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Definitions

• the present patent application relates to fused pyrimidinedinedione derivatives with transient receptor potential ankyrinl (TRPAl) activity.
• TRPAl transient receptor potential ankyrinl
• 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, ANKTMl) and TRPN (NOMPC) families.
• TRPC canonical
• TRPV vanilloid
• TRPM melastatin
• TRPP polycystin
• TRPML mucolipin
• TRPA ankyrin, ANKTMl
• TRPN nuclear factor C
• TRPV5 and TRP V6 are more closely related to each other than to TRPVl, TRP V2, 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 LTRPCl), TRPM3 (KIAA1616 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 KAA1616 or LTRPC3
• TRPM7 TRP-PLIK, ChaK(l), LTRPC7
• TRPM6 ChoK2
• TRPM2 TRPC7 or LTRPC2
• TRPM8 TRP-p8 or CMRl
• TRPM5 MTRl 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.
• TRP Al 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 LJ 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.
• R a and R b which may be same or different, are independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, -(CR x R y ) n OR x , -COR X , -COOR ⁇ -C0NR x R y , -S(O) m NR x R y , -NR x R y , -NR x (CR x R y ) n OR x , -(CH 2 ) n NR x R y
• R 1 and R 2 which may be same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R y ) n OR x , COR", COOR X , C0NR x R y , (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y , (CH 2 )NR x R y and (CH 2 ) n NHC0R x ;
• R 3 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, haloalkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl;
• L is a linker selected from -(CR x R y ) n - ; -O-(CR x R y ) n -, -C(O)-, -NR X -, -S(O) 01 NR"-, -NR x (CR x R y ) n - and -S(O) m NR x (CR x R y ) n ;
• U is selected from 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, pyroles, 1,2,3-triazoles and 1 ,2,4-triazole; and substituted or unsubstituted six membered heterocycles 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", -OR * , -C(0)NR x R y , -C(O)R X and -SO 2 NR x R y ; or U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, that may optinally include one or more heteroatoms selected from O, S and N; at each occurrence, R x and R y
• R 1 and R 2 which may be same or different, are independenly selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R y ) n OR ⁇ COR X , COOR X , C0NR x R y , (CH 2 ) n NR ⁇ R y , (CH 2 ) n CHR ⁇ R y , (CH 2 )NR x R y and (CH 2 ) n NHC0R ⁇
• U is selected from 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, pyroles, 1,2,3-triazoles and 1,2,4-triazole; and substituted or unsubstituted six membered heterocycles 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, .
• R a and R b which may be same or different, are independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, -(CR x R y ) n OR x , -C0R x , -COOR X , -C0NR ⁇ R y , -S(O) m NR x R y , -NR
• R a is hydrogen, halogen (for example bromine), alkyl (for example methyl) or alkylaminoalkyl (for example dimethylaminomethyl or diethylaminomethyl).
• R b is hydrogen or alkyl for example methyl.
• R 1 and R 2 are independently hydrogen or alkyl for example methyl.
• phenyl may be one or more are independently selected from halogen (for example F, Cl or Br), haloalkyl (for example CF 3 ), alkoxy (for example methoxy, ethoxy, 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 , OCH 2 CH 2 CF 3 or OCH 2 CH 2 CF 2 CF 3 ), cycloalkylalkoxy (for example cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy) and, substituted or unsubstituted arylalkoxy (for example triflu
• R 1 and R 2 are independently hydrogen or alkyl (for example methyl).
• V is substituted or unsubstituted aryl, preferably phenyl.
• the substitutents on phenyl may be one or more and are independently selected from halogen (for example F, Cl or Br), haloalkyl (for example CF 3 ), alkoxy (for example OCH 2 C(CH 3 ) 3 or haloalkoxy (for example OCH 2 CF 3 ).
• R 1 , R 2 , R , U and V are as defined herein above;
• R 1 and R 2 are alkyl, preferably methyl.
• R b is hydrogen or (Ci-C 4 ) alkyl, preferably methyl.
• R b is hydrogen or (Ci-C 4 ) alkyl, preferably methyl.
