solvent (e.g. toluene, xylene) to give compounds of the general formula
  • Compound of formula (3) can be converted to substituted triazinedione ester of general formula (4) by reaction with N-(chlorocarbonyl)isocyanate in the presence of suitable base (e.g., triethylamine, diisopropylethylamine) in a suitable solvent such as dichloromethane or tetrahydrofuran followed by alkylation with alkylating agent of formula R'X in the presence of suitable base (e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine) in suitable solvent such as DMF or THF.
  • suitable base e.g., triethylamine, diisopropylethylamine
  • suitable solvent such as dichloromethane or tetrahydrofuran
  • suitable base e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine
  • the carboxylic acid of a formula (5) is coupled with amine of a formula (2) under appropriate conditions using a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) to give compound of a general formula (la).
  • a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP)
  • Compound of formula (3') can be converted to substituted triazinedione ester of general formula (4') by reaction with N-(chlorocarbonyl)isocyanate in the presence of suitable base (e.g., triethylamine, diisopropylethylamine) in a suitable solvent such as dichloromethane or tetrahydrofuran followed by alkylation with alkylating agent of formula R'X in the presence of suitable base (e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine) in suitable solvent such as DMF or THF.
  • suitable base e.g., triethylamine, diisopropylethylamine
  • suitable solvent such as dichloromethane or tetrahydrofuran
  • suitable base e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine
  • the carboxylic acid of a formula (5') can be coupled with amine of a formula (2) under appropriate conditions using a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) to give compound of a general formula (la').
  • a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP)
  • intermediate of the general formula (4) can also be prepared as shown is Scheme 4.
  • 2-amino-4-methylthiazole (6) can be converted to substituted triazinedione of general formula (7) in two steps as described in Scheme 3.
  • LDA Lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazide
  • Intermediate (1 1) can also be alkylated stepwise using alkyl halide R'X followed by R 2 X to afford unsymmetrical Intermediate (12) in presence of a suitable base and solvent.
  • Formylation of (12) using phosphorusoxychloride and N,N-dimethylformamide followed by one carbon homologation using methoxymethyltriphenylphosphonium chloride (13) in the presence of a strong base under Wittig reaction conditions affords the enol ether (14).
  • Hydrolysis of enol ether (14) under acidic condition e.g., hydrochloric acid, boron tribromide
  • Oxidation of acetaldehyde intermediate (15) with suitable oxidizing agent e.g., Jones reagent, chromic acid, sodium chlorite
  • suitable oxidizing agent e.g., Jones reagent, chromic acid, sodium chlorite
  • carboxylic acid (16) Coupling of triazinedione acetic acid (16) with amine of a formula (2) under appropriate conditions with the help of a suitable coupling agent (e.g., DCC, EDCI, HATU, HBTU) gives compounds of the general formula (Ic).
  • 6-chloro-l,3-dialkyl-2,4(lH,3H)-dione of the formula (17) is commercially available or can be prepared according to a known literature methods. Nitration of compounds of the general formula (17) using an appropriate mixture of nitric acid and sulfuric acid followed by coupling with an appropriate amine of formula (18) affords the amino nitro compound of the formula (19).
  • a similar approach for the synthesis of intermediate (19) is described by Senda, S. et al, in J. Am. Chem. Soc. 1978, 100(24), 7661-7664. Reduction of nitro group of formula (19) using palladium catalyst gives diamino compound (20).
  • N-bromosuccinimde, N- chlorosuccinimide, F-TEDA [N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate)] ⁇ gives halo-furo[2,3-c ]pyrimidinetrione of formula (26).
  • compound of formula (26) can also be prepared from compound of formula (25) using dihaloacetyl chloride such as dichloroacetyl chloride or dibromoacetyl chloride.
  • dihaloacetyl chloride such as dichloroacetyl chloride or dibromoacetyl chloride.
