WO2010125469A1 - Composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de trpa1 - Google Patents

Composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de trpa1 Download PDF

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WO2010125469A1
WO2010125469A1 PCT/IB2010/001073 IB2010001073W WO2010125469A1 WO 2010125469 A1 WO2010125469 A1 WO 2010125469A1 IB 2010001073 W IB2010001073 W IB 2010001073W WO 2010125469 A1 WO2010125469 A1 WO 2010125469A1
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Prior art keywords
thiazol
dioxo
acetamide
dimethyl
pyrimidin
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PCT/IB2010/001073
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English (en)
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Sukeerthi Kumar
Abraham Thomas
Siddeshwar Shrimant Gaikwad
Sanjay Margal
Shantaram Kashinath Phatangare
Nageswara Rao Irlapati
Neelima Khairatkar-Joshi
Indranil Mukhopadhyay
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Glenmark Pharmaceuticals, S.A.
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Publication of WO2010125469A1 publication Critical patent/WO2010125469A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present patent application relates to pyrimidinedione-fused heterocyclic compounds with transient receptor potential ankyrinl (TRPAl) activity.
  • TRPAl transient receptor potential ankyrinl
  • TRP Transient Receptor Potential
  • TRPC canonical
  • TRPV vanilloid
  • TRPM melastatin
  • TRPP polycystin
  • TRPML mucolipin
  • TRPA ankyrin, ANKTMl
  • TRPN TRPN
  • TRPV5 and TRPV6 are more closely related to each other than to TRPVl, TRPV2, TRPV3, or TRPV4.
  • TRPAl is most closely related to TRPV3, and is more closely related to TRPVl and TRPV2 than to TRP V5 and TRPV6.
  • the TRPM family has 8 members.
  • Constituents include the following: the founding member TRPMl (melastatin or LTRPCl), TRPM3 (KIAAl 616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (TRP-p8 or CMRl), TRPM5 (MTRl or LTRPC5), and TRPM4 (FLJ20041 or LTRPC4).
  • TRPMl melastatin or LTRPCl
  • TRPM3 KAAl 616 or LTRPC3
  • TRPM7 TRP-PLIK, ChaK(l), LTRPC7
  • TRPM6 ChoK2
  • TRPM2 TRPC7 or LTRPC2
  • TRPM8 TRP-p8 or CMRl
  • TRPM5 MMRl 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, PCl
  • PKD-REJ PKD-REJ
  • PKD-ILl The sole mammalian member of the TRPA family is ANKTMl. 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 2010/036821, WO 2010/039289, WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO 2004/055054 and WO 2005/089206 describe various TRP channels modulators.
  • the present invention relates to compounds of the formula (I):
  • a 1 , A 2 and A 3 are independently selected from N and CR a ; with the proviso that A 1 , A 2 and A3 simulteneously are not CR a at any given instance and when Ai is CR a , A 2 is N, then A 3 is not CR a ;
  • R a is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, (CR x R y ) n OR x , COOR X , CONR x R y , S(O) m NR x R y , NR x (CR x R y ) n OR x , (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y , NR x (CR x R y ) n CONR x R y , (CH 2 ) n NHCOR x , (CH 2 ) n NH(CH 2 ) n SO 2 R x and (CH 2 ) n NHSO 2 R x ;
  • L is a linker selected from -(CR x R y ) n -, -O-(CR x R y ) n -, -C(O)-, -NR X -, -S(O) m NR x -, -NR x (CR x R y )n- and -S(O) m NR x (CR x R y ) n ;
  • R 1 and R 2 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 ) n OR x , COR X , COOR X , C0NR x R y , (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y and (CH 2 ) n NHC0R x ;
  • R 3 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and cycloalkenyl;
  • U is selected from -(CR x R y ) n -, substituted or unsubstituted aryl, substituted or unsubstituted five membered 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, or substituted or unsubstituted six membered heterocycle selected from the group consisting of 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, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(O)OR X , -OR X , -C(0)NR x R y , -C(O)R X and -SO 2 NR x R y ; or alternatively, U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring that may optionally include one or more heteroatoms selected from O, S and N; at each occurrence, R
  • R a is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and cycloalkylalkyl;
  • U is substituted or unsubstituted five membered heterocycle, for example selected from the group consisting of
  • R b is independently selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; at each occurrence, R z is independently selected from halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylallalkyl
  • 'm' and 'n' are independently selected from 0 to 2, both inclusive;
  • 'p' is independently selected from from 0 to 5, both inclusive.
  • each occurance of R a is independently hydrogen or alkoxy preferably methoxy.
  • each of R z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C 4 )alkyl], haloalkyl (for example -CF 3 ), haloalkoxy (for example -OCF 3 , or -OCH 2 CF 3 ) and dialkyl amine (for example diethylamine).
  • halogen for example F, Cl or Br
  • alkyl for example (Ci-C 4 )alkyl
  • haloalkyl for example -CF 3
  • haloalkoxy for example -OCF 3 , or -OCH 2 CF 3
  • dialkyl amine for example diethylamine
  • R a , R z , U and 'p' are as defined herein above.
