WO2009081222A1 - Pyrimidines ou pyridines tricycliques substituées ligands des récepteurs des vanilloïdes - Google Patents

Pyrimidines ou pyridines tricycliques substituées ligands des récepteurs des vanilloïdes Download PDF

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Publication number
WO2009081222A1
WO2009081222A1 PCT/IB2007/004076 IB2007004076W WO2009081222A1 WO 2009081222 A1 WO2009081222 A1 WO 2009081222A1 IB 2007004076 W IB2007004076 W IB 2007004076W WO 2009081222 A1 WO2009081222 A1 WO 2009081222A1
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Prior art keywords
substituted
unsubstituted
compound
pyrimidin
pain
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PCT/IB2007/004076
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English (en)
Inventor
Laxmikant Atmaram Gharat
Jitendra Maganbhai Gajera
Neelima Khairatkar-Joshi
Vidya G. Kattije
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Glenmark Pharmaceuticals, S.A.
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Priority to PCT/IB2007/004076 priority Critical patent/WO2009081222A1/fr
Publication of WO2009081222A1 publication Critical patent/WO2009081222A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to substituted tricyclic compounds, which can be used as vanilloid receptor ligands.
  • compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by vanilloid receptor- 1 (VRl).
  • pharmaceutical compositions and methods for treating or preventing diseases, conditions and/or disorders modulated by VRl are also provided herein.
  • Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limiting, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed., 1996). The sensation of pain can be triggered by any number of physical or chemical stimuli, and the sensory neurons which mediate the response to these harmful stimuli are known as "nociceptors".
  • 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.
  • VRl vanilloid receptors
  • Capsaicin (8-methyl-N-vanillyl-6-nonenamides; CAP) is known to stimulate pain pathways through the release of a variety of sensory afferent neurotransmitters via a specific cell surface capsaicin receptor, cloned as the first vanilloid receptor (VRl now known as TRPVl) (Caterina MJ, et.al, Science , Apr 14; 288 (5464): 306-13, 2000).
  • CAP has a wide spectrum of biological actions and not only exhibits effects on the cardiovascular and respiratory systems, but also induces pain and irritancy on local application.
  • CAP however, after such induction of pain induces desensitization, both to CAP itself and also to other noxious stimuli, thereby stopping the pain.
  • the analgesic component of VRl receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal.
  • CAP and its analogues such as olvanil, nuvanil, DA-5018, SDZ-249482, and resiniferatoxin are either used or are under development as analgesic agents or therapeutic agents for urinary incontinence or skin disorders (Wrigglesworth and Walpole, Drugs of the Future, 23: pp 531-538, 1998).
  • VRl is widely expressed in non-neuronal tissues in various organ systems, and the functional roles of VRl in various systems are not properly understood at this time.
  • An increasing number of animal studies have revealed the possible involvement of VRl receptors in a number of pathologies.
  • VRl is now being considered as a molecular target for various indications such as migraine, arthralgia, diabetic neuropathy, neurodegeneration, neurotic skin disorder, stroke, cardiac pain arising from an ischemic myocardium, Huntington's disease, memory deficits, restricted brain function, amyotrophic lateral sclerosis (ALS), dementia, urinary bladder hypersensitiveness, urinary incontinence, vulvodynia, pruritic conditions such as uremic pruritus, irritable bowel syndrome including gastro-esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn's disease, celiac disease and inflammatory diseases such as pancreatitis, and in respiratory disorders
  • VRl antagonists are likely to be useful in multiple sub-types of pain such as acute, chronic, neuropathic pain or post-operative pain, as well as in pain due to neuralgia (e.g., post herpetic neuralgia and trigeminal neuralgia), and in pain due to diabetic neuropathy, dental pain, and cancer pain. Additionally, VRl antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritis or osteoarthritis. VRl antagonists hold potential benefit in diabetes, obesity, urticaria, actinic keratosis, keratocanthoma, alopecia, Meniere's disease, tinnitus, hyperacusis and anxiety disorders.
  • neuralgia e.g., post herpetic neuralgia and trigeminal neuralgia
  • VRl antagonists will also prove useful in the treatment of inflammatory pain conditions such as arthritis or osteoarthritis.
  • VRl antagonists hold potential benefit in diabetes, obesity, urticaria, actinic
  • VRl vanilloid Receptor
  • Vanilloid agonists and antagonists have been developed for the treatment of pain.