  • Halo-furo[2,3-iflpyrimidinetrione compounds of formula (26) was converted into furo[2,3-i/]pyrirnidinedione ester of compounds of general formula (27) by reaction with the lithium salt of ethyl acetate (generated from dry ethyl acetate and LHMDS) followed by dehydration and isomerization under acidic conditions. Hydrolysis of furo[2,3-c/ ⁇ pyrimidinedione ester of general formula (27) under basic conditions affords corresponding carboxylic acid of general formula (28).
  • the carboxylic acid intermediate of the general formula (28) can be prepared as described in Scheme 10.
  • reaction of (cyanomethyl)lithium with furo[2,3-i ]pyrimidinetrione of formula (26) (where R 4 is halogen) in a suitable solvent gives furo[2,3-i ]pyrimidinyl acetonitrile of the formula (29).
  • This intermediate on hydrolysis under acidic conditions gives intermediates of the formula (28) required for the synthesis of compounds of the general formula (Ie).
  • the carboxylic acid (38) is coupled with an amine using standard amide coupling method to give compounds of formula (39).
  • Cyclisation of (39) with triphosgene produced the fused pyrimidine diene intermediate (40).
  • Intermediate (40) on alkylation using alkyl halide furnished intermediate (41).
  • Hydrolysis of ester of formula (41) with aqueous acid gives compounds of the formula (42).
  • the coupling of compounds of formula (42) with an amine of formula (2) by using a standard amide coupling method gives compounds of general formula (Ig).
  • Scheme 16 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (54) (wherein R 5 , R 6 and 'm' are as defined above in description) which is prepared from acetophenones of the formula (53) using known approaches. Certain di-and tri-substituted acetophenones were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (49) in three steps. Thus, acid of formula (49) was converted to the corresponding acid chloride of formula (50) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (50) was converted to corresponding Weinerb amide of formula
  • ketone (56) can also be synthesized in two steps by a-bromination of ketone (55) using bromine in acetic acid followed by condensation with thiourea in a suitable solvent such as ethyl alcohol at elevated temperature.
  • the 2-amino-4-aryl thiazole (56) is coupled with haloacetyl halide (e.g., chloroacetyl chloride or bromoacetyl bromide) of formula (57) in presence of suitable solvent such as dichloromethane gives aryl thiazolyl acetamide of the general formula (58).
  • haloacetyl halide e.g., chloroacetyl chloride or bromoacetyl bromide
  • 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, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • DMSO-i& Hexadeuterodimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • J Coupling constant in units of Hz
  • RT or rt room temperature (22-26°C)
  • Aq. aqueous
  • AcOEt ethyl acetate
  • Step 1 Ethyl (2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l ,3,5]triazin-6-yl)acetate: To a stirred suspension of ethyl (2-amino-l,3-thiazol-4-yl)acetate (0.500 g, 2.685. mmol) in anhydrous dichloromethane (10 ml), was added dropwise at 0°C, a solution of N- (chlorocarbonyl) isocyanate (0.425 g, 4.027 mmol) in anhydrous dichloromethane (10 ml) under nitrogen atmosphere.
  • Step 2 Ethyl (3-methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6- yl)acetate: To a magnetically stirred solution of step 1 intermediate (150 mg, 0.588 mmol) in anhydrous DMF (2.0 ml) was added diisopropyl ethylamine (DIPEA) (0.076 g, 0.588 mmol) followed by iodomethane (0.167 g, 1.176 mmol) at room temperature. Resulting suspension was further stirred for 18 hours under nitrogen atmosphere.
  • DIPEA diisopropyl ethylamine
  • Step 3 (3-Methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2- ][l,3,5]triazin-6-yl)acetic acid: A mixture of step 2 intermediate (0.700 g, 2.60 mmol) and concentrated HC1 (5.0 ml) was heated at 90 °C for 2 h.
  • Step 1 Ethyl (l, l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6] thiatriazin-7- yl)acetate: To a stirred and cooled (0°C) suspension of ethyl (2-amino-l,3-thiazol-4- yl)acetate (7.0 g, 37.587 mmol) in anhydrous dichloromethane (35 ml) was added dropwise a solution of chlorosulfonyl isocyanate (4.91 ml, 56.381 mmol) in anhydrous dichloromethane (15 ml) under nitrogen atmosphere.