  • each of R z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C 4 )alkyl], alkoxy [for example -OCH 3 , -OCH 2 C(CH 3 ) 3 ], haloalkyl (for example CF 3 ), haloalkoxy (for example -OCF 3 or -OCH 2 CF 3 ) and dialkyl amine (for example diethylamine).
  • halogen for example F, Cl or Br
  • alkyl for example (Ci-C 4 )alkyl
  • alkoxy for example -OCH 3 , -OCH 2 C(CH 3 ) 3
  • haloalkyl for example CF 3
  • haloalkoxy for example -OCF 3 or -OCH 2 CF 3
  • dialkyl amine for example diethylamine
  • R a , R z , U and 'p' are as defined herein above.
  • R a is hydrogen or alkyl preferably methyl.
  • each of R z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C 4 )alkyl], haloalkyl (for example CF 3 ), and haloalkoxy (for example OCF 3 ).
  • halogen for example F, Cl or Br
  • alkyl for example (Ci-C 4 )alkyl
  • haloalkyl for example CF 3
  • haloalkoxy for example OCF 3
  • R a , R z , U and 'p' are as defined herein above.
  • each of R z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C 4 )alkyl], haloalkyl (for example CF 3 ), and haloalkoxy (for example OCF 3 ).
  • halogen for example F, Cl or Br
  • alkyl for example (Ci-C 4 )alkyl
  • haloalkyl for example CF 3
  • haloalkoxy for example OCF 3
  • R a , R z , U and 'p' are as defined herein above.
  • each of R z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C 4 )alkyl], haloalkyl (for example CF 3 ) and haloalkoxy (for example OCF 3 ).
  • halogen for example F, Cl or Br
  • alkyl for example (Ci-C 4 )alkyl
  • haloalkyl for example CF 3
  • haloalkoxy for example OCF 3
  • Particularly contemplated are compounds of the formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) which possess IC50 of less than 1000 nM, preferably, less than 250 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.
  • the compounds and pharmaceutical compositions of the present invention are useful for modulating TRPAl receptors, which modulation is believed to be related to a variety of disease states.
  • the compound of the present invention may also modulate one or more receptor such as TRPVl, TRPV3, TRP V4 and TRPM8 along with TRPAl receptor.
  • 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 TRPAl 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 TRPAl 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 TRPAl 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_ 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 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. Unless set forth or recited to the contrary, all 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, Cl, 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. 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 cycloalkyl 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 cycloalkyl, wherein 'alkoxy' and 'cycloalkyl' are as defined above (either in the broadest aspect or a preferred aspect).
  • cycloalkylalkoxy groups include cyclopropylmethoxy, 1- or 2-cyclopropylethoxy, 1-, 2- or 3- cyclopropylpropoxy, 1-, 2-, 3- or 4-cyclopropyl- butoxy, cyclobutylmethoxy, 1- or 2- cyclobutylethoxy, 1-, 2- or 3- cyclobutylpropoxy, 1-, 2-, 3- or 4-cyclobutylbutoxy, cyclopentylmethoxy, 1- or 2-cyclopentylethoxy, 1-, 2- or 3- cyclopentylpropoxy, 1-, 2-, 3- or 4- cyclopentylbutoxy, cyclohexylmethoxy, 1- or 2- cyclohexylethoxy and 1-, 2- or 3- cyclohexylpropoxy.
  • 'cycloalkylalkoxy' is (C3-6)cycloalkyl-(Ci_6)alkoxy. Unless set forth or recited to the contrary, 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 rings wherein such rings may be fused. 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.
  • 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 CeH 5 or -C 2 H 4 CeH 5 . Unless set forth or recited to the contrary, all arylalkyl 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-oxopyrrolidiny
  • 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.
  • heterocyclyl refers to a heterocyclic ring radical as defined above.
  • the heterocyclyl 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 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.
  • 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), (Ib), (Ic), (Id) and (Ie) 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 of them.
  • 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), (Ib), (Ic), (Id) and (Ie) 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, ischaemia, neurodegeneration, stroke, post stroke pain,
  • Nociceptors are primary sensory afferent (C and A ⁇ 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).
  • the compounds described herein including compounds of general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) and specific examples, can be prepared by techniques known to in the art, for example, through the reaction scheme depicted in Schemes 1-13. Furthermore, in the following scheme, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof are envisioned as part of the present invention. The compounds obtained by using the general reaction scheme may be of insufficient purity.
  • a general approach for the synthesis of pyrimidinedione-fused heterocyclic compounds of the general formula (I), wherein A 1 , A 2 , A 3 , R 1 , R 2 , R 3 , U, V and L are as defined above in the general description can be prepared as shown in Scheme 1.
  • pyrido[2,3-fiT]pyrimidinyl acetic acid (14) can also be converted to the corresponding ester (15) by using well known esterification methods.
  • Sodium hydride mediated coupling reaction of (15) with various amines of the general formula (16) gives amides of the general formula (Ia-I).