  • the agonists work through desensitizing the receptor while antagonists block its stimulation by (patho) physiological ligands.
  • the first antagonist Capsazepine was developed by Novartis.
  • VRl antagonists which are at the preclinical stage, for example, Amore Pacific's PAC-20030, Neurogen's BCTC, Abbott's A-425619 and Amgen's AMG- 9810.
  • VRl antagonists at the clinical stages are for example, Amgen's AMG 571, Glaxo Smithkline's SB-705498, Merck's MK-2295 and Glenmark's GRC 6211.
  • Vanilloid receptor modulating compounds are disclosed in U.S. Patent Nos. 6,933,311, 6,939,891, and 7, ,037, 927, U.S. Publication No. 2006/0100460, and PCT Publication Nos. WO 02/08221, 02/16317, 02/16318, 02/16319, 2004/103281, 2004/108133, 2004/111009, 2006/044527 and 2006/045498.
  • vanilloid receptor modulators useful in the treatment of diseases, conditions, and/or disorders modulated by vanilloid receptors, including acute and chronic pain and neuropathic pain.
  • the present invention relates to VRl receptor ligands of formula (1):
  • Z is -Y-(CR,R 2 ) n - or -(CR 1 R 2 V Y; Y is a bond, NR 1, -O-, or -S-; n is an integer ranging from 0-3; V is N or CR 1 ; W is NR, or O;
  • Ring T is heteroaryl or heterocyclyl, optionally substituted with one or more R y ; each occurrence of R 1 , R 2 , R x and R y is independently hydrogen, nitro, cyano, halogen, -OR 3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or
  • the invention relates to compounds of formula (Ia)
  • Z is -Y-(CRi R 2 ) n , Y is -O-, n is 0.
  • V is N
  • W is selected from NH or O
  • T is heteroaryl, optionally substituted with one or more R y .
  • ring T is selected from optionally substituted benzothiazolyl, benzodioxinyl, quinolinyl or indazolyl.
  • R x for all R x substitutions
  • R y independently are selected from hydrogen, halogen, alkyl, NHCO-alkyl and -OR 3 (wherein R 3 is alkyl).
  • the invention relates to compounds of formula (Ib)
  • Z is -Y-(CR 1 R 2 V; Y is a bond; n is 2; V is N; W is NR 1 ; Ring T is aryl, heteroaryl or heterocyclyl, optionally substituted with one or more alkyl or NHCO-alkyl groups with alkyl; and Ri, R 2 , R x and R y are hydrogen.
  • the invention relates to compounds of formula (Ic)
  • Z is -Y-(CR 1 R 2 V; Y is O; n is 2;
  • V is N; W is NR 1 ;
  • Ri, R 2 , R x and R y are hydrogen;
  • Ring T is heteroaryl or heterocyclyl, optionally substituted with one or more NHCO- alkyl.
  • Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts thereof.
  • the present invention should not be construed to be limited to them.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of the present invention.
  • 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.
  • the compounds and pharmaceutical compositions of the present invention are useful in the treatment of diseases, conditions and/or disorders modulated by vanilloid antagonists.
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by vanilloid VRl receptor antagonists in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by vanilloid VRl receptor antagonists in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of formula 1.
  • alkyl refers to an optionally substituted 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 (t-butyl).
  • Ci -6 alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • alkenyl refers to an optionally substituted 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.
  • alkynyl refers to an optionally substituted 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.
  • alkoxy denotes an optionally substituted alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH 3 and -OC 2 H 5 .
  • cycloalkyl denotes an optionally substituted 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., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to an optionally substituted 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.
  • cycloalkenyl refers to an optionally substituted 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.
  • cycloalkenylalkyl refers to an optionally substituted cycloalkenyl group as defined above directly bonded to an alkyl group as defined above.
  • aryl refers to refers to an optionally substituted aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • arylalkyl refers to an optionally substituted aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 Hs and -C 2 HsC 6 H 5 .
  • heterocyclic ring refers to an optionally substituted 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, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidiny
  • heterocyclyl refers to an optionally substituted 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.
  • heterocyclylalkyl refers to an optionally substituted heterocyclic ring
  • 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.
  • heteroaryl refers to an optionally substituted 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.
  • heteroarylalkyl refers to an optionally substituted 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.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality while other functional groups on the compound may remain reactive.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl, benzyl, tetrahydropyranyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Suitable carboxy-protecting groups include, but are not limited to, -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p- nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, and nitroethyl.