  • Step 2 Ethyl (2-methyl-l, l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6] thiatriazin-7-yl)acetate: To a magnetically stirred solution of Step 1 intermediate (2.0 g, 6.865 mmol) in anhydrous DMF (10.0 ml) was added N ⁇ V-diisopropylethylamine (DIPEA) (1.2 ml, 6.865 mmol) followed by iodomethane (0.85 ml, 13.739 mmol) at room temperature under nitrogen atmosphere.
  • DIPEA N ⁇ V-diisopropylethylamine
  • Step 3 2-MethyI-l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7- yl)acetic acid: A mixture of Step 2 intermediate (680 mg, 2.227 mmol) and concentrated HC1 (3.0 ml) was heated at 90°C for 2 h. The reaction mixture was cooled to room temperature.
  • Step 1 l,3-Dimethylimidazo[l,2-a][l,3,5]triazine-2,4(lH,3H)-dione: To a stirred solution of sodium hydroxide (8.8 g, 221.879 mmol) in water (135 ml) was added imidazo[l,2- ][l,3,5]triazine-2,4(lH,3H)-dione (13.50 g, 88.757 mmol) at 0°C and the reaction mixture was stirred at the same temperature for 30 min. Dimethyl sulphate (21.0 ml, 221.879 mmol) was added dropwise at the same temperature and the resulting mixture was slowly warmed to room temperature.
  • Step 2 l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazine-6- carbaldehyde: Phosphorous oxychloride (5.1 ml) was added slowly to a solution of dry DMF (20.0 ml) at room temperature. Step 1 intermediate (4.0 g, 22.202 mmol) was added portion wise and the resulting reaction mixture was heated overnight at 80 °C. The excess of phosphorous oxychloride and DMF were distilled off under reduced pressure. The viscous residue obtained was poured into ice-cold water (100 ml) and neutralized with NaHC0 3 solution.
  • the aqueous layer was extracted with ethyl acetate (3 x 75 ml) and the combined organic layers were washed with saturated solution of NaHC0 3 (50 ml), followed by brine (50 ml), dried over Na 2 S0 4 and filtered.
  • Step 4 ( 1 ,3-Dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydroimidazo[ 1 ,2-a] [ 1 ,3,5]triazin-6-y 1) acetaldehyde: 1 N HC1 (1 ml) was added to a stirred solution of Step 3 intermediate (625 mg, 2.645 mmol) in THF (10 ml) at room temperature to give a turbid solution. After stirring for 2 h, the excess of solvent was evaporated and the residue obtained was neutralized with saturated solution of NaHC0 3 and extracted with ethyl acetate (3 x 75 ml).
  • Step 5 (l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2- ][l,3,5]triazin-6- yl)acetic acid: To a solution of Step 4 intermediate (575 mg, 2.587 mmol) and sulphamic acid (376 mg, 3.881 mmol) in acetone (10.0 ml) was added sodium chlorite (292 mg, 3.234 mmol) in water (4.0 ml) at 0 °C. After stirring for 1 h at room temperature, excess of solvent was distilled out. The residue obtained was diluted with brine and extracted with ethyl acetate (3 x 50 ml).
  • Step 1 6-Chloro-l,3-dimethyl-5-nitropyrimidine-2,4(lH,3H)-dione: 6-Chloro-l,3- dimethylpyrimidine-2,4(lH,3H)-dione (13.0 g, 74.464 mmol) was added portion wise to a stirred and cooled (15°C) solution of concentrated sulphuric acid (40 mL). The reaction temperature was maintained below 10 °C. Fuming nitric acid (15 mL) was added dropwise into the above reaction mixture and then stirred for 2 h at the same temperature.
  • Step 2 l,3-Dimethyl-6-(methylamino)-5-nitropyrimidine-2,4(lH3H)-dione: To a stirred solution of Step 1 intermediate (1 1.00 g, 50:095 mmol) in anhydrous chloroform (90 mL) was added dropwise a solution of 40 % aqueous methylamine (7.76 ml, 100.191 mmol) in anhydrous dichloromethane (20 mL) at room temperature under nitrogen atmosphere. After stirring for 1 h the reaction mixture was distilled under vacuo to give crude product.
