WO2007067756A2 - Certains types d'entites chimiques, compositions et methode de modulation de trpv1 - Google Patents

Certains types d'entites chimiques, compositions et methode de modulation de trpv1 Download PDF

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WO2007067756A2
WO2007067756A2 PCT/US2006/047002 US2006047002W WO2007067756A2 WO 2007067756 A2 WO2007067756 A2 WO 2007067756A2 US 2006047002 W US2006047002 W US 2006047002W WO 2007067756 A2 WO2007067756 A2 WO 2007067756A2
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optionally substituted
alkyl
chemical entity
chosen
trpvl
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PCT/US2006/047002
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WO2007067756A3 (fr
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Jose S. Mendoza
Carl Nicholas Hodge
John K. Dickson, Jr.
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Amphora Discovery Corporation
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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
    • C07D491/10—Spiro-condensed systems

Definitions

  • Nociceptors are primary sensory afferent (C and A.delta. fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH ⁇ 6) modalities.
  • the lipophilic vanilloid, capsaicin activates primary sensory fibers via a specific cell surface capsaicin receptor, cloned as TRPVl.
  • the intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia.
  • the analgesic component of TRPVl receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal.
  • capsaicin analogs as analgesic agents.
  • capsazepine a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. TRPVl receptors are also localized on sensory afferents which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.
  • the TRPVl receptor has been called a "polymodal detector" of noxious stimuli since it can be activated in several ways.
  • the receptor channel is activated by capsaicin and other vanilloids and thus is classified as a ligand-gated ion channel.
  • TRPVl receptor activation by capsaicin can be blocked by the competitive TRPVl receptor antagonist, capsazepine.
  • the channel can also be activated by protons. Under mildly acidic conditions (pH 6-7), the affinity of capsaicin for the receptor is increased, whereas at pH ⁇ 6, direct activation of the channel occurs.
  • membrane temperature reaches 43.degree. C, the channel is opened. Thus heat can directly gate the channel in the absence of ligand.
  • the capsaicin analog, capsazepine which is a competitive antagonist of capsaicin, blocks activation of the channel in response to capsaicin, acid, or heat.
  • the channel is a nonspecific cation conductor. Both extracellular sodium and calcium enter through the channel pore, resulting in cell membrane depolarization. This depolarization increases neuronal excitability, leading to action potential firing and transmission of a noxious nerve impulse to the spinal cord.
  • depolarization of the peripheral terminal can lead to release of inflammatory peptides such as, but not limited to, substance P and
  • TRPVl thus represents a pharmacological target of interest for the treatment of human disease.
  • the identification and development of compounds that modulate the functioning of TRPVl is therefore of considerable interest.
  • R 1 is independently chosen from sulfbnyl, nitro, halo, optionally substituted acyl, optionally subtituted amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • n 0, 1, 2, and 3;
  • R 2 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl,
  • R 3 and R 4 are independently chosen from hydrogen, optionally substituted alkyl, optionally
  • R 5 is independently chosen from sulfonyl, nitro, halo, optionally substituted acyl, optionally substituted amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; and
  • n is chosen from 0, 1, 2, and 3
  • composition comprising at least one
  • Also provided is a method of treating at least one disease or disorder modulated by TRPVl activity in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one chemical entity described herein.
  • Also provided is a method of modulating TRPVl in a subject comprising administering to the subject at least one chemical entity described herein.
  • a packaged pharmaceutical formulation comprising a
  • composition described herein and instructions for using the composition to treat a mammal.
  • a cosmetic composition comprising a cosmetically effective amount of at least one cehmical entity described herein, and at least one cosmetically acceptable carrier.
  • TRPVl Transient Receptor .Potential Vanilloid type I receptor. Unless otherwise specified, these terms encompass both rat and human TRPVl receptors (e.g., GenBank
  • a “TRPVl modulator,” also referred to herein as a “modulator,” is a compound that modulates TRPVl activation and/or TRPVl -mediated signal transduction.
  • a TRPVl modulator may be a TRPVl agonist, antagonist, inverse agonist or a positive or negative allosteric modulator.
  • a modulator is considered an "antagonist" if it detectably inhibits vanilloid ligand binding to TRPVl and/or TRPVl -mediated signal transduction; in general, such an antagonist inhibits TRPVl activation with a IC 50 value of less than 100 micromolar within the assay provided in Example 3.
  • TRPVl antagonists include neutral antagonists, inverse agonists and negative allosteric modulators, hi certain embodiments, capsaicin receptor antagonists provided herein are not vanilloids.
  • An "inverse agonist" of TRPVl is a compound that reduces the activity of TRPVl below its basal activity level in the absence of added vanilloid ligand. Inverse agonists of TRPVl may also inhibit the activity of vanilloid ligand at TRPVl, and/or may also inhibit binding of vanilloid ligand to TRPVl. The ability of a compound to inhibit the binding of vanilloid ligand to TRPVl may be measured by a binding assay. The basal activity of TRPVI, as well as the reduction in TRPVl activity due to the presence of TRPVl antagonist, may be determined from a calcium mobilization assay.
  • a "neutral antagonist" of TRPVl is a compound that inhibits the activity of vanilloid ligand at TRPVl, but does not significantly change the basal activity of the receptor (i.e., within a calcium mobilization assay performed in the absence of vanilloid ligand, TRPVl activity is reduced by no more than 10%, in some embodiments, by no more than 5%, for example, by no more than 2%; and in some embodiments, there is no detectable reduction in activity).
  • Neutral antagonists of TRPVl may inhibit the binding of vanilloid ligand to TRPVl.