• phenyl may be one or more and are independently selected from halogen (for example F, Cl or Br), cyano, alkyl (for example f-butyl or iso- butyl), haloalkyl (for example CF 3 ) and haloalkoxy (for example OCHF 2 , OCF 3 or OCH 2 CF 3 ).
• halogen for example F, Cl or Br
• alkyl for example f-butyl or iso- butyl
• haloalkyl for example CF 3
• haloalkoxy for example OCHF 2 , OCF 3 or OCH 2 CF 3
• the fused ring system is benzothiazole and the optional substituent is haloalkoxy (for example OCF 3 ).
• R 1 , R 2 , R a , U and V are as defined herein above;
• R 1 , R 2 , R a , U and V are as defined herein above;
• R a is hydrogen or (Ci -C 4 ) alkyl.
• phenyl may be same or different and are independently selected from halogen (for example F, Cl or Br), cyano, alkyl, haloalkyl (for example CF 3 ), alkoxy [for example OCH 2 CH(CH 3 ) 2 , OCH 2 CH 2 CH(CH 3 );, or OCH 2 C(CH 3 ) 3 ],cycloalkylalkoxy (for example cyclobutylmefhoxy) and haloalkoxy (for example OCHF 2 , OCF 3 , OCH 2 CF 3 or OCH 2 CH 2 CF 3 ).
• halogen for example F, Cl or Br
• cyano for example F, Cl or Br
• alkyl for example CF 3
• alkoxy for example OCH 2 CH(CH 3 ) 2 , OCH 2 CH 2 CH(CH 3 );, or OCH 2 C(CH 3 ) 3
• cycloalkylalkoxy for example cyclobutylmefhoxy
• Particularly contemplated are compounds of the formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) and (If) which possess IC 50 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.
• a pharmaceutically acceptable excipient such as a carrier or a diluent
• 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 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 (terf-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 (C 3-6 )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 C 6 Hs or -C 2 H 4 C 6 H 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 arid 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), (Ie) and (If) 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), (Ie) and (If) 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.
• 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, diabetic neuropathy, sciatica, HIV-related neuropathy, postherpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incon
• TRPAl The connection between therapeutic effect and inhibition of TRPAl is illustrated, for example, in Story GM et al, Cell, 2003, 1 12, 819-829; McMahon SB and Wood JN, Cell, 2006, 124, 1 123-1 125; Voorhoeve PM et al., Cell, 2006, 124, 1 169-1 181 ; Horbach U, Niemeyer BA and Flockerzi V, Biology of the Cell, 2004, 96, 47-54; Dayne YO, Albert YH & Michael X, Expert Opinion on Therapeutic Targets, 2007, 1 1(3), 391-401 and the references cited therein.
• 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 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).
• Nitro derivative of general formula (2) can be prepared by nitration of uracil derivative of formula (1) using mixture of sulphuric acid and fuming nitric acid followed by condensation with DMF-dimethyl acetal in a suitable " solvent (e.g., DMF, THF). Reductive cyclization of compound of formula (2) using 10% Pd-C under hydrogen atmosphere in suitable solvent (e.g., EtOH, MeOH) affords compound of general formula (3).
• suitable solvent e.g., EtOH, MeOH
• the intermediate (6) can be prepared by formylation of compound of formula (3) using mixture of phosphorous oxychloride and dimethyl formamide to give compound of formula (7) followed by reductive amination of the formyl group using a suitable amine of formula (5).
• a suitable base e.g., NaH, K 2 CO 3
• halopyrrole of general formula (14).
• suitable solvent e.g., EtOAc
• suitable halogenating reagent e.g., N- bromosuccinimide, iV-iodosuccinimide, Br 2 in acetic acid
• Halopyrrole of formula (14) on reaction with allyl boronic acid pinacol ester of the formula (15) in the presence of a palladium catalyst, such as bis(triphenylphosphine)palladium dichloride or tetrakis(triphenylphosphine) palladium(O) gives allyl pyrrole of the formula (16) [procedure is similar to the Suzuki-Miyaura Coupling described by Kotha, et al., Synlett, 2005, 12, 1877-1890]. Transformation of allyl pyrrole of formula (16) into corresponding aldehyde can be accomplished by methods known in the art [e.g., Postema, M. H. D.