  • Step 3 5-Amino-l,3-dimethyl-6-(methylamino)pyrimidine-2,4(lH,3H)-dione: To a stirred solution of Step 2 intermediate (13.5 g, 63.034 mmol) in methanol (700 mL) was added 10 % Palladium on carbon (50 % wet, 5.0 g) under hydrogen balloon atmosphere at room temperature. After overnight stirring, the reaction mixture was filtered through celite bed.
  • Step 4 l,3,9-Trimethyl-7,9-dihydro-lH-purine-2,6,8(3H)-trione: To a magnetically stirred solution of Step 3 intermediate (2.0 g, 10.857 mmol) in anhydrous THF (50.0 mL) was added ⁇ , ⁇ -carbonyldiimidazole (2.1 g, 13.029 mmol) at room temperature under nitrogen atmosphere. After refluxing for 18 h the excess of solvent was distilled under reduced pressure. The residue obtained was diluted with ethyl acetate (100 ml) and water (100 ml).
  • the aqueous layer was extracted with ethyl acetate (2 x 75 ml) and the combined organic layers were washed with water (2 x 25 ml) followed by brine (25 ml), dried (Na 2 S0 4 ) and filtered. The filtrate was concentrated under reduced pressure.
  • Step 1 6-Chloro-l,3-dimethylfiiro[2,3-i/lpyrimidine-2,4,5(lH,3H,6H)-trione: To a stirred solution of l,3-dimethylfuro[2,3-i ]pyrimidine-2,4,5(lH,3H,6H)-trione (5.0 g, 25.489 mmol) and azobisisobutyronitrile (AIBN) (83.71 mg, 0.509 mmol) in carbon tetrachloride (50 mL) was added N-chlorosuccinimide (4.084 g, 30.587 mmol). The resulting mixture was refluxed for 24 h.
  • AIBN azobisisobutyronitrile
  • reaction mixture was then cooled to room temperature and diluted with chloroform (100 mL) and water (100 mL). The layers were separated. Aqueous layer was extracted with chloroform (2 x 50 ml) and the combined organic layers were washed with brine (2 x 50 ml), dried (Na 2 S0 4 ) and filtered. The filtrate was concentrated under reduced pressure.
  • Step 2 Ethyl (2Z)-(6-chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5(6H)-ylidene)acetate: Anhydrous THF (100 mL) was cooled to -78°C. A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 2.5 g, 14.94 mmol) was added under nitrogen atmosphere. Then dry ethyl acetate (1.313 g, 14.94 mmol) was added and the resulting mixture was stirred at the same temperature for 1 h.
  • LiHMDS lithium bis(trimethylsilyl)amide
  • Step 3 Ethyl (2Z)-(6-chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5-yl)acetate: A mixture of Step 2 intermediate (1.0 g, 0.003 mmol) and glacial acetic acid (15.0 mL) was refluxed for 4 h.
  • Step 4 (6-Chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-i
  • Step 1 6-Bromo-l,3-dimethylfuro[2,3-i jpyrimidine-2,4,5(lH,3H,6H)-trione:
  • the title compound was prepared by reaction of l,3-dimethylfuro[2,3-c/)pyrirnidine- 2,4,5(1 H,3H,6H)-trione (500 mg, 2.548 mmol) and azobisisobutyronitrile (AIBN) (8.0 mg, 0.049 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (544 mg, 3.056 mmol) as described in the procedure of intermediate 8 step 1 to obtain 200 mg of the product as a white solid; ⁇ NMR (300 MHz, CDC1 3 ) ⁇ 3.36 (s, 3H), 3.53 (s, 3H), 6.55 (s, 1H); APCI (m/z) 275 (M) + .
