WO2011132017A1 - Dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de trpa1 - Google Patents

Dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de trpa1 Download PDF

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WO2011132017A1
WO2011132017A1 PCT/IB2010/002549 IB2010002549W WO2011132017A1 WO 2011132017 A1 WO2011132017 A1 WO 2011132017A1 IB 2010002549 W IB2010002549 W IB 2010002549W WO 2011132017 A1 WO2011132017 A1 WO 2011132017A1
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Prior art keywords
acetamide
dioxo
tetrahydropyrido
thiazol
pyrimidin
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PCT/IB2010/002549
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English (en)
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Sukkeerthi Kumar
Abraham Thomas
Nayan Taterao Waghmare
Neelima Khairatkar-Joshi
Indranil Mukhopadhyay
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Glenmark Pharmaceuticals S.A.
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Publication of WO2011132017A1 publication Critical patent/WO2011132017A1/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]

Definitions

  • the present patent application relates to pyrido[3,4-d]pyrimidinyl acetamide derivatives with transient receptor potential ankyrin l (TRPA l) activity.
  • TRP channels or receptors are pain receptors. They have been classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin, ANKTM 1) and TRPN (NOMPC) families.
  • TRPC canonical
  • TRPV vanilloid
  • TRPM melastatin
  • TRPP polycystin
  • TRPML mucolipin
  • TRPA ankyrin, ANKTM 1
  • TRPN nuclear factor-associated TRPN
  • TRPC family can be divided into 4 subfamilies (i) TRPC 1 (ii) TRPC2 (iii) TRPC 3, TRPC6, TRPC 7 and (iv) TRPC4, TRPC 5 based on sequence functional similarities.
  • TRPC can be divided into 4 subfamilies (i) TRPC 1 (ii) TRPC2 (iii) TRPC 3, TRPC6, TRPC 7 and
  • TRPV 5 and TRPV6 are more closely related to each other than to TRPV 1 , TRPV2, TRPV 3 or TRPV4.
  • TRPAl is most closely related to TRPV 3 and is more closely related to TRPV 1 and TRPV2 than to TRPV 5 and TRPV6.
  • the TRPM family has 8 members.
  • Constituents include the following: the founding member TRPM1 (melastatin or LTRPC 1 ), TRPM3 ( IAA 1616 or LTRPC3), TRPM7 (TRP-PLIK, Cha ( l ), LTRPC7), TRPM6 (Cha 2), TRPM2 (TRPC 7 or LTRPC2), TRPM8 (TRP-p8 or CMR1 ), TRPM5 (MTR1 or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4).
  • TRPM1 melastatin or LTRPC 1
  • TRPM3 IAA 1616 or LTRPC3
  • TRPM7 TRP-PLIK
  • Cha ( l ) LTRPC7
  • TRPM6 Cho ( l ), LTRPC7
  • TRPM2 TRPC 7 or LTRPC2
  • TRPM8 TRP-p8 or CMR1
  • TRPM5 MTR1 or LTRPC5
  • TRPM4 FLJ20041 or LTRPC4
  • TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have eleven.
  • TRPP2 P JD2
  • TRPP3 P D2L1
  • TRPP5 P D2L2
  • TRPPl P D2L1
  • TRPP5 P D2L2
  • TRPPl P I , PC I
  • PKD-REJ PKD-l Ll
  • ANKTM1 The sole mammalian member of the TRPA family is ANKTM1. It is believed TRPA l is expressed in nociceptive neurons. Nociceptive neurons of the nervous system sense the peripheral damage and transmit pain signals. TRPA l is membrane bound and most likely acts as a heterodimeric voltage gated channel.
  • TRPA l 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 TRPA l 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 TRPA l receptor.
  • TRPAl is also activated in receptor dependant fashion by Bradykinin (B ) which is released during tissue injury at peripheral terminals
  • TRPA l The difference between TRPA l and other TRP receptors is that TRPA l ligand binding persists for hours due to which the physiological response (e.g., pain) is greatly prolonged. Hence to dissociate the electrophile, an effective antagonist is required.
  • WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO 2004/055054 and WO 2005/089206 describe the TRP channels as the targets for the treatment of pain and related conditions.