  • a "capsaicin receptor agonist” or “TRPVl agonist” or a “TRPVl positive allosteric modulator” is a compound that elevates the activity of the receptor above the basal activity level of the receptor (i.e., enhances TRPVl activation and/or TRPVl -mediated signal transduction).
  • such an agonist has an EC 50 value of less than 100 micromolar within the assay provided in Example 3.
  • capsaicin receptor agonists provided herein are not vanilloids.
  • a vanilloid is capsaicin or any capsaicin analogue that comprises a phenyl ring with two oxygen atoms bound to adjacent ring carbon atoms (one of which carbon atom is located para to the point of attachment of a third moiety that is bound to the phenyl ring).
  • a vanilloid is a "vanilloid ligand” if it binds to TRPVl.
  • Vanilloid ligand agonists include capsaicin, olvanil, N-arachidonoyl-dopamine and resiniferatoxin (RTX).
  • Vanilloid ligand antagonists include capsazepine and iodo-resiniferatoxin.
  • a "capsaicin receptor modulatory amount” is an amount that, upon administration to a patient, achieves a concentration of TRPVl modulator at a capsaicin receptor within the patient that is sufficient to alter the binding of vanilloid ligand to TRPVl in vitro and/or TRPVl- mediated signal transduction.
  • the capsaicin receptor may be present, or example, in a body fluid such as blood, plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid, tears or urine.
  • Alkyl encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms.
  • C t -C 6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3- hexyl, 3-methyIpentyl, and the like.
  • Alkylene is another subset of alkyl, referring to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms.
  • Co alkylene indicates a covalent bond and Ci alkylene is a methylene group.
  • alkyl residue having a specific number of carbons is named, all geometric combinations having that number of carbons are intended to be encompassed; thus, for example, "butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; "propyl” includes n-propyl and isopropyl.
  • “Lower alkyl” refers to alkyl groups having one to four carbons.
  • alkenyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group maybe in either the cis or trans configuration about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl;
  • propenyls such as prop-1-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-1-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl; and the like.
  • an alkenyl group has from 2 to 20 carbon atoms and in other
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-l-yl, prop-2-yn-l-yl; butynyls such as but-1-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl; and the like.
  • an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms.
  • Cycloalkyl indicates a non-aromatic carbocyclic ring, usually having from 3 to
  • ring carbon atoms 7 ring carbon atoms.
  • the ring may be saturated or have one or more carbon-carbon double bonds.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
  • alkoxy is meant an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge. "Lower alkoxy” refers to alkoxy groups having one to four carbons.
  • R a and Rb are independently chosen from hydrogen and alkyl groups of the indicated number of carbon atoms, provided that R 3 and R b are not both hydrogen.
  • Acyl refers to the groups (alkyl)-C(O)-; (cycloalkyl)-C(O)-; (aryl)-C(O) -;
  • acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms.
  • a Cj-C 6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • amino is meant the group -NH 2 .
  • “Mono- and di-(alkyl)amino” encompasses secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl- amino.
  • aminocarbonyl refers to the group -CONR b R c , where
  • R b is chosen from H, optionally substituted C ⁇ -C ⁇ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted C1-C4 alkyl; or R b and R c taken together with the nitrogen to which they are bound, form an optionally substituted 5- to 7-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring;
  • each substituted group is independently substituted with one or more substituents independently selected from Ci-C 4 alky!, aryl, heteroaryl, aryl-Ci-C 4 alkyl-,
  • 6-membered carbocyclic aromatic rings for example, benzene
  • bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and
  • tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • aryl includes 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms chosen from N, O, and S.
  • bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • aryloxy refers to the group -O-aryl.
  • -R 8 , -OR b optionally substituted amino (including -NR c COR b , -NR 0 CO 2 R 3 , -NR c CONR b R c , - NR b C(NR c )NR b R c , -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R 15 ), aminocarbonyl (such as -CONR b R°), -OCOR b , -OCO 2 R 3 , -OCONRV, sulfanyl (such as SR b ), sulfinyl (such as —
  • R a is chosen from optionally substituted Cj-Cg alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • Rb is chosen from H, optionally substituted C1-C5 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted C1-C4 alkyl
  • Rb and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group; and where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from
  • -C(O)Ci-C 4 alkyl -C(O)C 1 -C 4 phenyl, -C(O)C 1 -C 4 haloalkyl, -OC(O)C 1 -C 4 alkyl, - SO 2 (C 1 -C 4 alkyl), -SO 2 (phenyl), -SO 2 (C 1 -C 4 haloalkyl), -SO 2 NH 2 , -SO 2 NH(C 1 -C 4 alkyl), -SO 2 NH(phenyl), -NHSO 2 (C 1 -C 4 alkyl), -NHSO 2 (phenyl), and -NHSO 2 (C 1 -C 4 haloalkyl).
  • halo includes fluoro, chloro, bromo, and iodo
  • halogen includes fluorine, chlorine, bromine, and iodine
  • Haloalkyl indicates alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • Heteroaryl encompasses:
  • bicyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and
  • heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring.
  • bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at either ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3- ⁇ yridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5- pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "- idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O " ) substituents, such as pyridinyl N-oxides.
  • heterocycloalkyl is meant a single, non-aromatic ring, usually with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • the ring may be saturated or have one or more carbon-carbon double bonds.
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3- piperidyl, 4-piperidyl, and 2,5-piperizinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • oxo 0
  • oxide 1-oxo-l- thiomorpholinyl
  • 1,1-dioxo-l-thiomorpholinyl 1,1-dioxo-l-thiomorpholinyl.