  • Step 2 Ethyl (2Z)-(6-bromo-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5(6H)-ylidene)acetate:
  • the title comopund was prepared by the reaction of 6-bromo-l,3-dimethylfuro[2,3-i ]pyrirnidine-2,4,5(lH,3H,6H)-trione (3.5 g, 12.62 mmol) with lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 3.169 g, 18.94 mmol) and dry ethyl acetate (1.829 g, 18.94 mmol) in dry THF (200 mL) as described for the preparation of step 2 of intermediate 8 to give 150 mg of the product as an off-white solid; ⁇ NMR (300 MHz, CDC1 3 ) ⁇ 1.28-1.36
  • Step 3 Ethyl (2Z)-(6-bromo-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i/]pyrimidin-5-yl)acetate:
  • the title compound was prepared according to procedure described for step 3 of intermediate 8 by using step 2 intermediate (150 mg, 0.473 mmol) and glacial acetic acid (5.0 mL) to give 65 mg of the product as an off-white solid;
  • Step 4 (6-Bromo-l,3-dimethyl-2,4-dioxo-l ,2,3,4-tetrahydrofuro[2,3-i ]pyrimidin-5- yl)acetic acid:
  • This intermediate was prepared according to procedure described for step 3 of intermediate 8 by using step 2 intermediate (60 mg, 0.189 mmol) to yield 45 mg of the product as an off- white solid.
  • Step 1 6-Chloro-l,3-dimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of 1,3- dimethylbarbituric acid (20.0 g, 128.09 mmol) in water (10 ml), phosphorous oxychloride (80 ml) was added slowly by externally cooling and reaction was then refluxed for 3 h. The reaction mixture was allowed to cool to 0°C and quenched with ice cold water (350 ml).
  • Step 2 6-(Hydroxyamino)-l,3-dimethylpyrimidine-2,4(lH,3H)-dione:
  • a solution of Step 1 intermediate (10 g, 57.261 mmol), hydroxylamine hydrochloride (12.15 g, 176.361 mmol) and sodium acetate (33.81 g, 412.28 mmol) in isopropyl alcohol (280 ml) were refluxed for 4 h.
  • the reaction mixture was concentrated under reduced pressure, diluted with water and stirred for 1 h.
  • Step 3 3,5,7-Trimethylisoxazolo[3,4-i/]pyrimidine-4,6(5H,7H)-dione: A mixture of Step 2 intermediate (9.5 g, 55.555 mmol) and acetic anhydride (48 ml) in dry pyridine (92 ml) were refluxed for 6 h under nitrogen atmosphere.
  • Step 4 Methyl (5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[3,4-i ]pyrimidin-3- yl)acetate: To a stirred solution of Step 3 intermediate (8.0 g, 41.02 mmol) in dimethylcarbonate (12.6 ml) was added sodium hydride (60 % dispersion in mineral oil, 3.93 g, 163.75 mmol) and mixture was refluxed overnight under nitrogen atmosphere.
  • Step 5 (5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[3,4-i/] rjyrimidin-3-yl)acetic acid: A mixture of Step 4 intermediate (9.0 g, 35.55 mmol) and 6 N H 2 S0 4 (88.93 ml) in dioxane (90 ml) stirred at reflux temperature for 1 h to give a homogeneous pale yellow solution. This solution was cooled, diluted with water and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, dried over Na 2 S0 4 and concentrated.
  • Step 1 tert-Butyl cyanoacetate: To a stirred solution of cyanoacetic acid (110 g, 1293.20 mmol) in dry diethyl ether (650 ml), phosphorus pentachloride was added in portions at 0 °C and stirred at room temperature for 3 h. The excess of solvent and phosphorus oxychloride were distilled out under reduced pressure.
  • the acid chloride was dissolved in dry diethyl ether (150 ml) and cooled 0-5 °C, ⁇ , ⁇ -dimethyl aniline (165 ml, 1293.20 mmol) and tert butanol (122.88 ml, 1293.20 mmol) in dry diethyl ether (150 ml) was added dropwise during 30 min and refluxed for 2 h and subsequently stirred at room temperature for overnight. The reaction mixture was then diluted with water and the product was extracted in ethyl acetate (200 ml x 2).