  • the present invention relates to compounds of the formula (I):
  • R 1 and R 2 are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyi, heterocyclylalkyl, and - (CR x R y ) n OR x ;
  • R 3 is selected from hydrogen, halogen, cyano, hydroxyl, amino, alkylamino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyi, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl
  • R a and R b are independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted cycloalkyl and cycloalkylalkyl;
  • U, V, W and Y are independently selected from CR C , N, O and S in such a way that it forms stable five-membered heterocyclic ring;
  • R c is selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyi, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; or
  • R c is absent
  • R x and R are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyi, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;
  • 'n' is selected from 0 to 2, both inclusive;
  • 'p' is selected from 0 to 5, both inclusive.
  • R° is selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyi, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;
  • R 3 is selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, alkylamino, substituted or unsubstituted alkyl, alkoxy, haloalkyi, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and
  • 'p' is selected from 0 to 5, both inclusive.
  • R 1 and R 2 are alkyl preferably methyl.
  • each occurrence of R 3 is selected from halogen (for example F, CI or Br), haloalkyi (for example CF3), haloalkoxy (for example OCHF 2 or OCF3,), alkylamino (for example methyamino or ethylamino), dialkylamino (for example dimethylamino or diethylamino) and heterocyclic ring (for example morpholinyl).
  • halogen for example F, CI or Br
  • haloalkyi for example CF3
  • haloalkoxy for example OCHF 2 or OCF3
  • alkylamino for example methyamino or ethylamino
  • dialkylamino for example dimethylamino or diethylamino
  • heterocyclic ring for example morpholinyl
  • Particularly contemplated are compounds of the formulas (I) and (II), which possess IC50 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.
  • TRPAl modulator is used herein because it is more selective for one TRP isoform than others, e.g., 2-fold, 5-fold, 10-fold, and more preferably at least 20, 40, 50, 60, 70, 80, or at least 100- or even 1000-fold more selective for TRPAl over one or more of TRPC6, TRPV5, TRPV6, TRPM8, TRPV1, TRPV2, TRPV4 and/or TRPV3.
  • TRPAl modulator over TRPV4 for e.g., 2-fold, 5-fold, 10-fold, and more preferably at least 20, 40, 50, 60, 70, 80, or even 100- fold more selective.
  • 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 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 TRPA 1 receptors, wherein modulation is believed to be related to a variety of disease states.
  • the compounds of the present invention can be administered alone or in combination with other therapeutic agents.
  • the TRPA1 modulator is administered conjointly with one or more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, antifungal agent, anti-viral agent, anti-septic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor
  • the present patent application further provides a method of inhibiting TRPA 1 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 (te -butyl).
  • _ 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, CI, Br or I.
  • haloalkyl include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl 4,4,4-trifluorobutyl, chloromethyl, dichloromethyl, trichloromethyl, 1 -bromoethyl and the like.
  • haloalkoxy examples include but are not limited to fluoromethoxy, 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).
  • Examples of 'cycloalkylalkoxy' groups is (C3_6)cycloalkyl-(Ci. 6 )alkoxy.
  • all cycloalkylalkoxy groups described herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described herein may be substituted or unsubstituted.
  • aryl means a carbocyclic aromatic system containing one, two or three fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc). If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated.
  • fused means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. The term “fused” is equivalent to the term “condensed”.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Unless set forth or recited to the contrary, all aryl groups described herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C6H 5 or -C2H4C6H5. 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-oxopyrrolidinyl
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclic ring described herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described herein may be substituted or unsubstituted.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroaryl groups described herein may be substituted or unsubstituted.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described herein may be substituted or unsubstituted.
  • treating or “treatment” of a state, disorder or condition includes; (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • IC50 refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity.
  • Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
  • Certain compounds of the present invention including compounds of formula (I), and (II) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers).
  • the present invention includes these stereoisomeric forms (including diastereomers and enantiomers) and mixtures thereof.
  • the various stereoisomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • the pharmaceutical composition of the present patent application includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition includes the compound(s) described herein in an amount sufficient to inhibit TRPA I in a subject (e.g., a human).
  • the inhibitory activity of compounds falling within the formulas (I) and (II) 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.
  • the pharmaceutical 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 tieatable by inhibition of TRPA l .