  • protecting groups and their use see, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • prodrug means a compound that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • treating or “treatment” of a state, disorder or condition includes: (1) 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;
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.
  • 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.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • the pharmaceutically acceptable salts of the present invention may be prepared by any conventional techniques known to a person of ordinary skill in the art, e.g., as described in Handbook of Pharmaceutical Salts-Properties, Selection and Use", P. Heinrich Stahl, Camille G. Wermuth [Eds.], VHCA and WILEY-VCH [2002].
  • solvates includes hydrates and other solvents of crystallization (such as alcohols).
  • the compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.
  • Certain compounds of present invention are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by known methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.
  • 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.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
  • the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • 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 route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by vanilloid VRl receptor antagonists.
  • the present invention further provides a method of treating a disease, condition and/or disorder modulated by vanilloid receptor antagonists in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • the method is particularly useful for treating diseases, conditions and/or disorders modulated by VRl receptor.
  • Diseases, conditions, and/or disorders that are modulated by vanilloid receptor antagonists which may be treated by the compounds and compositions of the present invention include, but are not limited to, pain, urinary incontinence, irritable bowel syndrome including gastro-esophageal reflux disease, enteritis, ileitis, stomach-duodenal ulcer, inflammatory bowel disease including Crohn's disease, celiac disease and inflammatory diseases such as pancreatitis.
  • respiratory disorders such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, dermatitis, and non-specific disorders such as retinopathy, muscle spasms, emesis, dyskinesias and depression.
  • Another embodiment is a method of treating or preventing a disease or disorder mediated or associated with the activity of the vanilloid receptor in a subject in need thereof (e.g., a mammal or human) by administering to the subject a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.
  • Such diseases and disorders include, but are not limited to, disorders such as pain, chronic pain, 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, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroesophageal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, emesis, stomach duodenal ulcer and pruritus.
  • disorders such as pain, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthriti
  • Yet another embodiment is a method of treating or preventing pain in a subject in need thereof by administering a therapeutically effective amount of the compound or pharmaceutical composition of the present invention.
  • the invention provides for the use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders mediated or associated with the activity of vanilloid receptor.
  • the compounds of the present invention have potent analgesic and anti-inflammatory activity, and the pharmaceutical compositions of the present invention thus may be employed to alleviate or relieve acute, chronic or inflammatory pain, suppress inflammation, or treat urgent urinary incontinence.
  • the compounds of the present invention may be used alone or in appropriate association, as well as in combination with other pharmaceutically active compounds.
  • the compounds and the pharmaceutical compositions of the present invention may be used alone or in combination with other pharmaceutically active compounds in the manufacture of a medicament for the therapeutic applications described herein.
  • the compounds of the present invention can be prepared by techniques known to one of ordinary skill in the art.
  • the compounds of the present invention can be prepared through the reaction sequences shown in Schemes I- VIII. Where specific bases, acids, reagents, solvents, oxidizing agents, reducing agents, halogenating agents, dehydrating agents, fiuorinating agents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, oxidizing agents, reducing agents, halogenating agents, dehydrating agents, fiuorinating agents, coupling agents etc., known in the art, may also be used, and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or a combination thereof, are envisioned as part of the present invention. All possible stereoisomers are also envisioned within the scope of this invention.
  • a compound of formula 9 is prepared by the process described in Scheme I above.
  • a compound of formula 2 ⁇ Synthetic Communications 24 (12), 1757-1760, 1994) is reacted with an ester of formula 3 (wherein Hal is halogen and R 3 is alkyl) in the presence of one or more bases, for example, piperidine, pyridine, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate or a mixture thereof, to form a compound of formula 4.
  • bases for example, piperidine, pyridine, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate or a mixture thereof, to form a compound of formula 4.
  • the reaction can be performed in one or more solvents, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran or a mixture thereof.
  • the compound of formula 4 is converted to a compound of formula 5, for example, by reaction with hydroxylamine hydrochloride to form an intermediary oxime which is dehydrated to form the compound of formula 5.
  • the reaction can be performed in the presence of one or more bases, for example, piperidine, pyridine, dimethylaminopyridine, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate or a mixture thereof in one or more solvents, for example, methanol, ethanol, isopropanol, dichloromethane, chloroform, dichloroethane, dibromoethane, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • bases for example, piperidine, pyridine, dimethylaminopyridine
  • potassium hydroxide sodium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate or
  • the compound of formula 6 (commercially available) can be reacted with a compound of formula 3 to form compound of formula 5.