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3
  • heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteratoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • modulation refers to a change in activity as a direct or indirect response to the presence of compounds of Formula I, relative to the activity of in the absence of the compound.
  • the change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the receptor, or due to the interaction of the compound with one or more other factors that in turn affect receptor activity.
  • the presence of the compound may, for example, increase or decrease receptor activity by directly binding to the receptor, by causing (directly or indirectly) another factor to increase or decrease the receptor activity, or by (directly or indirectly) increasing or decreasing the amount of receptor present in the cell or organism.
  • sulfanyl includes the groups: -S-(optionally substituted (Ci-C 6 )alkyl),
  • sulfanyl includes the group Ci-Ce alkylsulfanyl.
  • sulfinyl includes the groups: -S(O)-(optionally substituted (Ci-
  • sulfonyl includes the groups: -S( ⁇ 2)-(optionally substituted (Q-
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • alkoxycarbonyl such as -C ⁇ 2 R b
  • aminocarbonyl such as
  • R a is chosen from optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is chosen from hydrogen, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R° is independently chosen from hydrogen and optionally substituted C 1 -C 4 alkyl
  • R b andR c and the nitrogen to which they are attached, form an optionally substituted
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Cj-C 4 alkyl-, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl,
  • -OC 1 -C 4 alkylphenyl -Ci-C 4 alkyl-OH, -OCi-C 4 haloalkyl, halo, -OH, -NH 2 , -Cj-C 4 alkyl-NH 2 , -N(C-C 4 alkyl)(C,-C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(Ci-C 4 alkyl)(C r C 4 alkylphenyl), -NH(Cj-C 4 alkylphenyl), cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or heteroaryl), -CO 2 H, -C(O)OCi-C 4 alkyl, -CON(CrC 4 alkyl)(Ci-C 4 alkyl), -CONH(Ci-C 4 alkyl), -CONH 2 , -NH
  • substituted acyl refers to the groups (substituted alkyl)-C(O)-;
  • substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • -R a -OR b
  • optionally substituted amino including -NR c COR b , -NR 0 CO 2 R 8 , -NR°CONR b R c , - NR ⁇ (NR 0 JNR 15 R 0 , -NR b C(NCN)NR b R c , and -NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -C0R b ), optionally substituted alkoxycarbonyl (such as -CO 2 R b ), aminocarbonyl (such as -CONR b R°), -OCOR b , -OCO 2 R 8 , -OCONR 15 R 0 , sulfanyl (such as SR b ), sulfinyl (
  • R a is chosen from optionally substituted Ci-C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R b is chosen from H, optionally substituted Cj-C ⁇ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted Ci-C 4 alkyl; or
  • R b andR c and the nitrogen to which they are attached, form an optionally substituted
  • heterocycloalkyl group where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from Ci-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C 4 alkyl-, Ci-C 4 haloalkyl, -OCj -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -OCi-C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(CrC 4 B ⁇ yI)(C 1 -C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(C 1 -C 4 alkylXC-Q alkylphenyl),
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., -O-(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently chosen from:
  • -R a , -OR b optionally substituted amino (including -NR c COR b , -NR 0 CO 2 R 3 , -NR c CONR b R c , - NR b C(NR c )NR b R°, -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R b ), aminocarbonyl (such as -CONR b R c ), -OCOR b , -OCO 2 R 3 , -OCONR 13 R 0 , sulfanyl (such as SR b ), sulfin
  • R a is chosen from optionally substituted C 1 -Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R b is chosen from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R° is independently chosen from hydrogen and optionally substituted CpC 4 alkyl
  • R b andR c and the nitrogen to which they are attached, form an optionally substituted
  • heterocycloalkyl group where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C]-C 4 alkyl-, heteroaryl-C]-C 4 alkyl-, C 1 -C 4 haloalkyl, -OCj-C 4 alkyl, -OC 1 -C 4 alkylphenyl, -C 1 -C 4 alkyl-OH, -OC r C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(Ci-C 4 alkyl)(C r C 4 alkyl), -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl)(Ci-C 4 alkylphenyl),
  • a substituted alkoxy group is "polyalkoxy" or -O-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as -OCH2CH 2 OCH 3 , and residues of glycol ethers such as polyethyleneglycol, and -0(CH 2 CH 2 O) x CH 3 , where x is an integer of 2-20, such as 2-10, and for example, 2-5.
  • Another substituted alkoxy group is hydroxyalkoxy or -OCH 2 (CH 2 ) y OH, where y is an integer of 1-10, such as 1-4.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O-
  • -R a , -OR b optionally substituted amino (including -NR°COR b , -NR c CO 2 R a , -NR 0 CONR 13 R 0 , - NR b C(NR c )NR b R c , -NR b C(NCN)NR b R c , and -NR 0 SO 2 R 3 ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl, heterocycloalkyl, and heteroaryl), optionally substituted acyl (such as -COR b ), optionally substituted alkoxycarbonyl (such as -CO 2 R b ), aminocarbonyl (such as -CONR b R c ), -OCOR b , -OCO 2 R 8 , -OCONR b R c , sulfanyl (such as SR b ), sulf
  • R a is chosen from optionally substituted Ci-Ce alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R b is chosen from H, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b andR c and the nitrogen to which they are attached, form an optionally substituted
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 alkyl-, heteroaryl-Ci-C4 alkyl-, Ct-C 4 haloalkyl, -OC1-C4 alkyl, -OC 1 -C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -OC 1 -C 4 haloalkyl, halo, -OH, -NH 2 , -C 1 -C 4 alkyl-NH 2 , -N(C 1 -C 4 alkyl)(C r C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(CpC 4 alkyl)(Ci-C 4 alkylphenyl),
  • substituted amino refers to the group -NHR d or -NR d R e wherein R d is chosen from: hydroxy, optionally substitued alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycl ⁇ alkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R e is chosen from: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl,
  • R a is chosen from optionally substituted Ci-C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl
  • R b is chosen from H, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently chosen from hydrogen and optionally substituted C1-C4 alkyl
  • R b andR c and the nitrogen to which they are attached, form an optionally substituted
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C4 alkyl, aryl, heteroaryl, 3TyI-Q-C 4 alkyl-, heteroaryl-Cj-G t alkyl-, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 alkylphenyl, -Ci-C 4 alkyl-OH, -OCi -C 4 haloalkyl, halo, -OH, -NH 2 , -Ci-C 4 alkyl-NH 2 , -N(Ci-C 4 alkyl)(C,-C 4 alkyl), -NH(C 1 -C 4 alkyl), -N(Ci-C 4 alkyl)(C,-C 4 alkylphenyl),
  • substituted amino also refers to N-oxides of the groups -NHR d .