  • 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 TRPA l receptors: pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, chemotherapy - induced neuropathies, eye - irritation, bronchial - irritation, skin - irritation (atopic dermatitis), Frost - bites (cold - bite), spasticity, catatonia, catalepsy, parkinsons, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke,
  • the sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors".
  • Nociceptors are primary sensory afferent (C and ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal and proton (pH ⁇ 6) modalities. Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain
  • Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis.
  • Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant and often with an aching or throbbing quality.
  • Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized.
  • Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).
  • the aldehyde of formula (6) can be transformed into aldehyde amine of the formula (7) in three steps. Cyclisation of aldehyde amine (7) gives desired pyrido[3,4-d]pyrimidine-5-one of the formula (8).
  • the aromatization of compound (8) using phosphorous oxyhalide such as phosphorous oxychloride or phosphorous oxybromide in dry toluene in the presence of suitable base such as N,N-dimethyl aniline gives compounds of halo pyrido[3,4-d]pyrimidine of the formula (9).
  • Suzuki-Miyaura coupling of halo compound (9) with allylboronic acid ester followed by oxidative cleavage can give corresponding pyrido[3,4-i/]pyrimidinyl acetic acid of the formula ( ⁇ ) [ otha et al., in Synlett, (2005), 12, 1877-1890 and Sharpless, . B. et al. in J. Org. Chem., ( 1981 ), 3936-3938].
  • the coupling of compounds of formula ( ⁇ ) with amines of formula (2) by using a standard amide coupling method can give compounds of general formula (la).
  • pyrido[3,4-i/]pyrimidinyl acetamide derivatives of the general formula (la), wherein U, V, W, Y, R 3 and 'p' are as defined above can be prepared from a pyridine derivative as depicted in Scheme 3.
  • 3,5- dibromopridine-4-carbaldehyde of the formula (10) is converted to the corresponding nitrile of formula (1 1) by a known approach using ammonia in the presence of iodine.
  • Selective displacement of bromo compound (1 1) with methyl amine hydrochloride in the presence of suitable base gives compounds of the formula (12).
  • nitrile of formula ( 12) is converted to the corresponding amide of the formula (13) by using standard procedure as reported in the literature.
  • Cyclisation of compounds of the formula ( 13) with triphosgene or carbonyl dimidazole in the presence of suitable solvent gives the compounds of the formula (14), which on selective N-alkylation afforded compounds of the formula ( 15).
  • Aryl bromide of formula (15) on reaction with allylboronic acid pinacol ester of the formula ( 16) in the presence of Pd(0) catalyst gives ally! pyrido[3,4- i ]pyrimidinedione of the formula (17).
  • Oxidative cleavage of the terminal olefinic bond of intermediate ( 17) using sodium metaperiodate in the presence of catalytic amounts of ruthenium (III) chloride can give the desired pyrido[3,4- ⁇ /
  • the coupling of compounds of formula ( ) with amines of formula (2) by using a standard amide coupling method can give compounds of general formula (la).
  • Oxidative cleavage of the terminal olefinic bond of intermediate ( 17) using sodium metaperiodate in the presence of catalytic amounts of ruthenium (III) chloride can give the desired pyrido[3,4-i/]pyrimidinyl acetic acid of the formula ( ).
  • the coupling of compounds of formula ( ⁇ ) with amines of formula (2) by using a standard amide coupling method gives compounds of general formula (la).
  • Scheme 7 depicts synthesis of 2-amino-4-arylthiazoles of the formula (34) from aryl alkyl ketone of the formula (33) using known approaches.
  • Certain di-and tri- substituted aryl alkyl ketone were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (29) in three steps.
  • acid of formula (29) was converted to the corresponding acid chloride of formula (30) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane.
  • the acid chloride of formula (30) was converted to corresponding Weinerb amide of formula (32) by treating with N,0-dimethylhydroxylamine hydrochloride of formula (31) in the presence of a suitable base such as triethylamine.
  • aryl alkyl ketone derivative of formula (33) The addition of methyl magnesium iodide to Weinreb amide of formula (32) afforded aryl alkyl ketone derivative of formula (33). Conversion of aryl alkyl ketone derivative of formula (33) to 2-amino-4- substituted arylthiazole of the formula (34) can be effected by two approaches as described in Scheme 7. In the first case aryl alkyl ketone was converted to the corresponding a-bromo ketone, which in turn was reacted with thiourea in a suitable solvent such as tetrahydrofuran at refluxing condition.
