WO2007101007A2 - Aryl sulfonyl heterocycles - Google Patents

Aryl sulfonyl heterocycles Download PDF

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WO2007101007A2
WO2007101007A2 PCT/US2007/062406 US2007062406W WO2007101007A2 WO 2007101007 A2 WO2007101007 A2 WO 2007101007A2 US 2007062406 W US2007062406 W US 2007062406W WO 2007101007 A2 WO2007101007 A2 WO 2007101007A2
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compound
alkyl
salt
hydrate according
hydroxy
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WO2007101007A3 (en
WO2007101007A8 (en
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John M. Peterson
Guiying Li
David C. Ihle
Kevin J. Hodgetts
Qin Guo
Ping Ge
Alan J. Hutchison
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Neurogen Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/22—Eight-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This invention relates generally to aryl sulfonyl heterocycles, and to the use of such compounds to treat conditions responsive to bradykinin receptor-1 (B]) modulation.
  • the invention further relates to the use of such compounds as reagents for the identification of other agents that bind to B], and as probes for the detection and localization of Bj.
  • Nonsteroidal anti-inflammatory drugs are only moderately effective against pain, and have serious renal and gastrointestinal side effects at high doses.
  • Opiates, such as morphine are potent analgesics, but their usefulness is limited because of adverse side effects, such as physical addictiveness and withdrawal properties, as well as respiratory depression, mood changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting, and alterations in the endocrine and autonomic nervous systems. There is thus a need for effective agents for the treatment of pain.
  • Bradykinin is a nonapeptide that functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and pain.
  • the effects of BK are mediated by specific G protein-coupled BK receptors, of which there are at least two distinct subtypes termed B
  • the B 2 receptor is expressed constitutive Iy in a variety of tissues.
  • the Bi receptor is inducibly expressed in response to pathophysiological conditions such as inflammation, pain, trauma, bacterial infection, burns and shock. Accordingly, Bi is a particularly attractive drug target for these and other conditions, and agents that act at this receptor may be targeted specifically to injured tissues, with minimal effects in norma! tissues.
  • compounds that bind Lo Bi and/or modulate the activity of Bi also find use as research tools.
  • the present invention provides aryl sulfonyl heterocycles that satisfy Formula I, or are a pharmaceutically acceptable salt, solvate or ester of such a compound: O Formula I
  • n is O or 1; if n is 0, then m is 1 and q is O or 1 ; if n is 1, then either (i) m is 1 and q is 1 or 2 or (i) q is 1 and m is 1 or 2; X is NR 3 , O, S, SO or SO 3 ;
  • R 1 represents from O to 5 ring substituents; preferably such substituents are independently chosen from:
  • R 2 represents from O to 4 substituents; preferably any such substituents are independently chosen from oxo, hydroxy and C[-C 3 alkyl;
  • R 3 is hydrogen or a substituent such as CrCsalkyl or CpCgalkanoyl; Rio is hydrogen or a substituent such as Ci-Gjalkyl;
  • R A is hydrogen or a substituent such as d-C ⁇ alkyl, C 2 -C ⁇ alkenyl, C 2 -C 6 alkynyl, (C 3 -Cscycloalkyl)C 0 - C 4 alkyl, Co-C-ealkyl ether, or mono- or each of which is optionally substituted with hydroxy, amino or oxo; and
  • R B is a substituent such as C,-C ⁇ alkyl, Ca-Qalkenyl, C 2 -C 6 alkyriyl, (C 3 -C 3 cyc!oalkyl)Co-C 4 a]kyJ, C 2 - C ⁇ alkyl ether, mono- or di-(CrC6alkyl)aminoCi-C 4 alkyl 3 or (4- to 7-membered heterocyc!oalkyl)Co-C 4 alkyl.