  • N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • the person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
  • Compounds of Formula I include, but are not limited to, optical isomers of compounds of Formula I, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers, i.e., optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • compounds of Formula I include Z- and E- forms (or cis- and trans- forms) of compounds with carbon-carbon double bonds. Where compounds of Formula I exists in various tautomeric forms, chemical entities of the present invention include all tautomeric forms of the compound.
  • Chemical entities of the present invention include, but are not limited to compounds of Formula I and all pharmaceutically acceptable forms thereof.
  • Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • Cosmetically acceptable forms of the compounds receited herein include cosmetically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • the compounds described herein are in the form of pharmaceutically or cosmetically acceptable salts.
  • the terms "chemical entity” and “chemical entities” also encompass salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures.
  • “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • Cosmetic refers to articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance.
  • Cosmetic refers to articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance.
  • Cosmetically acceptable refers to generally recognized as suitable for use for cosmetic purposes for humans, see, for example, International Cosmetic Ingredient Dictionary, published by the Cosmetic, Toiletry, and Fragrance Association, Inc.
  • Cosmetically acceptable carrier refers to any substantially non-toxic carrier conventionally useable for topical administration of cosmetics in which the compositions will remain stable and bioavailable when applied directly to the skin surface.
  • Suitable cosmetically acceptable carriers include, but are not limited to, cosmetically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundation creams, suntan lotions, sunscreens, hand lotions, make-up and make-up bases, masks and the like.
  • Cosmetically acceptable salt refers to a salt of a compound that is cosmetically acceptable and that possesses the desired activity of the parent compound.
  • cosmetically acceptable salts are those with therapeutically acceptable organic acids, e.g., acetic, palmitic, oleic, stearic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, or pamoic acid, as well as polymeric acids such as tannic acid or
  • carboxymethyl cellulose and salts with inorganic acids such as the hydrohalic acids (e.g., hydrochloric acid), sulfuric acid or phosphoric acid.
  • cosmetically effective amount of a chemical entity of this invention means an amount effective, when administered to a human, to provide a cosmetic benefit and includes an amount whereby the subject's skin is cosmetically treated
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid,
  • cyclopentanepropionic acid glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
  • ethanesulfonic acid 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • “Pharmaceutically acceptable excipient, carrier or adjuvant” refers to an excipient, carrier or adjuvant that can be administered to a subject, together with at least one chemical entity of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which at least one chemical entity of the present disclosure is administered.
  • Promoiety refers to a form of protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug.
  • the promoiety can be attached to the drug via bond(s) that are cleaved by enzymatic or non- enzymatic means in vivo.
  • prodrugs also fall within the scope of chemical entities, for example ester or amide derivatives of the compounds of Formula I.
  • Prodrug refers to a derivative of a therapeutically effective compound that requires a transformation within the body to produce the therapeutically effective compound.
  • Prodrugs can be pharmacologically inactive until converted to the parent compound. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I.
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry,” (Wiley, 2 nd ed. 1991) and Harrison et al., “Compendium of Synthetic Organic Methods,” VoIs. 1-8 (John Wiley and Sons, 1971-1996).
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ”), tert-butoxycarbonyl
  • hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and aliyl ethers.
  • solvate refers to the chemical entity formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
  • chelate refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
  • non-covalent complex refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • active agent is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pharmaceutical utility.
  • significant is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • a therapeutically effective amount of a chemical entity of this invention means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease e.g., a therapeutically effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to modulation of TRPVl.
  • Disease refers to any disease, disorder, condition, symptom, or indication.
  • Extended release refers to dosage forms that provide for the delayed, slowed, over a period of time, continuous, discontinuous, or sustained release of the chemical entities of the present disclosure.
  • the term “inhibition” indicates a significant decrease in the baseline activity of a biological activity or process.
  • Treatment means any treatment of a disease in a patient, including: a) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;
  • Patient refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment.
  • the methods of the invention can be useful in both human therapy and veterinary applications.
  • the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is chosen from cats and dogs.
  • Subject includes mammals, such as humans.
  • human and “subject” are used interchangeably herein.
  • R 1 is independently chosen from sulfonyl, nitro, halo, optionally substituted acyl, optionally s ⁇ btituted amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • n 0, 1, 2, and 3;
  • R is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl
  • R 3 and R 4 are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R 5 is independently chosen from sulfonyl, nitro, halo, optionally substituted acyl, optionally substituted amino, hydroxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; and
  • n is chosen from 0, 1, 2, and 3
  • R 1 is independently chosen from halo, optionally substituted acyl, optionally substituted amino, hydroxy, optionally substituted alkoxy, and optionally substituted alkyl. In certain embodiments, R 1 is independently chosen from halo, optionally substituted acyl, hydroxy, optionally substituted lower alkoxy, and optionally substituted lower alkyl.