• Pyrrolidinone of formula (22) can be converted to halopyrrole of formula (23) (wherein X is halogen) using triflic anhydride or hydrazine followed by iodine.
• Halopyrrole of formula (23) on reaction with allyl boronic acid pinacol ester of the formula (15) in the presence of a palladium catalyst, such as bis(triphenylphosphine)palladium dichloride or tetrakis(triphenylphosphine) palladium(O) gives allyl pyrrole of the formula (24).
• Transformation of allyl pyrrole of formula (24) to the corresponding aldehyde followed by further oxidation of aldehyde thus formed can be carried out by oxidation methods well known in the literature to give corresponding carboxylic acid of general formula (25).
• Coupling of carboxylic acid of formula (25) with appropriate amines of formula (18) by using a standard amide coupling method gives compounds of general formula (Ic-I).
• ester of general formula (29) Deoxygenation of ⁇ -keto ester of general formula (28) with triethylsilane in the presence of trifluoroacetic acid affords ester of general formula (29) [similar procedure described by Han, Q. et al., J Med Chem , 2000, 43, 4398-4415]. Acidic hydrolysis of ester of formula (29) gives corresponding carboxylic acid of formula (25). Coupling of carboxylic acid of formula (25) with appropriate amines of formula (18) by using a standard amide coupling method give compounds of general formula (Ic-I).
• the 2-haloacetamides of formula (53) (wherein R z is selected from alkyl, cyano, halogen, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkoxy and arylalkoxy, and 'p' is selected from 0 to 5) required for the synthesis of compound of the present invention can be prepared according to methods known to one skilled in the art (Carroll, L. et al., J. Am Chem Soc, 1950, 72, 3722-3725; Ohkubo, M. et al., Chem Pharm Bull , 1995, 43(9), 1497-1504).
• this transformation can be carried out using excess thionyl chloride.
• the acid chloride (47) was converted to corresponding Weinreb amide (48) by treating with jV,O-dimethyl hydroxylamine hydrochloride in the presence of a suitable base such as triethylamine.
• a suitable base such as triethylamine.
• Addition of methyl magnesium iodide to Weinreb amide (48) gives acetophenone derivative of the formula (49).
• commercially unavailable aryl alkyl ketones were prepared from mono or di-substitued phenol (50) as depicted in Scheme 1 1.
• acetylation of phenol (50) with acetic anhydride followed by Fries rearrangement of the ester formed in the presence of Lewis acid e.g.
• the aryl alkyl ketone of the formula (49) is converted to 2-aminothiazole of the formula (52) in one step by its reaction with thiourea in the presence of iodine in ethanol.
• This conversion is similar to the one described by Carroll, K. et al., J Am Chem Soc. 1950, 3722; and Naik, S., J.; Halkar, U. P., ARKIVOC, 2005, xiii, 141-149.
• 2-aminothiazoles of the formula (52) can be prepared by the reaction of compounds of formula (49) with bromine in acetic acid to give the alpha halo intermediate, which on reaction with thiourea in THF at reflux condition give compounds of the formula (52).
• the compound of the formula (52) is converted to 2-bromo-N-thiazolyl acetamide of the formula (53) by acylation with bromoacetyl bromide in the presence of a suitable base (e.g., pyridine or triethylamine) and in a suitable solvent (e.g., THF, DMF).
• a suitable base e.g., pyridine or triethylamine
• a suitable solvent e.g., THF, DMF
• 5-Aryl-lH-imidazol-2-amines of the formula (55) were prepared as shown in Scheme 12.
• the deacetylation of (54) in the presence of catalytic amount of concentrated sulphuric acid using suitable solvent afforded desired 5-Aryl-lH- imidazol-2-amine of the formula (55). (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. The following abbreviations are used in the text: DMSO- ⁇ 6 : Hexadeuterodimethyl sulfoxide; DMF: N,N-dimethylformamide, M.