  • Step 2 1-fert-Butyl 5-ethyl (2£)-3-amino-2-cyanopent-2-enedioate: To a stirred solution of step 1 intermediate (114 g, 808.5 mmol) and ethyl (3£)-3-ethoxy-3-iminopropanoate hydrochloride (158.20 g, 808.5 mmol) in dry chloroform was added triethyl amine (588.24 ml, 4041.2 mmol) and mixture was vigoruosly stirred and heated to reflux for 72 h under nitrogen atomosphere.
  • step 1 intermediate 114 g, 808.5 mmol
  • ethyl (3£)-3-ethoxy-3-iminopropanoate hydrochloride 158.20 g, 808.5 mmol
  • triethyl amine 588.24 ml, 4041.2 mmol
  • Step 3 tert-Butyl 5-amino-3-(2-ethoxy-2-oxoethyl)-l,2-oxazole-4-carboxylate: A mixture of step 2 intermediate (105 g, 413 mmol), hydroxylamine hydrochloride (57.44 g, 826.77 mmol) and sodium acetate (122.07 g, 1488.16 mmol) in dry ethanol (830 ml) was stirred and refluxed for overnight. The excess of ethanol was distilled off under reduced pressure, diluted with water (250 ml) and extracted with ethyl acetate (3x500 ml) and dried (Na 2 S0 4 ).
  • Step 4 5-Amino-3-(2-ethoxy-2-oxoethyl)-l,2-oxazole-4-carboxylic acid: To a stirred solution of step 3 intermediate (45.8 g, 169.6 mmol) in dichloromethane was added trifluoro acetic acid (274 ml) at 0 °C and subsequently stirred at room temperature for 2 h. The reaction solvent was removed under reduced pressure, diluted with water, it was adjusted to PH 6.4 with saturated sodium hydrogen carbonate aqueous solution.
  • Step 5 Ethyl [5-amino-4-(methylcarbamoyl)-l,2-oxazol-3-yl]acetate: To a stirred solution of step 4 intermediate (26.5 g, 123.8 mmol) in 1,2-dichloroethane (310 ml) was added EDCI.HC1 (28.48 g, 148.5 mmol) and HOBt (16.7 g, 123.7 mmol). The reaction mixture was then stirred at room temperature for 30 min. Methyl amine (33% in dry ethanol) (23.3 ml, 247.5 mmol) was added at 15-20 °C and stirred at room temperature for 24 h.
  • Step 6 Ethyl (5-methyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3- yl)acetate: To a stirred solution of Step 5 intermediate (17.5 g, 77.09 mmol) in dry THF (256 ml) was added triphosgene (1 1.43 g, 38.51 mmol) and mixture was refluxed for overnight.
  • Step 7 Ethyl(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-d]pyrimidin-3- yl)acetate: A solution of Step 6 intermediate (7.5 g, 29.64 mmol) in dry acetone (185 ml) was added anhydrous K 2 C0 3 (5.33 g, 38.53 mmol) and the mixture was stirred at room temperature for 15 min. Methyl iodide (9.24 ml, 147.9 mmol) was added slowly with stirring and further stirred at room temperature for 4 h.
  • Step 8 (5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[5,4-i/]pyrimidin-3-yl)acetic acid: A mixture of Step 7 intermediate (5.5 g, 20.59 mmol) and 6 N H 2 S0 4 (50 ml) in 1,4- dioxane (50 ml) was stirred at reflux temperature for 2.5 h to give a homogeneous pale yellow solution. The solvent was evaporated completely under reduced pressure, diluted with water and extracted with dichloromethane (3 x 100 ml). The combined organic layers were washed with water, dried over Na 2 S0 4 and concentrated.
  • the salt was then treated with saturated solution of NaHC0 3 to re-generate the amine.
  • the mixture was extracted with dichloromethane (2x 50 mL) and the combined organic extracts were washed with water and brine. The solvent was evaporated under reduced pressure to afford the 2-amino-4-aryl-thiazole derivative.