  • a suitable solvent such as tetrahydrofuran at refluxing condition.
  • aryl alkyl ketone derivative of formula (33) can be converted to 2-amino-4-aryl thiazole (34) 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-Amino- 3-aryloxadiazoles of the formula (38) were prepared as shown in Scheme 8.
  • the reaction of aryl nitrile of the formula (35) with dry ethanol in presence of dry HCl gas in dry diethyl ether gives imido ester hydrochloride of formula (36).
  • the cyclisation of imido ester hydrochloride (36) using cyanamide and hydroxyl amine hydrochloride in presence of a suitable solvent gives desired oxadiazole amine of the formula (38).
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • DMSO-i/ 6 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
  • Ethyl pyrido[3,4-i/]pyrimidinyl acetate used for the preparation of compounds of the present invention is prepared according to the synthetic schemes provided in 'General Methods of Preparation'.
  • this intermediate can be prepared by alternative approaches reported in the literature or by methods known to people skilled in the art of organic synthesis. Detailed experimental procedures for the synthesis of intermediates are given below.
  • 2-Amino-4-arylthiazoles were prepared by known literature methods starting from either substituted acetophenone or substituted benzoic acid as shown below.
  • 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 (1 10.92 g, 907.955 mmol) in dry pyridine (1.4 L) was added acetic anhydride (905.86 g, 2996.254 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for overnight. The excess of solvent was distilled under reduced pressure, quenched with 2 N HC1 (1000 ml) and extracted with chloroform (3 x 300 ml).
  • Step 2 6-[(£)-2-(Dimethylamino)vinyl]- l,3-dimethylpyrimidine-2,4(lH,3H)-dione:
  • a mixture of Step 1 intermediate (40.0 g, 259.70 mmol) and N,N-dimethyl formamide dimethyl acetal (206 ml, 1549.12 mmol) in dry DMF (80 ml) was heated at 90°C for 48 h.
  • the reaction mixture was cooled to room temperature and diluted with diethyl ether (100 ml).
  • the precipitated solid was filtered, washed with diethyl ether (2 x 50 ml) and dried to obtain 34 g of product as off-white solid.
  • Step 3 l ,3-Dimethyl-2,6-dioxo-l ,2,3,6-tetrahydropyrimidine-4-carbaldehyde: Sodium periodate ( 104.30 g, 488.01 mmol) was slowly added to a well stirred solution of Step 2 intermediate (34.0 g, 162.67 mmol) in a mixture of THF-water (650 ml). The reaction mixture was stirred at room temperature for 3 h. Chloroform ( 1000 ml) was added to the reaction mixture and stirred for 1 h after which it was filtered to remove the inorganic material. The filtrate was extracted with chloroform, dried (Na 2 S0 4 ) and concentrated to yield the crude product.
  • Step 4 6- ⁇ (£)-[(2,2-Dimethoxyethyl)imino]methyl ⁇ -l,3-dimethylpyrimidine-2,4(lH,3H)- dione: To a well stirred solution of Step 3 intermediate (30 g, 178.57 mmol) in dry toluene (615 ml) was added aminoacetaldehyde dimethylacetal (29.10 ml, 267.75 mmol) and was refluxed overnight.
  • Step 5 6- ⁇ [(2,2-Dimethoxyethyl)amino]methy 1 ⁇ - 1 ,3-dimethylpyrimidine-2,4( 1 H,3H)- dione:
  • sodium borohydride (9.3 g, 247.05 mmol) was added portion wise at 0-5°C and the reaction was further stirred for 5 h at room temperature.
  • the reaction mixture was then quenched with acetic acid and the excess of solvent was distilled out under reduced pressure.
  • the reaction mass was diluted with water (500 ml) and extracted with dichloromethane (750 ml x 3).
  • Step 6 (l ,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-i/
  • Step 7 Ethyl (l ,3-dimethyl-2,4-dioxo-l ,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5- yl)acetate: To a well stirred solution of Step 6 intermediate (67.0 g, 234.50 mmol) in dry ethanol (670 ml) was added concentrated sulfuric acid (6 ml) and the reaction mixture was refluxed overnight. The excess of solvent was distilled out under reduced pressure, the reaction mass was diluted with water (200 ml) and neutralized by saturated sodium bicarbonate solution.