• Step 1 l,3,6-Trimethyl-5-nitrouracil: A mixture of concentrated H 2 SO 4 (7.0 mL) and fuming HNO 3 (7.0 mL) was cooled to 0-5 0 C and l,3,6-trimethylpyrimidine-2,4(lH,3H)- dione (3.5 g, 22.702 mmol) was gradually added to the reaction mixture. After stirring for 2 h. at the same temperature the reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with brine (2 x 50 mL), dried (Na 2 SO 4 ) and evaporated under reduced pressure.
• Step 2 l,3-Dimethyl-6-[2-(dimethylamino)vinyl]-5-nitrouracil: To a solution of Step 1 intermediate, l,3,6-Trimethyl-5-nitrouracil (0.60 g, 3.012 mmol) in dry N, N- dimethylformamide (5.0 mL) was added N,7V-dimethylformamide dimethyl acetal (0.53 g, 4.447 mmol) and the reaction mixture was stirred at room temperature for 2 h.
• Step 3 l,3-Dimethyl-lH-pyrrolo[3,2-(/]pyrimidine-2,4(3H,5H)-dione: To a solution of Step 2 intermediate (0.40 g, 1.573 mmol) in MeOH (80 mL) was added 10% Pd-C (0.2 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered through a celite bed and was thoroughly washed with MeOH (50 mL).
• Step 1 5-Amino-l,3-dimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of 1,3- dimethyl-5-nitropyrimidine-2,4(lH,3H)-dione (2.0 g, 10.802 mmol) in methanol (200 mL), 10% Pd-C (0.500 g) was added under hydrogen atmosphere and the reaction mixture was stirred at room temperature for 2 h. Reaction mixture was filtered through a celite bed and washed with methanol. The filtrate was collected and concentrated under reduced pressure to give 1.5 g of the product.
• Step 2 l,3-Dimethyl-5-(prop-2-yn-l-ylamino)pyrimidine-2,4(lH,3H)-dione: To a stirred solution of Step 1 intermediate (1.4 g, 9.023 mmol) in 1:1 mixture of dichloromethane and methanol (28 mL) was added propargyl bromide (1.4 mL) and the mixture was stirred at room temperature for 2 h. Reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give 500 mg of the product.
• Step 3 l,3,6-Trimethyl-lH-pyrrolo[3,2-£/]pyrimidine-2,4(3H,5H)-dione: A solution of Step 2 intermediate (500 mg, 2.587 mmol) in dry iV.jV-dimethylformarnide (20 mL) was refiuxed for 40 h under nitrogen atmosphere.
• Step 1 l,3-Dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-l//-pyrrolo[3,2-c/]pyrimidine-7- carbaldehyde: At a temperature of 5-10°C, phosphorous oxychloride (1.84 ml, 20.087 mmol) was mixed with iV.iV-dimethylformamide (2 mL). Then a solution of Intermediate 1 (600 mg, 3.348 mmol) in vV.jV-dimethylformamide (3 mL) was added while stirring. The reaction mixture was held for 2 h at 95 0 C, cooled and poured onto ice (10 g).
• Step 2 l ,3,7-Trimethyl-lH-pyrrolo[3,2-c/]pyrimidine-2,4(3H,5H)-dione: To a stirred and cooled (-10 0 C) solution of trifluoroacetic acid (5 mL) was added triethylsilane (294 mg, 2.528 mmol) followed by portionwise addition of Step 1 intermediate (150 mg, 0.723 mmol). The reaction mixture was warmed ro room temperature and stirred for another 1 h. Reaction mixture was diluted with ethyl acetate (25 mL) and water (25 mL). Two layers were seperated. The aqueous layer was extracted with ethyl acetate (2 x 25 mL).
• Step 1 To a stirred solution of diethyl amine (52 mg, 0.723 mmol) in dichloromethane (5 mL) Intermediate 3, Step 1 (150 mg, 0.723 mmol) was added portionwise followed by the addition of sodium triacetoxyborohydried (230 mg, 1.085 mmol) at room temperature.