  • the reaction can be performed in one or more solvents, for example, dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran or a mixture thereof.
  • the compound of formula 5 is reacted with an amide, for example formamide, optionally in the presence of one or more solvents, for example, dichloromethane, dichloroethane, dibromomethane, isopropanol, dioxane, tetrahydrofiiran, /-butanol or a mixture thereof, to form a compound of formula 7.
  • an amide for example formamide
  • solvents for example, dichloromethane, dichloroethane, dibromomethane, isopropanol, dioxane, tetrahydrofiiran, /-butanol or a mixture thereof
  • the compound of formula 7 is reacted with a halogenating agent, for example, phosphorous trichloride, phosphorous oxychloride, or thionyl chloride, to form a compound of formula 8, where Li is a halogen (e.g., chlorine).
  • a halogenating agent for example, phosphorous trichloride, phosphorous oxychloride, or thionyl chloride
  • the compound of formula 8 is reacted with a compound of formula 8a optionally in the presence of one or more bases, for example, cesium carbonate, sodium t-butoxide, triethylamine, diisopropylethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene or a mixture thereof, to form a compound of formula 9.
  • bases for example, cesium carbonate, sodium t-butoxide, triethylamine, diisopropylethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene or a mixture thereof, to form a compound of formula 9.
  • the reaction between the compounds of formulas 8 and 8a can be performed by a method described in "Metal-catalyzed cross-coupling reactions", F. Diederich and P. J. Stang (eds) Wiley- VCH, Weinheim, 1998.
  • the reaction can be performed in the presence of palladium catalysts (e.g., palladium acetate) and a ligand, for example, BINAP, tol-BINAP or 2-alkoxy BINAP.
  • the reaction between the compounds of formulas 8 and 8a can be performed in one or more solvents, for example, toluene, ethylenedichloride, methanol, ethanol, isopropanol, n- butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate, N,N- dimethylformamide, N-methylformamide, dimethylsulfoxide, or a mixture thereof.
  • solvents for example, toluene, ethylenedichloride, methanol, ethanol, isopropanol, n- butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate, N,N- dimethylformamide, N-methylformamide, dimethylsulfoxide, or a mixture thereof.
  • a compound of formula 14 is prepared using the process shown in Scheme II.
  • the compound of formula 10 ⁇ Journal of Organic Chemistry, 1962, 27, 70-76; Tetrahedron, 2002, 58, 5203-5208) is treated with a compound of the formula R 3 OCOHaI (wherein Hal is halogen and R 3 is alkyl) or dialkyl carbonate to form a compound of formula 11.
  • the reaction can be performed in the presence of one or more bases, for example, potassium hydroxide, sodium hydroxide, sodium hydride, potassium-t- butoxide, lithium diisopropylamide or lithium hexamethyldisilazide, in one or more solvents, for example, dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran or a mixture thereof.
  • bases for example, potassium hydroxide, sodium hydroxide, sodium hydride, potassium-t- butoxide, lithium diisopropylamide or lithium hexamethyldisilazide
  • solvents for example, dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran or a mixture thereof.
  • the reaction can be performed in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, ammonia, pyridine or a mixture thereof optionally in the presence of one or more solvents, for example, methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, dimethylformamide or a mixture thereof.
  • the compound of formula 11 is converted to the corresponding enamine by reacting it with a source of ammonia, for example, ammonium hydroxide, ammonium formate, ammonium acetate or a mixture thereof, followed by reaction with an amide, for example, formamide, to form the compound of formula 12.
  • a source of ammonia for example, ammonium hydroxide, ammonium formate, ammonium acetate or a mixture thereof
  • an amide for example, formamide
  • the compound of formula 12 is reacted with a halogenating agent (e.g., a chlorinating agent such as phosphorous oxychloride, thionyl chloride) to form a compound of formula 13.
  • a halogenating agent e.g., a chlorinating agent such as phosphorous oxychloride, thionyl chloride
  • the reaction can be performed in one or more solvents, for example, carbon tetrachloride, dichloromethane, dichloroethane, dibromoethane, chloroform or a mixture thereof.