  • Step 1 3-Fluoro-4-(trifluoromethyl)benzamide: To a stirred solution of 3-fluoro-4- (trifluoromethyl)benzoic acid (2.8 g, 13.46 mmol), dry DMF ( 1 -2 drops) in dry dichloromethane (30 ml) was added oxalyl chloride (1.4 ml, 16.15 mmol) drop wise at 0- 5°C and stirred at room temperature for 2 h. The excess of solvent was evaporated under reduced pressure. The acid chloride was dissolved in dry acetone and was added to aqueous ammonia solution (50 ml) at 0-5°C.
  • Step 2 3-Fluoro-4-(trifluoromethyl)benzonitrile: To a stirred solution of Step 1 intermediate (2.5 g, 12.077 mmol) in dry pyridine (25 ml) was added phosphorous pentachloride (3.01 g, 14.49 mmol) and refluxed for 2 h. The reaction mass was then quenched into 1 N HCl and extracted in ethyl acetate (25 ml x 3). The combined organic layer was washed with water, brine, dried (Na 2 S0 4 ) and concentrated to yield 1.55 g of the product as yellow solid.
  • Step 3 Ethyl 3-fluoro-4-(trifluoromethyl)benzenecarboximidoate hydrochloride: To a stirred solution of Step 2 intermediate (1.5 g, 7.93 mmol) in dry diethyl ether (15 ml) was added dry ethanol (0.5 ml). The solution was cooled (0-5°C) and dry HCl gas was bubbled through for 2 h. Reaction mass was kept in refrigerator for 3 days and then stirred for 2 h at room temperature. To the reaction mixture was added diethyl ether (20 ml) and solid thus obtained was filtered and dried to yield 1.21 g of off-white solid as a product.
  • Step 4 N-Cyano-3-fluoro-4-(trifluoromethyl)benzenecarboximidamide: To a stirred solution of Step 3 intermediate (1.2 g, 4.418 mmol) in dry ethanol (9 ml) was added tri ethyl amine (750 L) and cooled at 0-5°C. Cyanamide (222 mg, 5.303 mmol) was then added and stirred at room temperature for overnight.
  • Step 5 5-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-amine: To a stirred solution of hydroxy! amine hydrochloride (292 mg, 4.210 mmol) in dry ethanol (12 ml). were added triethylamine (590 ih, 4.210 mmol) and Step 4 intermediate (800 mg, 3.508 mmol) in dry ethanol dropwise at 0-5 °C and temperature of the reaction mass was then gradually increased to room temperature and stirred for overnight. Excess of solvent was evaporated under reduced pressure, diluted with water, precipitated solid was filtered and dried to obtain crude product.
  • Step 2 l -[3-(Trifluoromethyl)phenyl]-lH-pyrazol-3-amine: To a well stirred solution of step 1 intermediate (720 mg, 3.144 mmol) in dry toluene ( 1 1 ml) was added N- bromosuccinimide (558 mg, 3.134 mmol) and reaction mixture was refluxed for 1 h. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 x 25 ml). Combined organic layer was washed with brine (25 ml), dried (Na 2 S04) and solvent was evaporated under reduced pressure.
  • the salt was then treated with saturated solution of NaHCC 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.
  • the compounds of invention represented by the general structure (I) can be prepared by coupling ethyl pyrido[3,4-d]pyrimidinyl acetate derivative with an appropriate amine of the formula (2) using the general procedure given below.
  • General procedure for the preparation of Examples To a stirred solution of appropriate thiazoleamine (1.2 equiv.) in dry toluene, sodium hydride (60 % dispersion in mineral oil, 1.4 equiv.) was added and after stirring for 30 min at room temperature ethyl pyrido[3,4- djpyrimidinyl acetate ( 1.0 equiv.) was added and the mixture was heated to reflux for overnight. The mixture was acidified to pH 6.0 by the addition of 2N hydrochloric acid. The solid precipitated out was collected by filtration. The product was further purified by crystallization or by silica gel column chromatography using methanol-chloroform mixture.
  • the illustrative examples of the present invention are screened for TRPA l activity according to a modified procedure described in (a) Toth, A. et al. Life Sciences, 2003, 73, 487-498. (b) McNamara C, R. et al, Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13525- 13530.