  • Step 1 A mixture of appropriate aryl alkyl ketone (1.0 equiv.), thiourea (2.0 eqiv.) and iodine (1.0 equiv.) in dry ethanol (5 volumes) was refluxed for 24 h. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of sodium thiosulphate. The organic layer was treated with IN HCl and the precipitated salt was collected by filtration. The salt was then treated with saturated solution of NaHC0 3 and extracted with dichloromethane, washed with brine, dried over sodium sulfate and the solvent was evaporated to afford the 2-aminothiazole derivative.
  • Step 2 To a stirred and cooled (0°C) solution of appropriate amine (1.0 equiv.) and pyridine (1.2 equiv.) in dichloromethane (5 vol.) was added bromoacetyl bromide (1.2 eq.) over 5 min and the resulting mixture was allowed to warm to room temperature. After stirring for 2 h, the reaction mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water, followed by brine, dried (Na 2 S0 4 ) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5-10% ethyl acetate in petroleum ether to obtain the desired product as an off-white solid.
  • Method A To a stirred solution of isoxazole acetic acid (1.0 equiv.) in 1,2-dichloroethane was added EDCI (1.2 equiv.), HOBt (0.3 equiv.) and 4-dimethylaminopyridine (0.1 equiv.) and the mixture was stirred at room temperature for 10-15 min. An appropriate amine (1.0 equiv.) was then added and mixture was stirred under nitrogen atmosphere at the same temperature for 48 h or heated at reflux temperature for 24 h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with methanol and stirred at room temperature for 30 min. The solid separated out was collected by filtration. The solid product was further purified by recrystalisation from isopropanol or methanol to give the desired products.
  • Method B To a stirred solution of isoxazole acetic acid (1.1 equiv.) in dry dichloromethane were added appropriate amine (1.1 equiv.), HOBt (0.37), N-methyl morpholine (1.16) and EDCI (1.16) 0-5° C and stirred at the same temperature for 30 min. The temperature of the reaction mixture was then gradually increased to room temperature and stirred for overnight. The reaction mass was directly loaded on silica gel column chromatography to give the desried product.
  • the illustrative examples of the present invention are screened for TRPAl activity according to a modified procedure described in (a) Toth, A. et al. Life Sciences, 2003, 73, 487-498. (b) McNamara C, R. et al, Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13525- 13530.
  • the screening of the compounds can be carried out by other methods and procedures known to persons skilled in the art.
  • TRPAl receptor activation was measured as inhibition of allyl isothiocyanate (AITC) induced cellular uptake of radioactive calcium.
  • Test compounds were dissolved in 100% DMSO to prepare 10 mM stock and then diluted using plain medium with 0.1% BSA and 1.8 mM CaCl 2 to get the desired concentration. The final concentration of DMSO in the reaction was 0.5% (v/v).
  • Human TRPAl expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 ⁇ g / ml of G-418.
  • Rat TRPAl expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 ⁇ g / ml of Zeocin.
  • Test compound is formulated immediately prior to dosing by making a suspension
  • Example 29 (2.5 ⁇ 7 ⁇ Tween-80 and 0.5 % methylcellulose suspension in geometric dilution).
  • the animals were provided with food and water ad libitum throughout the study period.
  • Male rats SD are administered orally a dose of 10 mg/kg (dose volume lOmL/kg body weight) of test compound by a gavage needle.
  • Blood samples (approximately 250 ⁇ ) were collected from retro orbital sinus using rat capillary tubes at regular intervals of 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 24.0 hrs after dose administration into rat. Samples were centrifuged immediately at lOOOg for 10 min at 4°C. Plasma samples were processed and analyzed by LCMS/MS as per standard operating procedures. Plasma concentration of test compound was recorded and used to calculate the pharmacokinetic parameters such as C max , area under the curve, T max etc using Pharsight Winonlin software.