  • the compound of formula 13 is converted to a compound of formula 14 by following the procedure described in scheme I.
  • a compound of formula 14 is prepared using the process shown in Scheme III.
  • the compound of formula 15 can be reacted with a compound of formula 16 in the presence of a nucleophile, for example, triarylphosphine and dialkylazodicarboxylate, to form a compound of formula 17 (wherein each occurrence of Lj is independently a halogen).
  • the reaction can be performed in one or more solvents, for example, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • the compound of formula 17 can be cyclized in the presence of one or more catalysts, for example, palladium acetate, nickel chloride, zinc or a mixture thereof in one or more solvents, for example, dimethylformamide, pyridine, acetonitrile, tetrahydrofuran, dichloroethane, dibromoethane or a mixture thereof.
  • catalysts for example, palladium acetate, nickel chloride, zinc or a mixture thereof in one or more solvents, for example, dimethylformamide, pyridine, acetonitrile, tetrahydrofuran, dichloroethane, dibromoethane or a mixture thereof.
  • the compound of formula 13 is converted to a compound of formula 14 by following the procedure described in scheme I.
  • a compound of formula 14 is prepared using the process shown in Scheme IV.
  • the compound of formula 18 (wherein Pi is a protecting group, each occurrence of Li is independently a leaving group) can be reacted with the compound of formula 16 in the presence of one or more catalysts, for example, palladium acetate, nickel chloride, zinc or a mixture thereof in one or more solvents, for example, dimethylformamide, pyridine, acetonitrile, tetrahydrofuran, dichloroethane, dibromoethane or a mixture thereof, to form a compound of formula 19.
  • catalysts for example, palladium acetate, nickel chloride, zinc or a mixture thereof
  • solvents for example, dimethylformamide, pyridine, acetonitrile, tetrahydrofuran, dichloroethane, dibromoethane or a mixture thereof
  • the compound of formula 19 is deprotected, for example, by reaction with a deprotecting agent (such as catalytic hydrogenation, hydrochloric acid, hydrobromic acid (e.g., in acetic acid), methane sufonic acid, and pyridimium hydrochloride) to form a compound of formula 20.
  • a deprotecting agent such as catalytic hydrogenation, hydrochloric acid, hydrobromic acid (e.g., in acetic acid), methane sufonic acid, and pyridimium hydrochloride
  • the compound of formula 20 is cyclized, for example, in the presence of a reagent such as triarylphosphine and dialkylazodicarboxylate, to form a compound of formula 13.
  • the reaction can be performed in one or more solvents, for example, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • solvents for example, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • the compound of formula 13 is converted to a compound of formula 14 by following the procedure described in scheme I.
  • a compound of formula 14 is prepared using the process shown in Scheme V.
  • the proton abstraction of a compound of formula 21 (wherein P 1 is a protecting group and R 3 is alkyl) is carried out with a base (preferably a strong base, for example, potassium hydroxide, sodium hydroxide, sodium hydride, potassium-t-butoxide, lithium diisopropylamide or lithium hexamethyldisilazide) and further reacted with a compound of the formula OH-(CRiR 2 )-Hal (where Hal is a halogen) to form a compound of formula 22.
  • a base preferably a strong base, for example, potassium hydroxide, sodium hydroxide, sodium hydride, potassium-t-butoxide, lithium diisopropylamide or lithium hexamethyldisilazide
  • bases for example, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, ammonia, pyridine or a mixture thereof
  • solvents for example, methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran, dimethylformamide or a mixture thereof.
  • the compound of formula 22 is converted to the corresponding enamine by reacting it with a source of ammonia, for example, ammonium hydroxide, ammonium formate, ammonium acetate or a mixture thereof, followed by reaction with an amide, for example, formamide, to form a compound of formula 23.
  • a source of ammonia for example, ammonium hydroxide, ammonium formate, ammonium acetate or a mixture thereof
  • an amide for example, formamide
  • the compound of formula 23 is deprotected (for example, by reaction with a deprotecting agent such as catalytic hydrogenation, hydrochloric acid, hydrobromic acid (e.g., in acetic acid), methane sufonic acid, and pyridimium hydrochloride) followed by cyclization, for example, in the presence of a reagent such as triarylphosphine and dialkylazodicarboxylate, to form a compound of formula 12.