  • the ester (35) is also prepared by coupling 5-halo pyridopyrimidinedione (29) with a beta keto ester such as ethyl acetoacetate (34) in the presence of suitable base such as sodium hydride followed by deacetylation using a suitable base.
  • suitable base such as sodium hydride
  • the reaction proceeds via a retro Claisen reaction as reported by Hamamichi, N. et al. J. Heterocyclic Chem. (1990), 27, 2011-2015 and Yamazaki, M. et al. J. Heterocyclic Chem. (2001), 38, 269-21 A).
  • ester (35) with amines of the formula (16) using a suitable base such as sodium hydride in the presence of a suitable solvent such as toluene or xylene affords compounds of the general formula (Ib-I).
  • a suitable base such as sodium hydride
  • a suitable solvent such as toluene or xylene
  • pyrido[4,3- ⁇ i]pyrimidinyl ester (35) can be hydro lysed to corresponding acid and coupled with amines of the formula (16) using a suitable coupling agent gives compounds of general formula (Ib-I).
  • ester (47) Sodium hydride mediated coupling reaction of ester (47) with an amine of the formula (16) in a suitable solvent such as toluene or xylene affords compounds of the general formula (Ic).
  • compound of formula (47) can be hydrolysed to corresponding acid and coupled with amines of the formula (16) using a suitable coupling agent gives compounds of general formula (Ic).
  • Halogenation and aromatisation of (50) using phosphorous oxybromide or phosphorous oxychloride in dry toluene in the presence of suitable base such as N,N-dimethylaniline affords 4-halo pyrimido[4,5- c]pyridazinedione of the formula (51).
  • Reaction of intermediate (51) with ethyl ethynyl ether in the presence of dichlorobis(triphenylphosphine)palladium [PdCl 2 (Pli3) 2 ] and cuprous iodide in dry DMF in the presence of triethylamine gave (52).
  • Halogenatiopn and aromatisation of (59) using phosphorous oxychloride or phosphorous oxybromide in dry toluene in the presence of suitable base such as N,N-dimethyl aniline gives 5-halo-pyrimido[4,5- ⁇ i]pyridazinedione of the formula (60).
  • suitable base such as N,N-dimethyl aniline
  • the reaction of aryl halide (60) with dialkyl malonate in the presence of suitable base gives diester of the formula (61).
  • Dealkoxycarbonylation of (61) as desribed in Scheme 3 gives the desried pyrimido[4,5-fiT]pyridazinyl acetic ester of the formula (62).
  • the coupling of pyrimido[4,5- ⁇ i]pyridazinyl acetic ester of the formula (62) with amines of formula (16) by using a suitable base and solvent gives compounds of general formula (Ie-I).
  • Scheme 12 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (68) from acetophenones of the formula (67) 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 (63) (wherein R z and 'p' are as defined in description) in three steps.
  • acid of formula (63) was converted to the corresponding acid chloride of formula (64) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane.
  • the acid chloride of formula (64) was converted to corresponding Weinerb amide of formula (66) by treating with N, O- dimethylhydroxylamine hydrochloride of formula (65) in the presence of a suitable base such as triethylamine.
  • a suitable base such as triethylamine.
  • the addition of methyl magnesium iodide to Weinreb amide of formula (66) afforded acetophenone derivative of formula (67).
  • acetophenone derivative of formula (67) can be converted to 2-amino-4-substituted aryl thiazole of the formula (68) in two approaches as described in Scheme 12.
  • acetophone was converted to the corresponding phenacyl bromide, which in turn was reacted with thiourea in a suitable solvent such as tetrahydrofuran at refluxing condition.
  • acetophenone derivative of formula (67) can be converted to 2-amino-4-aryl thiazole (68) in one step by its reaction with thiourea and iodine in refluxing ethanol (Carroll, K. et al. J. Am. Chem. Soc. 1950, 3722 and Naik, S. J.; Halkar, U. P., ARKIVOC 2005, xiii, 141-149).
  • 5-Aryl-lH-imidazol-2-amines of the formula (70) were prepared as shown in Scheme 13.
  • the deacetylation of (69) in the presence of catalytic amount of concentrated sulphuric acid using suitable solvent afforded desired 5-Aryl-lH- imidazol-2-amine of the formula (70). (This is similar to procedure reported by Thomas, L. et al., J. Org. Chem., 1994, 59, 7299-7305).
  • 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-fife 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; equiv. or eq.: equivalents.
  • Step 1 Ethyl (2£)-2-cyano-3-[(l,3-dimethyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4- yl)amino]acrylate: A solution of 6-amino-l,3-dimethyl uracil (80.0 g, 515.596 mmol) and ethyl 2-cyano-3-ethoxyacrylate (87.22 g, 515.596 mmol) in anhydrous N,N-dimethyl formamide (1.0 lit.) was added anhydrous potassium carbonate (106.8 g, 773.395 mmol) and the mixture was heated to 90 0 C under nitrogen atmosphere for 2 h.