  • m is 1.
  • m is 0.
  • R 2 is chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments, R 2 is chosen from hydrogen and lower alkyl. In certain embodiments, R 2 is chosen from lower alkyl. In certain embodiments, R 2 is methyl.
  • R 3 and R 4 are independently chosen from hydrogen and optionally substituted lower alkyl. In certain embodiments, R 3 and R 4 are independently chosen from hydrogen and lower alkyl. In certain embodiments, R 3 and R 4 are independently chosen from hydrogen and methyl.
  • R 5 is independently chosen from halo, optionally substituted acyl, optionally substituted amino, hydroxy, optionally substituted alkoxy, and optionally substituted alkyl.
  • R 5 is independently chosen from halo, optionally substituted acyl, optionally substituted amino, hydroxy, optionally substituted lower alkoxy, and optionally substituted lower alkyl.
  • m is 1.
  • m is 0.
  • the methods described herein comprise administering at least one chemical entity chosen from
  • Chemical entities of the present disclosure can be prepared by methods well known in the art. Chemical entities of the present disclosure can be prepared from readily available starting materials using the flowing general methods and procedures. It will be appreciated that where typical or preferred process conditions, such as, reaction temperatures, times, mole ratios of reactants, solvents, pressures, are given, other process conditions can also be used unless otherwise stated. Reaction conditions may vary with the reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • stereoisomers of the present disclosure can contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers, and enriched mixtures thereof, are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers, and enriched mixtures thereof, can be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • chemical entities of the present disclosure exhibit TRPVl modulating activity.
  • one use of the chemical entities of the present present disclosure includes the administration of at least one chemical entity of the present disclosure to a subject, such as a human. This administration serves to arrest, ameliorate, reduce the risk of acquiring, reduce the development of or at least one of the clinical symptoms of, or reduce the risk of developing or at least one of the clinical symptoms of diseases or conditions regulated by TRPVl.
  • the present disclosure relates to methods of treating a disease regulated by TRPVl in a subject.
  • diseases or disorders that are known or believed to be regulated by TRPVl include:
  • Pain including action on small sensory nerve fibers to inhibit, counteract, mask, attenuate or otherwise reduce the activation, transmission, or integration of the neuronal signal for somatic, visceral and neuropathic pain, such as nociceptive pain, neurogenic pain, pain associated with chronic peripheral polyneuropathy, neuropathic pain, postmastectomy pain syndrome, stump pain after amputation, phantom limb pain, oral neuropathic pain, toothache, postherpetic neuralgia, pain associated with diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, fibromyalgia, pain associated with Guillai ⁇ -Barre syndrome, Charcot's pain, Crohn's Disease, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causal gia, neuritis, neuronitis, neuralgia, AIDS-related neuropathy, MS-related neuropat
  • A.delta. sensory nerves and epithelium in the bladder and ureter such as bladder overactivity, hyperactive urinary bladder, hypersensitive urinary bladder, interstitial cystitis, painful bladder disorders, and urinary incontinence.
  • Obstructive Breathing Disorders including action on the sensory nerves that mediate the sensations of breathing disorders, for example to cause refreshed breathing, less sneezing and throat irritation, less cough, decreased inspiratory effort, and relief of dyspnea, for example, the treatment of cough, hiccup, bronchial asthma, or chronic obstructive pulmonary disease.
  • Bowel Dysfunction including counteracting the pain and discomforts of gut discomfort and inflammation, for example, by reducing intestinal perception of noxious signals by blocking the afferent nerve receptors, for example, treating the symptoms of enteritis, colitis, and proctitis, caused by conditions such as irritable bowel disease, irritable bowel syndrome, intestinal gas, the side-effects of prostate brachytherapy, and other forms of gastrointestinal dysfunction.
  • Inflammatory disease or condition such as neurogenic inflammation, arthritis, gout, allergic and vasomotor rhinitis, eczema, urticaria or hives, and psoriasis; inflammatory thermal hyperalgesia
  • Allergy or autoimmune disease such as rheumatoid arthritis, conjunctivitis, rhinitis, sinusitis and otitis media with effusion.
  • noxious sensory disorders include, but are not limited to, heat exhaustion, the flushing sensations of menopause and fatigue.
  • TRPVl can be modulated by contact with at least one chemical entity of the present disclosure.
  • In vivo TRPVl can be modulated by administration through routes and using compositions comprising at least one chemical entity of the present disclosure.
  • contacting TRPVl with at least one chemical entity of the present disclosure can include, for example, combining liquid reagents or combining a reagent and TRPVl and/or chemical entityof the present disclosure attached to a solid support.
  • the TRPVl and at least one chemical entity of the present disclosure can be contacted in any appropriate device such as an affinity chromatography column, a microarray, a microfluidic device, assay plate, or other appropriate chemical or biotechnology apparatus used to perform biochemical analysis, assay, screening, and the like.
  • any appropriate device such as an affinity chromatography column, a microarray, a microfluidic device, assay plate, or other appropriate chemical or biotechnology apparatus used to perform biochemical analysis, assay, screening, and the like.
  • compositions of the present disclosure maybe administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, or by any other appropriate route.
  • compositions of the present disclosure can contain one or more pharmaceutically acceptable vehicles.
  • the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or the delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, interasynovial, intrasternal, interathecal, intralesional, and intracranial injection or infusion techniques.
  • compounds disclosed herein can be delivered orally.