  • a deprotecting agent such as catalytic hydrogenation, hydrochloric acid, hydrobromic acid (e.g., in acetic acid), methane sufonic acid, and pyridimium hydrochloride) followed by cyclization, for example, in the presence of a reagent such as triarylphosphine and dialkylazodicarboxylate, to form a compound of formula 12.
  • the reaction can be performed in one or more solvents, for example, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • solvents for example, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • the compound of formula 12 is converted to a compound of formula 14 by following the procedure described in scheme II.
  • a compound of formula 14 is prepared using the process shown in Scheme VI.
  • the compound of formula 24 ⁇ Journal of American Chemical Society, 1946, 68, 86-89) (wherein Hal is halogen) is converted to a compound of formula 25 by reaction with a cyanating agent, for example, sodium cyanide, trimethylsilyl cyanide, copper (I) cyanide or a mixture thereof optionally in one or more solvents, for example, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran or a mixture thereof.
  • a cyanating agent for example, sodium cyanide, trimethylsilyl cyanide, copper (I) cyanide or a mixture thereof optionally in one or more solvents, for example, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran or a mixture thereof.
  • the compound of formula 25 is converted to a compound of formula 26, for example, by reaction with hydroxyl amine chloride or sulphate optionally in one or more solvents, for example, carbon tetrachloride, dichloromethane, dichloroethane, dibromoethane, chloroform or a mixture thereof, to form a compound of formula 26.
  • the compound of formula 26 is reduced to a compound of formula 27, for example, by reaction with a reducing agent (such as zinc/acetic acid, catalytic hydrogenation, iron / hydrochloric acid or a mixture thereof).
  • a reducing agent such as zinc/acetic acid, catalytic hydrogenation, iron / hydrochloric acid or a mixture thereof.
  • the reaction can be performed in one or more solvents, for example, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • solvents for example, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • the compound of formula 27 is cyclized to form a compound of formula 12, for example, by reaction with a compound of formula R y CON(CH 3 ) 2 , optionally in one or more solvents, toluene, ethylene dichloride, methanol, ethanol, isopropanol, dichloromethane, chloroform, dichloroethane, dibromoethane, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate or a mixture thereof.
  • the compound of formula 12 is converted to a compound of formula 14 by following the procedure described in scheme II.
  • a compound of formula 31 is prepared according to scheme VII.
  • the compound of formula 28 (for example, prepared by a procedure described in Tetrahedron, vol. 51, No. 12, 3587-3606, 1995) is converted to a compound of formula 29, for example, by reaction with ammonium acetate in the presence of formamide to form a compound of formula 29.
  • the compound of formula 29 is halogenated with a halogenating agent, for example, phosphorus oxychloride, to form a compound of formula 30.
  • the compound of formula 30 is reacted with a compound of formula 30a to form a compound of formula 31 optionally in one or more solvents, for example, toluene, ethylenedichloride, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate, N,N-dimethylformamide, N-methylformamide, dimethylsulfoxide or a mixture thereof.
  • solvents for example, toluene, ethylenedichloride, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate, N,N-dimethylformamide, N-methylformamide, dimethylsulfoxide or a mixture thereof.
  • a compound of formula 35 is prepared according to scheme VIII.
  • the compound of formula 32 (for example, prepared by a procedure described in Tetrahedron vol. 58, No. 12, 5203-5208, 2002) is converted to a compound of formula 33, for example, by reaction with ammonium acetate in the presence of formamide.
  • the compound of formula 33 is halogenated with a halogenating agent, for example, phosphorus oxychloride, to form a compound of formula 34.
  • the compound of formula 34 is reacted with a compound of formula 30a in one or more solvents, for example, toluene, ethyl enedichloride, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate, N,N-dimethylformamide, N-methylformamide, dimethylsulfoxide or a mixture thereof, to form a compound of formula 35.
  • solvents for example, toluene, ethyl enedichloride, methanol, ethanol, isopropanol, n-butyl alcohol, ethylene glycol, dioxane, tetrahydrofuran, ethyl acetate, butyl acetate, N,N-dimethylformamide, N-methylformamide, dimethylsulfoxide or a mixture thereof, to form a compound
  • Example 3 Ethyl ⁇ 2-[(hvdroxyimino)methyl]-5-methylphenoxy ⁇ acetate Hydroxyl amine hydrochloride (1.68 mmol) and sodium bicarbonate (1.68 mmol) were dissolved in water and stirred for about 15 minutes. Ethanolic solution of ethyl (2-formyl-5- methylphenoxy)acetate ( 1.126 mmol in 2.5 mL) and added dropwise to the above solution. The entire reaction mixture was stirred at room temperature for about 3- 4 hours. The solvent was evaporated under vacuum. Cold water was added to obtain a solid which was then filtered. The solid was washed with petroleum ether and dried to obtain the entitled compound.