  • Step 2 Ethyl 5-amino-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3- ⁇ i] pyrimidine- 6-carboxylate: A solution of Step 1 intermediate (75.0 g, 269.532 mmol) and diphenyl ether (539 ml) was refluxed for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature.
  • Step 3 5-Amino-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidine-6- carboxylic acid: A mixture of Step 2 intermediate (40.0 g, 147.745 mmol), acetic acid (718 ml) and 40 % HBr (287 ml) was refluxed for 18 h.
  • Step 4 5-Amino-l,3-dimethylpyrido[2,3-(i]pyrimidine-2,4(lH,3H)-dione: Copper powder (2.714 g, 396.0 g atom) was added to a suspension of Step 3 intermediate (33.0 g, 132.0 mmol) in quinoline (660 ml) and the resulting mixture was stirred and heated at 235- 240 0 C for 3 h under nitrogen. The reaction mixture was cooled to room temperature, diluted with chloroform, filtered to remove insoluble residue.
  • Step 5 5-Iodo-l,3-dimethylpyrido[2,3-(i]pyrimidine-2,4(lH,3H)-dione: To a stirred solution of tert-butyl nitrite (6.0 ml, 50.971 mmol) in acetonitrile (135.9 ml) was added copper iodide (7.76 g, 40.776 mmol) slowly during 10-15 min. Step 4 intermediate (7.0 g, 33.981 mmol) was added portion-wise at room temperature. The reaction was heated at 65°C for 3 h.
  • Step 6 5-Allyl-l,3-dimethylpyrido[2,3- ⁇ T
  • Step 7 (l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetic acid: To a stirred solution of Step 6 intermediate (2.5 g, 10.822 mmol) in a 1 :3:3 mixture of water, acetonitrile and carbon tetrachloride (56.1 ml) at room temperature was added sodium metaperiodate (14.4 g, 67.324 mmol) and ruthenium (III) chloride hydrate (46 mg, 0.216 mmol). The biphasic mixture was stirred vigorously at room temperature for 24 h. The mixture was cooled and filtered.
  • Step 1 Diethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3- ⁇ i]pyrimidin-5- yl)malonate: To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.883 g, 22.04 mmol) in dry DMSO (28 ml) was added dropwise diethyl malonate (3.36 ml, 22.04 mmol) at room temperature. After evolution of hydrogen ceased, Step 5 of intermediate 1 (3.5 g, 11.02 mmol) was added and heated at 80 0 C for 4h.
  • Step 2 Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5- yl)acetate: To a stirred solution of Step 1 intermediate (2.67 g, 7.646 mmol) in dry ethanol (38 ml) was added a catalytic amount of sodium hydride (60% dispersion in mineral oil, 30 mg, 0.767 mmol) at room temperature and reaction was refluxed for 2 h.
  • a catalytic amount of sodium hydride 60% dispersion in mineral oil, 30 mg, 0.767 mmol
  • Step 1 5-Hydroxy-l,3-dimethylpyrido[2,3-d]pyrimidine-2,4,7(lH,3H,8H)-trione: A mixture of 6-amino- 1,3 -dimethyl uracil (16.0 g, 103.12 mmol) and dimethyl malonate (33.036 g, 206.25 mmol) in diphenyl ether (80 ml) was refluxed for 2 h under nitrogen atmosphere.
  • Step 2 5-Hydroxy-7-methoxy-l,3-dimethylpyrido[2,3-(i]pyrimidine-2,4(lH,3H)-dione:
  • Step 1 intermediate 9.6 g, 43.049 mmol
  • anhydrous cesium carbonate (14.026 g, 43.049 mmol)
  • Methyl iodide (6.111 g, 43.049 mmol) was added slowly with stirring and further stirred at room temperature for overnight.
  • the reaction mixture was diluted with water and extracted with ethyl acetate (2x100 ml).
  • Step 3 7-Methoxy-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl trifluoromethanesulfonate: To a stirred solution of Step 2 intermediate (4.2 g, 18.834 mmol) in dry dichloromethane (10 ml) was added triethylamine (2.86 g, 28.251 mmol) at room temperature and reaction mixture was cooled to 0 0 C. Triflic anhydride (6.38 g, 22.601 mmol) was added slowly and reaction was allowed to warm to room temperature.