  • Suitable dosage ranges for oral administration can depend on the potency of the compounds, but generally can range from 0.1 mg to 20 mg of a compound per kilogram of body weight.
  • Appropriate dosages can be in the range of 25 to 500 mg/day and the dose of compounds administered can be adjusted to provide an equivalent molar quantity of compound in the plasma of a subject. Dosage ranges can be readily determined by methods known to those skilled in the art.
  • a dosage can be delivered in a composition by a single administration, by multiple applications, by sustained release or by controlled sustained release, or any other appropriate intervals and/or rates of release.
  • Chemical entities of the present disclosure can be assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity prior to therapeutic use in mammals.
  • in vitro assays can be used to determine whether administration of a specific chemical entity of the present disclosure or a combination of such chemical entities is effective for modulating the activity of TRPVl or treating at least one disease.
  • Chemical entities of the present disclosure can also be demonstrated to be effective and safe using animal model systems.
  • a therapeutically effective dose of at least one chemical entity of the present disclosure can, in certain embodiments, provide therapeutic benefit without causing substantial toxicity.
  • Toxicity of chemical entities of the present disclosure can be determined using standard pharmaceutical procedures and can be readily ascertained by the skilled artisan.
  • the dose ratio between toxic and therapeutic effect is the therapeutic index.
  • Chemical entities of the present disclosure can exhibit high therapeutic indices in treating diseases and disorders.
  • the dosage of a compound of the present present disclosure can be within a range of circulating concentrations that include an effective dose with little or no toxicity.
  • compositions When employed as pharmaceuticals, chemical entities of the present disclosure can be administered in the form of pharmaceutical compositions.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and can comprise at least one chemical entity of the present disclosure.
  • compositions of the present disclosure can comprise a
  • compositions of the present disclosure can additionally comprise at least addional compound that enhances the therapeutic efficacy of one or more chemical entities of the present disclosure. For example, such compounds
  • compounds can enhance the therapeutic efficacy of chemical entities of the present disclosure by effectively increasing the plasma concentration of the compounds.
  • certain compound can decrease the degradation of the chemical entities of the present disclosure prior to administration or during transport to the plasma, or within the plasma.
  • compositions of the present disclosure can also include additional therapeutic agents that are normally administered to treat a disease or disorder.
  • a pharmaceutical composition can include at least one chemical entity of the present disclosure and at least one additional therapeutic agent appropriate for effecting combination therapy.
  • compositions of the present disclosure can be administered by oral routes.
  • the compositions can be prepared in a manner well known in the pharmaceutical art and can comprise at least one chemical entity of the present disclosure.
  • compositions of the present disclosure contain a therapeutically effective amount of at least one chemical entity of the present disclosure, which can be in purified form, together with a therapeutically effective amount of at least one additional therapeutic agent, and a suitable amount of at least one pharmaceutically acceptable excipient, so as to provide the form for proper administration to a subject
  • compositions that contain, as the active ingredient, of one or more chemical entities of the present disclosure associated with pharmaceutically acceptable excipients.
  • the active ingredient can be mixed with an excipient, diluted by an excipient, or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent
  • the excipient can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, and syrups containing, for example, from 1% to 90% by weight of at least one chemical entities of the present disclosure using, for example, soft and hard gelatin capsules.
  • the active compound In preparing a composition, it can be necessary to mill the active compound to provide the appropriate particle size prior to combining with other ingredients. If the active compound is insoluble, the active component ordinarily can be milled to a particle size of less than 200 rriesh. If the active compound is water soluble, the particle size can be adjusted by milling to provide a uniform distribution in the formulation, e.g. 40 mesh.
  • excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, modified
  • compositions of the present disclosure can additionally include, lubricating agents such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxy- benzoates, sweetening agents, and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propylhydroxy- benzoates
  • sweetening agents and flavoring agents.
  • Compositions of the present disclosure can 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.
  • Some compositions of the present disclosure can be formulated in unit dosage form, each dosage containing, for example, 0.1 mg to 2 g of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, diluent, carrier and/or adjuvant.
  • compositions of the present disclosure can be formulated in multiple dosage forms. The amount of the chemical entities of the present disclosure that can be combined with other materials and therapeutic agents to produce compositions of the present disclosure in a single dosage form will vary depending upon the subject and the particular mode of administration.
  • chemical entities of the present disclosure can be administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.
  • the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present present disclosure.
  • a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present present disclosure.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the solid preformulation can then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 mg to 2 g of the therapeutically effective compound of the present present disclosure.
  • the tablets or pills comprising certain compositions of the present disclosure can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • a "pharmaceutically acceptable derivative or prodrug” refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of the present disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure or an active metabolite or residue thereof.
  • derivates or prodrugs include those that increase the bioavailability of the chemical entities of the present disclosure when such compounds are administered to a mammal, e.g., by allowing an orally administered compound to be more readily absorbed into the blood, or which enhance delivery of the parent compound to a biological compartment, e.g., the brain or lymphatic system, relative to the parent species.
  • acceptable formulation materials can be nontoxic to recipients at the dosages and concentrations employed.
  • a pharmaceutical composition of the present disclosure can contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition.