  • the entitled compound is prepared by following the procedures as described in WO 2006064355
  • Example 12 N-(2.3-dihydro-l ,4-benzodioxin-6-yl)-7-methyl[11benzofiiro[3,2- ⁇ f
  • Example 13 A/-(4-[(7-tert-butyl[llbenzofuro[3,2-(/1pyrimidin-4-yl)aminol-l,3-benzothiazol- 2-yl)acetamide (Compound No. 3)
  • Example 14 ,/V-(2,3-dihvdro- 1 ,4-benzodioxin-6-yl)-7-tert-butyl[ 1 ]benzofuro[ " 3,2- (fipyrimidin-4-amine (Compound No. 4)
  • Example 30 Screening for TRPVl antagonist using 45 CaI cium uptake assay:
  • a stock solution of capsaicin was made in ethanol and test compounds were prepared in 100% DMSO. Stock solutions were diluted to appropriate final concentrations in assay buffer keeping the final DMSO concentration between 0.1% and 0.55%. 45 Ca was used at a final concentration of 2.5 ⁇ Ci/ml ( 45 Ca, ICN). Assay buffer was composed of F- 12 DMEM medium supplemented with 1.8 mM CaCl 2 (final cone.) and 0.1% Bovine serum albumin.(BSA from SIGMA) The wash buffer was Tyrodes solution supplemented with 0.1% BSA and 1.8 mM calcium.
  • Lysis buffer contained 50 mM Tris-HCl, pH7.5, 150 mM NaCl, 1% Triton X-100, 0.5% deoxycholate and 0.1% Sodium dodecyl sulphate (SDS 5 SIGMA ).
  • the assay was carried out with some modifications of the procedure as described by Toth et.al. ⁇ See Toth A et. ai, Life Sciences 73 p 487-498, 2003).
  • Human TRPVl expressing CHO cells were grown in F- 12 DMEM (Dulbecco's modified Eagle's medium -GIBCO) medium with 10% FBS (fetal bovine serum Hyclone), 1% penicillin-streptomycin solution, and 400 ⁇ g / ml of G-418. Cells were seeded 48 h prior to the assay in 96 well plates to obtain ⁇ 50,000 cells per well on the day of experiment. Plates were incubated at 37°C in the presence of 5 % CO 2 .
  • Radioactivity in samples was measured as counts per minute (cpm) using Packard Biosciences Top Count.
  • the drug / vehicle / capsaicin treated 45 Ca uptake values were normalized over basal 45 Ca value. Data was expressed as % inhibition of 45 Ca uptake by test compound with respect to maximum 45 Ca uptake induced by capsaicin alone.
  • IC 50 value was calculated from dose response curve by nonlinear regression analysis using GraphPadPRISM software. Results were expressed as percent inhibition at various concentrations.
  • % inhibition of the test compounds at 300 nM ranged from between about 20% to about 25%; at 1 ⁇ M ranged from between about 2% to about 20%, from between about 20% to about 75%; at 3 ⁇ M ranged from between about 50% to about 100%.

Abstract

La présente invention concerne des composés tricycliques substitués, qui peuvent être utilisés en tant que ligands des récepteurs des vanilloïdes. Les composés décrits dans le présent document sont notamment utiles pour le traitement ou la prévention de maladies, conditions et/ou troubles modulés par le récepteur-1 des vanilloïdes (VR1). La présente invention concerne également des compositions pharmaceutiques et des procédés de traitement ou de prévention de maladies, de conditions et/ou de troubles modulés par VR1.
PCT/IB2007/004076 2007-12-21 2007-12-21 Pyrimidines ou pyridines tricycliques substituées ligands des récepteurs des vanilloïdes WO2009081222A1 (fr)

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US10700291B2 (en) 2013-03-26 2020-06-30 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, compound, organic compound, display module, lighting module, light-emitting device, display device, lighting device, and electronic device
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US11600789B2 (en) 2013-03-26 2023-03-07 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, compound, organic compound, display module, lighting module, light-emitting device, display device, lighting device, and electronic device
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