  • Step 4 5-Allyl-7-methoxy-l,3-dimethylpyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione:
  • the title compound was prepared according to the procedure as described for Intermediate 1, by coupling of Step 3 intermediate (7.7 g, 20.867 mmol) with allyl boronic acid pinacol ester (6.3 g, 37.561 mmol) in the presence of tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.982 mmol) and cesium fluoride (6.34 g, 41.734 mmol) in 1,4-dioxane (80 ml) to give 3.65 g of the product as an off-white solid; 1 H-NMR (300 MHz, DMSO- ⁇ 6 ) ⁇ 3.44 (s, 3H), 3.68 (s, 3H), 3.95-4.02 (m, 5H), 5.00-5.13 (m, 2H), 6
  • Step 5 (7-Methoxy-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5- yl)acetic acid:
  • the title compound was prepared according to procedure as described for Intermediate 1 by oxidative cleavage of Step 4 intermediate (3.5 g, 14.171 mmol) using ruthenium(III) chloride hydrate (0.06 g, 0.283 mmol) and sodium metaperiodate (18.2 g, 85.026 mmol) in mixture of water, acetonitrile and carbon tetrachloride to give 2.2 g of the product as an off-white solid;
  • 1 H-NMR 300 MHz, DMSO- ⁇ 6 ) ⁇ 3.23 (s, 3H), 3.56 (s, 3H), 3.98 (s, 3H), 4.02 (s, 2H), 6.65 (s, IH), 12.27 (br s, IH);
  • Step 1 l,3,6-Trimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of N, N- dimethyl urea (80.0 g, 907.955 mmol) and 4-dimethylaminopyridine (110.92 g, 907.955 mmol) in dry pyridine (1.4 lit.), acetic anhydride (905.86 g, 2996.254 mmol) was added dropwise at 0 0 C. The reaction mixture was stirred at room temperature for overnight. The excess of solvent was evaporated under reduced pressure and quenched into 2 ⁇ HCl (1.0 lit.) and extracted with chloroform (3 x 300 ml).
  • Step 2 l,3,6-trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde: To a stirred solution of Step 1 intermediate (95.00 g, 616.883 mmol) in dry DMF (94 ml) was added phosphorous oxychloride (118 ml) dropwise at 0 0 C and reaction mixture was heated at 120 0 C for 4 h. The reaction mixture was allowed to room temperature and extracted with chloroform (3x250 ml). The combined organic extracts were dried over Na 2 SO 4 and concentrated.
  • Step 3 l,3,6-Trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime: A mixture of Step 2 intermediate (28.7 g, 157.692 mmol), hydroxylamine hydrochloride (13.05 g, 189.231 mmol) and triethylamine (19.14 g, 157.692 mmol) in ethanol (300 ml) was stirred at room temperature for 3 h.
  • Step 4 l,3,6-Trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbonitrile: Step 3 of intermediate (29.7 g, 150.616 mmol) was added portion-wise to phosphorous oxychloride (267.3 ml) at room temperature and reaction was stirred further for 1 h. The excess of phosphorous oxychloride was evaporated under reduced pressure. The crude residue obtained was washed with diethyl ether several times and triturated with water.
  • Step 5 6-[(£)-2-(Dimethylamino)vinyl]-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydro pyrimidine-5-carbonitrile:
  • a mixture of Step 4 intermediate (20.00 g, 111.731 mmol) and N,N-dimethyl formamide dimethyl acetal (15.95 g, 134.078 mmol) in dry DMF (40 ml) was heated at 80 0 C for 2h. The reaction mixture was cooled to room temperature and diluted with diethyl ether (100 ml).
  • Step 6 5-Hydroxy-l,3-dimethylpyrido[4,3-(i]pyrimidine-2,4(lH,3H)-dione: To a stirred solution of 75 % sulfuric acid (291 ml), Step 5 intermediate (23.5 g, 102.174 mmol) was added portion-wise and the reaction was then heated at 90 0 C for 4 h. The reaction mixture was cooled to room temperature and diluted with ice cold water (500 ml).
  • Step 7 5-Bromo-l,3-dimethylpyrido[4,3-(i]pyrimidine-2,4(lH,3H)-dione: A solution of Step 6 intermediate (5.0 g, 24.154 mmol) in dry toluene (80 ml) were added N, N- dimethylaniline (2.93 g, 24.154 mmol) followed by phosphorous oxybromide (8.3 g, 29.014 mmol). The reaction mixture was refluxed for 24 h. The solvent was completely evaporated under reduced pressure and diluted with water (400 ml).
  • Step 8 Diethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5- yl)malonate:
  • the title comopound was prepared by following the procedure as described for step 1 of Intermediate 2 by the reaction of Step 7 intermediate (1.9 g, 7.063 mmol), sodium hydride (60% dispersion in mineral oil, 0.339 g, 14.126 mmol), diethyl malonate (2.26 g, 14.126 mmol) and dry DMSO (15 ml) to give 1.73 g of the product as a white solid;
  • Step 9 Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3- ⁇ i]pyrimidin-5- yl)acetate:
  • the title comopound was prepared by following the procedure as described for step 2 of Intermediate 2 by Step 8 intermediate (1.67 g, 4.785 mmol), sodium hydride (60% dispersion in mineral oil, 11.5 mg, 0.478 mmol) and dry ethanol (32 ml) to obtain 630 mg of the desired product as a white solid;
  • Stepjj 6-Chloro- 1 ,3 -dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxaldehyde: Phosphorous oxychloride (1.720 lit.) was added slowly to dry DMF (450 ml) at 0 0 C. The mixture was then allowed to warm to room temperature. 1,3-Dimethylbarbituric acid (150 g, 960.737 mmol) was added portion wise and the resultant mixture refluxed for 45 min. The excess of phosphorous oxychloride and DMF were distilled off under reduced pressure and the viscous residue was poured into ice-cold water (3000 ml).