  • the pharmacokinetic profile of Example 29 is depicted

Abstract

Cette invention concerne des amides de composés hétérocycliques à titre de modulateurs de la sous-famille A à potentiel de récepteur transitoire (TRPA). En particulier, les composés ci-décrits sont utiles pour traiter ou prévenir les maladies, les affections et/ou les troubles modulés par TRPA1 (sous-famille A à potentiel de récepteur transitoire, membre 1). Des procédés pour préparer les composés ci-décrits, les intermédiaires utilisés pour leur synthèse, des compositions pharmaceutiques les contenant, et des méthodes pour traiter ou prévenir des maladies, des affections et/ou des troubles modulés par TRAP1 sont également décrits. (I).
PCT/IB2010/002218 2010-03-15 2010-09-07 Amides de composés hétérocycliques à titre d'inhibiteurs de trpa1 WO2011114184A1 (fr)

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WO2012172475A1 (fr) 2011-06-13 2012-12-20 Glenmark Pharmaceuticals S.A. Traitement de troubles respiratoires au moyen d'antagonistes de trpa1
WO2012176105A1 (fr) 2011-06-22 2012-12-27 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste du trpa1 et un antagoniste du récepteur de leucotriènes
WO2012176143A1 (fr) 2011-06-22 2012-12-27 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste de trpa1 et un agoniste de bêta-2
WO2013014597A1 (fr) 2011-07-25 2013-01-31 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste du récepteur trpa1 et un stéroïde
CN103012288A (zh) * 2012-12-24 2013-04-03 济南圣泉唐和唐生物科技有限公司 6-氯-1,3-二甲基脲嘧啶的制备方法
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US9533952B2 (en) 2012-10-01 2017-01-03 Orion Corporation N-prop-2-ynyl carboxamide derivatives and their use as TRPA1 antagonists
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WO2017064068A1 (fr) 2015-10-14 2017-04-20 Almirall, S.A. Nouveaux antagonistes de trpa1
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US9073955B2 (en) 2010-12-20 2015-07-07 Glenmark Pharmaceuticals, S.A. 2-amino-4-arylthiazole compounds as TRPA1 antagonists
US8889862B2 (en) 2010-12-20 2014-11-18 Glenmark Pharmaceuticals, S.A. 2-amino-4-arylthiazole compounds as TRPA1 antagonists
WO2012085662A1 (fr) 2010-12-20 2012-06-28 Glenmark Pharmaceuticals S.A. Composés 2-amino-4-arylthiazoles en tant qu'antagonistes de la trpa1
WO2012172475A1 (fr) 2011-06-13 2012-12-20 Glenmark Pharmaceuticals S.A. Traitement de troubles respiratoires au moyen d'antagonistes de trpa1
US9186360B2 (en) 2011-06-13 2015-11-17 Glenmark Pharmaceuticals S.A. Treatment of respiratory disorders using TRPA1 antagonists
WO2012176143A1 (fr) 2011-06-22 2012-12-27 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste de trpa1 et un agoniste de bêta-2
WO2012176105A1 (fr) 2011-06-22 2012-12-27 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste du trpa1 et un antagoniste du récepteur de leucotriènes
WO2013014597A1 (fr) 2011-07-25 2013-01-31 Glenmark Pharmaceuticals Sa Composition pharmaceutique comprenant un antagoniste du récepteur trpa1 et un stéroïde
US9193729B2 (en) 2011-08-09 2015-11-24 Cubist Pharmaceuticals, Inc. Inhibiting transient receptor potential ion channel TRPA1
WO2013084153A1 (fr) 2011-12-05 2013-06-13 Glenmark Pharmaceuticals S.A. Composition pharmaceutique comprenant un antagoniste de trpa1 et un agent anticholinergique
US9533952B2 (en) 2012-10-01 2017-01-03 Orion Corporation N-prop-2-ynyl carboxamide derivatives and their use as TRPA1 antagonists
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CN103012288B (zh) * 2012-12-24 2015-06-17 济南圣泉唐和唐生物科技有限公司 6-氯-1,3-二甲基脲嘧啶的制备方法
US9394308B2 (en) 2013-01-18 2016-07-19 Merck Sharp & Dohme Corp. Inhibiting the transient receptor potential A1 ion channel
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