  • suitable formulation materials include, but are not limited to, amino acids such as glycine, glutamine, asparagine, arginine or lysine; antimicrobials; antioxidants such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite; buffers such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids; bulking agents such as mannitol or glycine; chelating agents such as ethylenediamine tetraacetic acid (EDTA); complexing agents such as caffeine,
  • amino acids such as glycine, glutamine, asparagine, arginine or lysine
  • antimicrobials such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite
  • buffers such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organic acids
  • bulking agents such as mannitol or glycine
  • chelating agents such
  • polyvinylpyrrolidone beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutyl ether ⁇ - cyclodextrin; fillers; monosaccharides; disaccharides; and other carbohydrates such as glucose, mannose, or dextrins; proteins such as serum albumin, gelatin or immunoglobulins; coloring, flavoring and diluting agents; emulsifying agents; hydrophilic polymers such as
  • polyvinylpyrrolidone low molecular weight polypeptides
  • salt-forming counterfoils such as sodium
  • preservatives such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide
  • solvents such as glycerin, propylene glycol or polyethylene glycol
  • sugar alcohols such as mannitol or sorbitol
  • suspending agents surfactants or wetting agents such as pluronics, PEG, sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton, tromethamine, lecithin, cholesterol, tyloxapal
  • stability enhancing agents such as sucrose or sorbitol
  • tonicity enhancing agents such as alkali metal halides, such as sodium or potassium chloride, mannitol, sorbi
  • the optimal pharmaceutical composition can be determined by one skilled in the art depending upon, for example the intended route of administration, delivery format, and desired dosage. See, for example, Remington's
  • compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the antibodies of the present disclosure.
  • the primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature.
  • the primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature.
  • a suitable vehicle or carrier can be water for injection, physiological saline solution or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration.
  • neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • pharmaceutical compositions comprise Tris buffer of pH 7 to 8.5, or acetate buffer of pH 4 to 5.5, which can further comprise sorbitol or a suitable substitute thereof.
  • buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from 5 to 8.
  • compositions of the present disclosure can be selected for parenteral delivery.
  • compositions can be selected for inhalation or for delivery through the digestive tract, such as orally.
  • the preparation of such pharmaceutically acceptable compositions is within the skill of the art.
  • composition components can be present in
  • a therapeutic composition when parenteral administration is contemplated, can be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising at least one chemical entity of the present disclosure, with or without additional therapeutic agents, in a pharmaceutically acceptable vehicle.
  • a vehicle for parenteral injection can be sterile distilled water in which at least one chemical entity of the present disclosure, with or without at least one additional therapeutic agent, is formulated as a sterile, isotonic solution, properly preserved.
  • the pharmaceutical composition can include
  • implantable drug delivery devices can be used to introduce a compound of the present disclosure to the plasma of a subject, within a target organ, or to a specific site within the subject's body.
  • a pharmaceutical composition can be formulated for inhalation.
  • a compound of the present disclosure, with or without at least one additional therapeutic agent can be formulated as a dry powder for inhalation.
  • an inhalation solution comprising a compound of the present disclosure with or without at least one additional therapeutic agent can be formulated with a propellant for aerosol delivery.
  • solutions can be nebulized.
  • solutions, powders or dry films of chemical entities of the present disclosure can be aerosolized or vaporized for pulmonary delivery.
  • formulations can be administered orally.
  • a compound of the present disclosure, with or without at least one additional therapeutic agent that can be administered orally can be formulated with or without carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation in the region of the gastrointestinal tract where bioavailability can be maximized and pre-systemic degradation minimized.
  • At least one additional agent can be included in the formulation to facilitate absorption of the compound of the present disclosure and/or any additional therapeutic agents into the systemic circulation, hi certain embodiments, diluents, flavorings, low-melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can be employed.
  • a pharmaceutical composition of the present disclosure can include an effective quantity of chemical entities of the present disclosure, with or without at least one additional therapeutic agent, in a mixture with at least one pharmaceutically acceptable vehicle suitable for the manufacture of tablets.
  • suitable excipients include inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the frequency of dosing will take into account the pharmacokinetic parameters of the chemical entities of the present disclosure and/or any additional therapeutic agents in the pharmaceutical composition used.
  • a clinician can administer the composition until a dosage is reached that achieves the desired effect.
  • the composition can be administered as a single dose, or as two or more doses, which may or may not contain the same amount of the therapeutically active compound time, or as a continuous infusion via an implantation device or catheter. Further refinement of an appropriate dosage can be routinely made by those of ordinary skill in the art. For example, therapeutically effective amounts and regimens can be determined through use of appropriate dose-response data.
  • the route of administration of the pharmaceutical composition can be in accord with known methods, e.g. orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; by sustained release systems or by implantation devices.
  • the compositions can be administered by bolus injection or continuously by infusion, or by an implantation device.
  • the composition can be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired compound of the present disclosure has been absorbed or encapsulated.
  • the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule via diffusion, timed-release bolus, or continuous administration.
  • a pharmaceutical composition comprising a compound of the present disclosure, with or without at least one additional therapeutic agent, in an ex vivo manner.
  • cells, tissues and/or organs that have been removed from a subject are exposed to a pharmaceutical composition comprising a compound of the present disclosure, with or without at least one additional therapeutic agent, after which the cells, tissues and/or organs are subsequently implanted back into the subject.
  • compositions according to the present disclosure can take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • administration is topical to inflamed skin or mucous membranes, and the therapeutic effectiveness is in relieving itch, irritation or pain.
  • compositions of the present disclosure can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device can be accompanied by instructions for
  • the quantity of a compound of the present disclosure required for the treatment of a particular condition can vary depending on the compound, and the condition of the subject to be treated. In general, daily dosages can range from 100 ng/kg to 100 mg/kg, e.g., 0.01 mg/kg to
  • compositions of the present disclosure can be administered as sustained release systems.
  • the chemical entities of the present disclosure can be delivered by oral sustained release
  • the chemical entities of the present disclosure can be administered, for example, twice per day and, once per day.