  • Step 2 6-Chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime: To a mixture of Step 1 intermediate (120 g, 594.059 mmol) and hydroxylamine hydrochloride (51.6 g, 742.574 mmol) in methanol (1.2 lit.) was added dropwise a solution of KOH (41.6 g, 742.574 mmol) in water (75 ml) over a period of 1 h, while reaction mixture was maintained below 10 0 C.
  • Step 3 6-Chloro- 1 ,3-dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydropyrimidine-5-carbonitrile:
  • the title compound was prepared following the procedure as described for step 4 of Intermediate 4 by the reaction of Step 2 intermediate (95 g, 436.560 mmol) with phosphorous oxychloride (850 ml) to give 78.63 g of the product as an off-white solid;
  • 1 H NMR 300 MHz, DMSO-d 6 ): ⁇ 3.38 (s, 3H), 3.69 (s, 3H).
  • Step 3 ⁇ -Azido-l ⁇ -dimethyl ⁇ -dioxo-l ⁇ -tetrahydropyrimidine-S-carbonitrile: To a stirred solution of Step 3 of intermediate (20.0 g, 103.092 mmol) in dry ethanol (103 ml), sodium azide (8.042 g, 123.711 mmol) was added and the mixture was further stirred for 2 h at room temperature. Solid precipitated out was collected by filtration, washed with ethanol and dried to give 24.1 g of the product as an off-white solid; 1 H-NMR (300 MHz, DMSO-(Z 6 ) ⁇ 3.17 (s, 3H), 3.30 (s, 3H).
  • Step 4 ⁇ -Amino-l ⁇ -dimethyl ⁇ -dioxo-l ⁇ -tetrahydropyrimidine-S-carbonitrile: To a stirred solution of Step 3 intermediate (17.9 g, 89.27 mmol) in mixture of ethanol (357 ml) and water (5.5 ml), stannous chloride (30.21 g, 40.229 mmol) was added and mixture was stirred at room temperature for 2 h.
  • Step 5 N l -(5-Cyano-l,3-dimethyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4-yl)-N,N- dimethylimidoformamide:
  • the title compound was prepared according to the procedure as described for step 5 of Intermediate 4 by the reaction of Step 4 intermediate (7.0 g, 40.229 mmol) with N,N-dimethylformamide dimethyl acetal (19.1 g, 160.919 mmol) in dry DMF (80 ml) to give 8.75 g of the product as a white solid;
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ 3.15 (s, 3H), 3.24 (s, 3H), 3.34 (s, 3H), 3.41 (s, 3H), 8.12 (s, IH).
  • Step 6 5-Hydroxy-l,3-dimethylpyrimido[4,5-(i]pyrimidine-2,4(lH,3H)-dione:
  • the title compound was prepared following the procedure as described for Intermediate 4 by cycisation of Step 5 intermediate (8.75 g, 37.234 mmol) using 75 % sulfuric acid (106 ml) to give 6.1 g of the product as an off-white solid;
  • 1 H-NMR 300 MHz, DMSCM 6 ) 5 3.18 (s, 3H), 3.46 (s, 3H), 8.39 (s, IH), 12.89 (br s, IH).
  • Step 7 5-Bromo-l,3-dimethylpyrimido[4,5-d]pyrimidine-2,4(lH,3H)-dione:
  • the title compound was prepared according to the procedure described for Intermediate 4 by reaction of Step 6 intermediate (5.38 g, 25.844 mmol) with phosphorous oxybromide (8.87 g, 31.013 mmol) in dry toluene (103 ml) and N,N-dimethylaniline (3.29 ml, 25.844 mmol) to obtain 3.98 g of the product as a white solid;
  • 1 H-NMR 300 MHz, DMSO- ⁇ 6 ) ⁇ 3.27 (s, 3H), 3.52 (s, 3H), 8.87 (s, IH).
  • Step 8 Diethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(/]pyrimidin-4- yl)malonate:
  • the title compound was prepared according to the procedure described for Intermediate 2 by the reaction of Step 7 intermediate (3.0 g, 11.071 mmol) with diethyl malonate (3.37 ml, 22.140 mmol) using sodium hydride (60% dispersion in mineral oil, 0.850 g, 22.140 mmol) in dry DMSO (30.7 ml) to obtain 3.62 g of the product as a white solid;
  • Step 9 Ethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5- ⁇ i]pyrimidin-4- yl)acetate:
  • the title compound was obtained by following the procedure as described for Intermediate 2 by deethoxycarbonylation of Step 8 intermediate (3.5 g, 10.00 mmol) in dry ethanol (71 ml) using a catalytic amount of sodium hydride (60% dispersion in mineral oil, 38.4 mg, 1.00 mmol) to obtain 2.45 g of the desired product as a white solid;
  • Stepl (lZ)-N'-(5-cyano-l,3-dimethyl-2,6-dioxo- 1,2,3, 6-tetrahydropyrimidin-4-yl)-N,N- dimethylethanimidamide:
  • the title compound was prepared according to the procedure as described for Intermediate 4 by the reaction 6-Amino-l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carbonitrile (10.5 g, 60.34 mmol) with N,N-dimethylacetamide dimethyl acetal (32.1 g, 241.37 mmol) in dry DMF (21 ml) to give 6.50 g of the product as a white solid;
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ 2.24 (s, 3H), 3.16 (s, 3H), 3.19 (s, 3H), 3.34 (s, 6H).