  • the screening of the compounds can be carried out by other methods and procedures known to persons skilled in the art.
  • TRPAl receptor activation was measured as inhibition of ally 1 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 TRPA l expressing CHO cells were grown in F- 12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 / ml of G-418.
  • Rat TRPA l 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. ICs 0 values can be calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.

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Abstract

L'invention concerne des dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de l'Ankyrine à potentiel de récepteur transitoire (TRPA). En particulier, les composés décrits ici sont utiles pour le traitement ou la prévention de maladies, d'affections et/ou de troubles modulés par l'ankyrine 1 à potentiel de récepteur transitoire (TRPA1). L'invention concerne également des procédés de préparation des composés décrits ici, des intermédiaires utilisés dans leur synthèse, des compositions pharmaceutiques de ceux-ci et des méthodes de traitement ou de prévention de maladies, d'affections et/ou de troubles modulés par TRPA1. Formule (I).
PCT/IB2010/002549 2010-04-19 2010-10-08 Dérivés de pyrido[3,4-d]pyrimidinyl acétamide comme modulateurs de trpa1 WO2011132017A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2012085662A1 (fr) 2010-12-20 2012-06-28 Glenmark Pharmaceuticals S.A. Composés 2-amino-4-arylthiazoles en tant qu'antagonistes de la trpa1
WO2012172475A1 (fr) * 2011-06-13 2012-12-20 Glenmark Pharmaceuticals S.A. Traitement de troubles respiratoires au moyen d'antagonistes de trpa1
WO2014056958A1 (fr) * 2012-10-12 2014-04-17 F. Hoffmann-La Roche Ag Composés substitués du phénylcarbamate
WO2015155306A1 (fr) * 2014-04-11 2015-10-15 Almirall, S.A. Nouveaux antagonistes de trpa1
US9388172B2 (en) 2012-11-08 2016-07-12 Hoffmann-La Roche Inc. Substituted carbamate compounds
US9533952B2 (en) 2012-10-01 2017-01-03 Orion Corporation N-prop-2-ynyl carboxamide derivatives and their use as TRPA1 antagonists
WO2017060488A1 (fr) 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
WO2017064068A1 (fr) 2015-10-14 2017-04-20 Almirall, S.A. Nouveaux antagonistes de trpa1
JP2017523228A (ja) * 2014-08-11 2017-08-17 ハイドラ バイオサイエンシズ インコーポレイテッドＨｙｄｒａ Ｂｉｏｓｃｉｅｎｃｅｓ，Ｉｎｃ． ピリド［３，４−ｄ］ピリミジン−２，４（１Ｈ，３Ｈ）−ジオン誘導体
EP3251674A2 (fr) 2012-11-16 2017-12-06 BioCryst Pharmaceuticals, Inc. Nucléosides antiviraux contenant de l'azasucre
WO2018033467A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Procédé de préparation de 3-amino-1-(2,6-disubstitué-phényl)pyrazoles
CN112794860A (zh) * 2021-03-24 2021-05-14 上海肇钰医药科技有限公司 噁唑嘧啶酮酰胺类化合物或其可药用盐，制备方法及用途
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN114891003A (zh) * 2022-04-27 2022-08-12 成都施贝康生物医药科技有限公司 新型二氢嘧啶类化合物、中间体或盐及其制备方法和用途
US11655245B2 (en) 2018-03-19 2023-05-23 Genentech, Inc. Oxadiazole transient receptor potential channel inhibitors

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US20090325987A1 (en) * 2008-06-17 2009-12-31 Glenmark Pharmaceuticals, S.A. Quinazolinedione derivatives as trpa1 modulators
WO2010125469A1 (fr) * 2009-04-29 2010-11-04 Glenmark Pharmaceuticals, S.A. Composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de trpa1