• Step 1 l,3-Dimethyl-lH-pyrrolo[2,3- ⁇ 0pyrimidine-2,4(3H,7//)-dione: (374-ABK-023)
• chloroacetaldehyde dimethyl acetal (26.0 g, 208.717 mmol) in water (60 mL)
• concentrated hydrochloric acid (4 mL) was added at room temperature and the reaction mixture was stirred at near boiling until a homogeneous solution was obtained.
• Solution of sodium acetate (8.0 g, 97.525 mmol) was then added.
• Step 2 7- [(Dimethylamino)methyl] - 1 ,3 -dimethyl- 1 //-pyrrolo[3 ,2-c/]pyrimidine- 2,4(3H,5H)-dione:
• sodium hydroxide 3.4 g, 84.830 mmol
• Step 1 intermediate 7.6 g, 42.415 mmol
• Dimethyl sulfate (10.7 g, 84.830 mmol) was added dropwise to the reaction mixture and stirred for another 4 h. Solid was precipitated out and collected by filtration, washed with water.
• Step 3 Methyl oxo(l,3,7-trimethyl-2,4-dioxo-2,3,4,7-tetrahydro-lH-pyrrolo[2,3- ⁇ /]pyrimidin-5-yl)acetate: To a well stirred solution of oxalyl chloride (1.6 g, 12.939 mmol) in dichloromethane (10 mL) was added Step 2 intermediate (1.0 g, 5.176 mmol) in small portions at -10 0 C and the resulting mixture was stirred overnight at room temperature. The excess of solvent was removed under vacuum and the residue was again taken in dichloromethane (10 mL).
• reaction mixture was cooled to -10°C and dry methanol (10 mL) was added dropwise over a period of 10-15 min.
• the resulting reaction mixture was stirred overnight at room temperature. Excess of solvent was evaporated under vacuum.
• the residue obtained was basified with saturated solution of NaHCO 3 (25 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried (Na 2 SO 4 ).
• Step 4 Methyl (1 ,3,7-trimethyl-2,4-dioxo-2,3,4,7-tetrahydro-lH-pyrrolo[2,3- ⁇ yrimidin- 5-yl)acetate: To a stirred solution of triethylsilane (364 mg, 3.133 mmol) in trifluoroacetic acid (4.0 mL) was added Step 3 intermediate (250 mg, 0.892 mmol) slowly at -10 0 C. The resulting mixture was warmed slowly to room temperature. After overnight stirring at room temperature, excess of solvent was removed under reduced pressure and the residue obtained was neutralized with saturated solution Of NaHCO 3 (15 mL). Two layers were seperated after the addition of ethyl acetate (25 mL).
• Step 5 (l,3,7-Trimethyl-2,4-dioxo-2,3,4,7-tetrahydro-l//-pyrrolo[2,3-c/]pyrimidin-5- yl)acetic acid: A mixture of Step 4 intermediate (130 mg, 0.491 mmol) and concentrated hydrochloric acid (4 mL) was heated at 60 0 C for 2 h.
• Step 1 6-Chloro-l,3-dirnethylpyrimidine-2,4(l//,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 in externally cooling condition and then the reaction was slowly warmed to room temeperature. After refluxing for 3 h the reaction mixture was allowed to cool to 0°C and quenched with ice cold water (350 ml). The reaction mixture was extracted with chloroform (2 x 200 ml) and the combined organic extracts were washed with water (2 x 100 ml), dried over Na 2 SO 4 and concentrated.
• Step 2 6-Hydrazino-l,3-dirnethylpyrirnidine-2,4(lH,3H)-dione: A mixture of Step 1 intermediate (17 g, 97.34 mmol) and hydrazine hydrate (1 19 ml) in isopropyl alcohol (280 ml) were refluxed for 1 h.
• Step 3 l-Acetyl-3,5,7-trimethyl-lH-pyrazolo[3,4-c/]pyrimidine-4,6(5H,7H)-dione: A mixture of Step 2 intermediate (8.0 g, 47.01 mmol) and acetic anhydride (40 ml) in dry pyridine (78 ml) were refluxed for 3 h. The reaction mixture was cooled to O 0 C and acidified with IN HCl (200 ml).