  • Step 2 5-Hydroxy-l,3,7-trimethylpyrimido[4,5-(i]pyrimidine-2,4(lH,3H)-dione:
  • the title compound was prepared according to the procedure described for Intermediate 4 by cycisation of Step 1 intermediate (1.10 g, 4.41 mmol) using 75 % sulfuric acid (12.57 ml) to give 460 mg of the product as an off-white solid.
  • Step 3 5-Bromo-l,3,7-trimethylpyrimido[4,5-(i]pyrimidine-2,4(lH,3H)-dione:
  • the title compound was prepared according to the procedure described for Intermediate 4 by reaction of Step 2 intermediate (4.35 g, 19.55 mmol) with phosphorous oxybromide (6.72 mg, 23.51 mmol) in dry toluene (65 ml) and N,N-dimethylaniline (2.4 g, 19.55 mmol) to obtain 400 mg of the product as a white solid;
  • 1 H-NMR 300 MHz, CDC13) ⁇ 2.73 (s, 3H), 3.46 (s, 3H), 3.68 (s, IH).
  • Step 4 Diethyl (2,6,8-trimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4- yl)propanedioate:
  • the title compound was prepared according to the procedure described for Intermediate 2 by the reaction of Step 3 intermediate (470 mg, 1.65 mmol) with diethyl malonate (529 mg, 3.30 mmol) using sodium hydride (60% dispersion in mineral oil, 79 mg, 3.30 mmol) in dry DMSO (2.2 ml) to obtain 470 mg of the product as a white solid;
  • Step 5 ethyl (2,6,8-trimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4- yl)acetate:
  • the title compound was obtained by following the procedure as described for Intermediate 2 by deethoxycarbonylation of Step 4 intermediate (470 mg, 1.29 mmol) in dry ethanol (9 ml) using a catalytic amount of sodium hydride (60% dispersion in mineral oil, 6.4 mg, 0.12 mmol) to obtain 180 mg of the product as a white solid;
  • Step 2 6-Hydrazino-l,3-dimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of Step 1 intermediate (10.0 g, 57.30 mmol) in isopropanol (30 ml) was added hydrazine hydrate (30 ml, 573.00 mmol).
  • Step 3 6,8-Dimethylpyrimido[4,5-c]pyridazine-4,5,7(lH,6H,8H)-trione: To a stirred solution of Step 2 intermediate (5.0 g, 29.411 mmol) in dry ethanol (50 ml) was added glyoxylic acid (2.9 g, 32.35 mmol) at room temperature and the resulting suspension was refluxed till a clear solution was obtained. Immediately heating was stopped and the reaction mixture was cooled to room temperature.
  • glyoxylic acid 2.9 g, 32.35 mmol
  • Step 3 4-Bromo-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione:
  • the title compound was prepared according the same procedure as described for Initermediate 4 by the reaction of Step 2 intermediate (3.0 g, 14.423 mmol) with phosphorous oxybromide (4.96 g, 17.307 mmol) in dry toluene (30 ml) and N,N-dimethylaniline (1.75 g, 14.423 mmol) to afford 2.6 g of the product as an off-white solid;
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ 3.50 (s, 3H), 3.86 (s, 3H), 8.25 (s, IH).
  • Step 4 Ethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4- yl)acetate: To a stirred suspension of Step 3 of intermediate (3.0 g, 11.070 mmol) in a mixture of dry N,N-dimethylformamide and triethylamine (1 : 1, 36 ml) were sequentially added bis(triphenylphosphine)Pd(II) chloride (0.16 g, 0.221 mmol), copper(I)iodide (21 mg, 0.110 mmol) and ethyl ethynyl ether (40% solution in hexane, 1.16 g, 16.605 mmol) at room temperature.
  • bis(triphenylphosphine)Pd(II) chloride (0.16 g, 0.221 mmol
  • copper(I)iodide 21 mg, 0.
  • the resulted black colored reaction mixture was stirred for 24 h.
  • the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 100 ml).
  • the combined organic layers were washed with water (50 ml), brine (50 ml) and dried over anhydrous Na 2 SO 4 .
  • Step 1 l ⁇ j ⁇ -Trimethyl ⁇ -dioxo-l ⁇ -tetrahydropyrimidine-S-carboxylic acid: To a stirred of l,3,6-trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Step 2 of Intermediate 4) (17.0 g, 93.406 mmol) and sulphamic acid (18.13 g, 186.81 mmol) in acetone (467 ml) was added sodium chlorite (12.67 g, 140.109 mmol) in water (93 ml) and reaction mixture was stirred at room temperature for 2 h.