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WO2007073505A2 (fr) * 2005-12-22 2007-06-28 Hydra Biosciences, Inc. Méthodes et compositions de traitement de la douleur
US20090325987A1 (en) * 2008-06-17 2009-12-31 Glenmark Pharmaceuticals, S.A. Quinazolinedione derivatives as trpa1 modulators
WO2010125469A1 (fr) * 2009-04-29 2010-11-04 Glenmark Pharmaceuticals, S.A. Composés hétérocycliques fusionnés à une pyrimidine dione en tant que modulateurs de trpa1

Cited By (24)

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Publication number Priority date Publication date Assignee Title
US8592398B2 (en) 2010-12-20 2013-11-26 Glenmark Pharmaceuticals, S.A. 2-amino-4-arylthiazole compounds as TRPA1 antagonists
WO2012085662A1 (fr) 2010-12-20 2012-06-28 Glenmark Pharmaceuticals S.A. Composés 2-amino-4-arylthiazoles en tant qu'antagonistes de la trpa1
US8889862B2 (en) 2010-12-20 2014-11-18 Glenmark Pharmaceuticals, S.A. 2-amino-4-arylthiazole compounds as TRPA1 antagonists
US9073955B2 (en) 2010-12-20 2015-07-07 Glenmark Pharmaceuticals, S.A. 2-amino-4-arylthiazole compounds as TRPA1 antagonists
US9186360B2 (en) 2011-06-13 2015-11-17 Glenmark Pharmaceuticals S.A. Treatment of respiratory disorders using TRPA1 antagonists
WO2012172475A1 (fr) * 2011-06-13 2012-12-20 Glenmark Pharmaceuticals S.A. Traitement de troubles respiratoires au moyen d'antagonistes de trpa1
US9533952B2 (en) 2012-10-01 2017-01-03 Orion Corporation N-prop-2-ynyl carboxamide derivatives and their use as TRPA1 antagonists
US20150218144A1 (en) * 2012-10-12 2015-08-06 Hoffmann-La Roche Inc. Substituted phenylcarbamate compounds
US9353096B2 (en) 2012-10-12 2016-05-31 Hoffmann-La Roche Inc. Substituted phenylcarbamate compounds
WO2014056958A1 (fr) * 2012-10-12 2014-04-17 F. Hoffmann-La Roche Ag Composés substitués du phénylcarbamate
US9388172B2 (en) 2012-11-08 2016-07-12 Hoffmann-La Roche Inc. Substituted carbamate compounds
EP3251674A2 (fr) 2012-11-16 2017-12-06 BioCryst Pharmaceuticals, Inc. Nucléosides antiviraux contenant de l'azasucre
WO2015155306A1 (fr) * 2014-04-11 2015-10-15 Almirall, S.A. Nouveaux antagonistes de trpa1
JP2017523228A (ja) * 2014-08-11 2017-08-17 ハイドラ バイオサイエンシズ インコーポレイテッドＨｙｄｒａ Ｂｉｏｓｃｉｅｎｃｅｓ，Ｉｎｃ． ピリド［３，４−ｄ］ピリミジン−２，４（１Ｈ，３Ｈ）−ジオン誘導体
WO2017060488A1 (fr) 2015-10-09 2017-04-13 Almirall, S.A. Nouveaux antagonistes de trpa1
WO2017064068A1 (fr) 2015-10-14 2017-04-20 Almirall, S.A. Nouveaux antagonistes de trpa1
WO2018033467A1 (fr) 2016-08-15 2018-02-22 Bayer Cropscience Aktiengesellschaft Procédé de préparation de 3-amino-1-(2,6-disubstitué-phényl)pyrazoles
US10738012B2 (en) 2016-08-15 2020-08-11 Bayer Cropscience Aktiengesellschaft Process for the preparation of amino-pyrazoles
US11655245B2 (en) 2018-03-19 2023-05-23 Genentech, Inc. Oxadiazole transient receptor potential channel inhibitors
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN112794860A (zh) * 2021-03-24 2021-05-14 上海肇钰医药科技有限公司 噁唑嘧啶酮酰胺类化合物或其可药用盐，制备方法及用途
CN112794860B (zh) * 2021-03-24 2021-06-29 上海肇钰医药科技有限公司 噁唑嘧啶酮酰胺类化合物或其可药用盐，制备方法及用途
CN114891003A (zh) * 2022-04-27 2022-08-12 成都施贝康生物医药科技有限公司 新型二氢嘧啶类化合物、中间体或盐及其制备方法和用途
CN114891003B (zh) * 2022-04-27 2023-10-13 成都施贝康生物医药科技有限公司 新型二氢嘧啶类化合物、中间体或盐及其制备方法和用途

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