• Step 4 3,5,7-Trimethyl-lH-pyrazolo[3,4-fi0pyrimidine-4,6(5H,7H)-dione: Step 3 above intermediate (6.9 g, 29.211 mmol) was refluxed in 1 N sodium hydroxide (69 ml) for 10 min. The reaction mixture was cooled to room temperature and poured into ice water and stirred for 2 h. The precipitated solid was collected by filteration and dried to give 5.1 g of the desried product as off-white solid; 1 H NMR (300 MHz, CF 3 CO 2 D): ⁇ 3.05 (s, 3H), 3.78 (s, 3H), 3.93 (s, 3H).
• Step 5 2,3,5,7-Tetramethyl-2H-pyrazolo[3,4-£/]pyrimidine-4,6(5H,7H)-dione:
• a solution of Step 4 intermediate (5.2 g, 26.77 mmol) in 1 N sodium hydroxide (52 ml) was added dimetyl sulphate (5.2 ml) and stirred at room temperature for 1 h.
• the reaction mixture was diluted with water and the solid precipitated out was filtered, washed with water and dried to give 3.85 g of the product as off white solid;
• 1 H NMR 300 MHz, CDCl 3 ): ⁇ 2.59 (s, 3H), 3.36 (s, 3H), 3.48 (s, 3H), 3.79 (s, 3H).
• Step 6 Methyl (2,5,7-trimethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4- ⁇ /] pyrimidin-3-yl)acetate: To a stirred solution of Step 5 intermediate (3.8 g, 18.24 mmol) in dimethylcarbonate (91 ml) was added sodium hydride (60 % dispersion in mineral oil, 4.5 g, 187.5 mmol) at room temperature. The reaction mixture was heated to reflux for overnight.
• Step 7 (2,5,7-Trimethyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl) acetic acid: A mixture of Step 6 intermediate (1.0 g, 3.755 mmol) and 6 N H 2 SO 4 (9.3 ml) in dioxane (9.3 ml) stirred at reflux temperature for 2 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 SO 4 and concentrated.
• Step 1 5-Amino-l,3,6-trimethylpyrimidine-2,4(lH,3H)-dione: To a stirred suspension of 5-nitro-l ,3,6-trimethylpyrimidine-2,4(lH,3H)-dione (4.2 g, 20.084 mmol) in 1 :1 mixture of methanol and toluene (200 ml) was added 10% Pd-C (1.2 g). The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. The mixture was then filtered over a celite bed and was thoroughly washed with methanol (200 ml).
• Step 2 4,6-Dimethyl-lH-pyrazolo[4,3-i/]pyrimidine-5,7(4//,6//)-dione: To a stirred solution of Step 1 intermediate (4.0 g, 23.634 mmol) in a mixture of ice (24 g) and concentrated HCl (5 ml) was added a solution of sodium nitrite (1.42 g, 20.580 mmol) in water (5 ml). The resulting suspension was stirred below 10°C for 30 min.
• Step 1 ⁇ r - ⁇ 4-[3-fluoro-4-(trifluoromethyl)phenyl]-l//-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.
• the salt was then treated with saturated solution of NaHCO 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.
• 5-(4-Bromophenyl)isoxazol-3-amine used for the preparation of Examples 33, 65 and 84 is purchased from Aldrich.
• 5-(Trifluoromethoxy)-l,3-benzothiazol-2-amine used for the preparation of Example 66 is also purchased from Aldrich.
• 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 antagonist using the 43 Calcium uptake assay
• the inhibition of TRPAl receptor activation was measured as inhibition of allyl isothiocyanate (AITC) induced cellular uptake of radioactive calcium.
• Test compounds were dissolved in DMSO to prepare 10 mM stock solution and then diluted using plain medium with 0.1% BSA and 1.8 mM CaCl 2 to get desired concentration. 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, 400 ⁇ g / ml of G-418.

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• Nitrogen Condensed Heterocyclic Rings (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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