  • Step 2 Methyl l,3,6-trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The title compound was prepared according the procedure described for Intermediate 2 (Route 2) by refluxing Step 1 intermediate (14.0 g, 70.646 mmol) in dry methanol (350 ml) in the presence of cone. H 2 SO 4 (1.5 ml) for 24 h to give 11.46 g of the product as an off-white solid; 1 H-NMR (300 MHz, CDCl 3 ) ⁇ 2.36 (s, 3H), 3.34 (s, 3H), 3.47 (s, 3H), 3.89 (s, 3H).
  • Step 3 Methyl 6-(dibromomethyl)-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate: A mixture of Step 2 intermediate (11.46 g, 54.056 mmol), N- bromosuccinimide (28.86 g, 162.169 mmol), glacial acetic acid (22.92 ml) and carbon tetrachloride (450 ml) was stirred and refluxed for 75 h. The mixture was then cooled, washed with saturated aqueous sodium bicarbonate solution, dried and evaporated.
  • Step 4 l,3-Dimethylpyrimido[4,5-uT]pyridazine-2,4,5(lH,3H,6H)-trione: To a stirred solution of Step 3 intermediate (5.0 g, 13.513 mmol) in glacial acetic acid (50 ml) was added hydrazine hydrate (2.36 g, 47.297 mmol) at room temperature. The reaction mixture was refluxed for 75 h. The acetic acid was evaporated under under reduced pressure. The sticky mass obtained was dissolved in chloroform, dried over Na 2 SO 4 and filtered. The filtrate was concentrated and and residue obtained was as used for the next step.
  • Step 5 5-Bromo-l,3-dimethylpyrimido[4,5- ⁇ i]pyridazine-2,4(lH,3H)-dione:
  • the title compound was prepared according to the procedure described for Intermedaite 4 by using Step 4 intermediate (7.1 g, 34.134 mmol), dry toluene (70 ml), N,N-dimethyl aniline (4.13 g, 34.134 mmol) and phosphorusoxybromide (9.78 g, 34.134 mmol) to obtain 137 mg of the product as a light yellow solid;
  • 1 H-NMR 300 MHz, CDCl 3 ) ⁇ 3.50 (s, 3H), 3.71 (s, 3H), 9.27 (s, IH).
  • APCI-MS (m/z) 271.21 (M) + .
  • Step 6 Diethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5- ⁇ i]pyridazin-5- yl)propanedioate:
  • the title compound was prepared following the same procedure as described for Intermediate 2 by the reaction of Step 5 intermediate (225 mg, 0.830 mmol), diethylmalonate (267 mg, 1.060 mmol), sodium hydride (60 % dispersion in mineral oil, 67 mg, 1.661 mmol) in dry DMSO (2.3 ml) to obtain 115 mg of the product as a yellow solid;
  • Step 7 Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5- ⁇ i]pyridazin-5- yl)acetate:
  • the title compound was prepared according to procedure described for Intermediate 2 by deethoxycarbonylation of Step 6 intermediate (110 mg, 0.314 mmol) in dry ethanol (2.1 ml) in the presence of a catalytic amount of sodium hydride (60% dispersion in mineral oil, 1.5 mg, 0.314 mmol) to give 60 mg of the product as an off- white solid;
  • APCI-MS (m/z) 279.11 (M+H
  • Step 1 N- ⁇ 4-[3-fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl ⁇ acetamide: To a stirred solution of 2-bromo-l-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (4.5 g, 15.73 mmol) in acetonitrile (45 ml) was added acetyl guanidine (2.38 g, 23.60 mmol). The reaction mixture was stirred and refluxed for overnight.
  • Step 2 4-[3-Fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-amine: To a stirred solution of Step 1 intermediate (1.1 g, 3.829 mmol) in a mixture of methanol (20 ml) and water (20 ml) was added cone. H 2 SO 4 (2 ml) and the resulting mixture was refluxed for 24 h. The reaction mixture was cooled to room temperature, saturated solution of potassium carnonate was added and extracted with ethyl acetate (2 x 50 ml). The organic layers were combined and dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Example 70 N- ⁇ 4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl ⁇ -2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 - ⁇ i]pyrimidin-4-y l)acetamide
  • the illustrative examples of the present invention are screened for TRPAl activity according to a modified procedure described in (a) T ⁇ th, 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.
  • Concentration response curves were plotted as a % of maximal response obtained in the absence of test antagonist. IC50 values can be calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

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Abstract

La présente invention concerne de nouveaux composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de TRPA (sous-famille A du potentiel de récepteur transitoire). En particulier, les composés décrits par les présentes s'utilisent pour traiter ou prévenir des maladies, des états et/ou des troubles modulés par TRPA1 (sous-famille A du potentiel de récepteur transitoire, membre 1). La présente invention concerne également des procédés de préparation des composés décrits par les présentes, des intermédiaires utilisés dans leur synthèse, des compositions pharmaceutiques de ceux-ci et des procédés de traitement ou de prévention de maladies, d'états et/ou de troubles modulés par TRPA1.
PCT/IB2010/001073 2009-04-29 2010-04-28 Composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de trpa1 WO2010125469A1 (fr)

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