  • sustained and/or extended release dosage forms include, but are not limited to, beads comprising a dissolution or diffusion release compositon and/or structure, an oral sustained release pump, enteric-coated preparations, compound-releaseing lipid matrices, compound releasing waxes, osmotic delivery systems, bioerodible polymer matrices, diffusible polymer matrices, a plurality of time-release pellets, and osmitic dosage forms.
  • sustained release oral dosage forms can provide a therapeutically effective amount of a compound of die present disclosure over a period of at least several hours.
  • the extended release dosage form can provide a constant therapeutically effective concentration of a compound of the present disclosure in the plasma of a subject for a prolonged period of time, such as at least several hours.
  • the sustained release oral dosage form can provide a controlled and constant concentration of a therapeutically effective amount of a compound of the present disclosure in the plasma of a subject.
  • Dosage forms comprising compositions and chemical entities of the present disclosure can be administered at certain intervals such as, for example, twice per day or once per day.
  • Exemplary dosage ranges for oral administration are dependent on the potency of the compound of the present disclosure, but can range from 0.1 mg to 20 mg of the compound per kilogram of body weight. Dosage ranges may be readily determined by methods known to those skilled in the art.
  • packaged pharmaceutical formulations include a pharmaceutical composition comprising at least one chemical entity of the present disclosure, and instructions for using the composition to treat a mammal (typically a human patient). In some embodiments, the instructions are for using the pharmaceutical composition to treat a patient suffering from a disease responsive to modulation of TRPVl .
  • prescribing information for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.
  • a cosmetic composition comprising a cosmetically effective amount of at least one chemical entity described herein and at least one cosmetically acceptable carrier.
  • the cosmetic composition is chosen from an after-sun product, a pre-shave product, an after-shave product, a pre-depilation product and an after-depilation product.
  • Chemical entities of the present disclosure can be assayed in vitro and in vivo, to determine and optimize therapeutic or prophylactic activity prior to use in subjects. For example, in vitro assays can be used to determine whether administration of a specific compound of the present disclosure or a combination of such compounds exhibits therapeutic efficacy. Chemical entities of the present disclosure can also be demonstrated to be effective and safe using animal model systems.
  • a therapeutically effective dose of a compound of the present disclosure provide therapeutic benefit without causing substantial toxicity.
  • Toxicity of chemical entities of the present disclosure can be determined using standard pharmaceutical procedures and can be readily ascertained by the skilled artisan.
  • the dose ratio between toxic and therapeutic effect is the therapeutic index, hi certain embodiments, chemical entities of the present disclosure can exhibit particularly high therapeutic indices in treating diseases and disorders.
  • the dosage of a compound of the present disclosure can be within a range of circulating concentration that exhibits therapeutic efficacy with limited or no toxicity. Examples
  • MS ions were detected using a Sciex API-100 electrospray single quadrupole mass spectrometer interfaced to the HPLC system.
  • TRPVl mammalian expression system A variety of molecular engineering strategies can be employed to express functional TRPVl protein in mammalian cell systems.
  • the gene encoding human TRPVl (GenBank Accession No. AF196175) was subcloned into a suitable vector to generate BacMam virus that was subsequently used to infect HEK293 cells (also expressing the Ebstein Barr Virus Nuclear Antigen or EBNA) to induce expression of constitutively active human TRPVl protein.
  • HEK293/EBNA cells were cultured in Dulbecco's Modified Eagle Medium
  • Cells were washed twice in a balanced salt solution of the following composition with supplements (final concentrations): NaCl (135 mM), MgCl 2 (1-0 mM), KCl (5.0 mM), HEPES (15.0 mM), glucose (10.0 mM), probenecid (5.0 ⁇ M), and Pluronic F-68 (0.1%, v:v), pH 7.4. Cells were resuspended at 5 x 10 6 cells/ml in the above balanced salt solution supplemented further with Optiprep (3.0 %, v:v) and DMSO (1.0%, v:v).
  • Caliper 250 assay Two hundred ⁇ l of dye-loaded cells were added to the appropriate wells of a Caliper 418D (calcium antagonist assay) microfluidic chip. 'Agonist wells' contained cell resuspension buffer supplemented with CaCl 2 (20.0 mM) in the absence or presence of capsaicin (500 nM). The 'waste wells' contained 50 ⁇ l of cell resuspension buffer supplemented with additional Optiprep (6.0%, v:v). Caliper 250 settings follow:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur des entités chimiques choisies parmi des composés de formule (I) et sur des sels acceptables d'un point de vue pharmaceutique ou cosmétique, des solvates, des chélates, des complexes non covalents, des promédicaments et des mélanges de ceux-ci. Les entités chimiques modulent TRPV1 et sont utiles dans le traitement d'au moins une maladie ou trouble modulé par l'activité de TRPV1.
PCT/US2006/047002 2005-12-08 2006-12-05 Certains types d'entites chimiques, compositions et methode de modulation de trpv1 WO2007067756A2 (fr)

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Cited By (4)

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US7943666B2 (en) 2006-07-24 2011-05-17 Trinity Laboratories, Inc. Esters of capsaicin for treating pain
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
US9187464B2 (en) 2011-06-17 2015-11-17 Glaxosmithkline Intellectual Property (No. 2) Limited TRPV4 antagonists

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7943666B2 (en) 2006-07-24 2011-05-17 Trinity Laboratories, Inc. Esters of capsaicin for treating pain
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
US8691855B2 (en) 2008-07-02 2014-04-08 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist and pharmaceutical compositions containing the same
US9187464B2 (en) 2011-06-17 2015-11-17 Glaxosmithkline Intellectual Property (No. 2) Limited TRPV4 antagonists

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