  • each of whicli is optionally substituted and each of which is preferably substituted with from 0 to 6 substituents independently chosen from: (i) amino, halogen, hydroxy, cyano and oxo; and
  • substituents that are taken together to form a spiro C ⁇ Ciocarbocycle or a spiro 4- to 10- mcr ⁇ bercd hetcrocyclc; each of which (ii) and (iii) is optionally substituted and is preferably substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, oxo, cyano, Ci-C ⁇ alkyl, C]-C 6 a1koxy, (C 3 -Ci 0 carbocycle)Co-C4aIkyl and (4- to l ⁇ -membered heterocycle)C ⁇ >-C 4 alkyI.
  • aiyl sulfony! heterocycles of Formula 1 further satisfy formula 11:
  • aryl sulfonyl heterocycles of Formula 1, and other Formulas provided herein are B 1 modulators and exhibit a K,- of no greater than 5 micrornolar, 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in me B 1 binding assay provided in Example 6, herein, and/or have an EC 5 ⁇ > or IC 5 0 value of no greater than 5 micromolar, 2 micromolar, 1 micromolar, 500 nanomolar, ⁇ G0 nanomolar, 50 nanomolar or i0 nanomolar in an assay for determination of B3 agonist or antagonist activity as provided in Example 7, herein.
  • aryl sulfonyl heterocycles of Formula I are B] antagonists; preferably such antagonists exhibit no detectable B 1 agonist activity.
  • aryl sulfonyl heterocycles of Formula I are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).
  • a detectable marker e.g., radiolabeled or fluorescein conjugated
  • the present invention further provides, within other aspects, pharmaceutical compositions comprising at least one aryl sulfonyl heterocycle of Formula I in combination with a physiologically acceptable carrier or excipie ⁇ t.
  • Methods are further provided for inhibiting agonist-induced B 1 activity.
  • the inhibition takes place in vitro.
  • Such methods comprise contacting a Bi receptor with at least one Bj antagonist as described herein;, under conditions and in an amount or concentration sufficient to detectably inhibit agonist-induced B 1 activity.
  • the Bj receptor is in a patient.
  • Such methods comprise contacting cells expressing a Bi receptor in a patient with at least one B] antagonist as described herein in an amount or concentration that would be sufficient to detectably inhibit agonist-induced Bi activity in cells expressing a cloned Bi receptor in vitro.
  • the present invention further provides methods for treating a condition responsive to Bi receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one aryl sulfonyl heterocycle of Formula I.
  • methods for treating pain in a patient, comprising administering to a patient suffering from (or at risk for) pain a therapeutically effective amount of at least one aryl sulfonyl heterocycle of Formula I.
  • Pain conditions that may be treated include, but are not limited to, inflammatory pain, acute pain, dental pain, back pain, surgical pain, headache, neuropathic pain, and pain associated with osteoarthritis or trauma.
  • the present invention provides methods for determining the presence or absence of Bi in a sample, comprising: (a) contacting a sample with an aryl sulfonyl heterocycle of Formula I under conditions that permit binding of the compound to Bi; and (b) detecting a signal indicative of a level of the compound bound to Bt-
  • the present invention provides methods of preparing the compounds disclosed herein, including the intermediates.
  • the present invention provides aryl sulfonyl heterocycles. Such compounds may be used in vitro or in vivo in a variety of contexts, as described herein.
  • aryl sulfonyl heterocycles encompasses all compounds of Formula I, and includes pharmaceutically acceptable salts, solvates and esters of such compounds.
  • a “pharmaceutically acceptable salt” of a compound recited herein is an acid or base salt that is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Specific pharmaceutically acceptable anions for use in salt formation include, but are not limited to, acetate, 2-acetoxybenzoate, ascorbate, benzoate, bicarbonate, b ⁇ tartrate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochloride, diphosphate, edetate, estoiate (ethylsuccinate), formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glyco ⁇ ylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate,
  • pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaiue, choline, diethanolamine, ethylenediamine, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile, is preferred.
  • nonaqueous media such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile
  • prodrugs of the compounds provided herein are a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group mat, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, or sulfhydryl group, respectively-
  • Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon.
  • Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-Cgftlkyl), from 1 to 6 carbon atoms (C ⁇ -C 6 alky!) and from I to 4 carbon atoms (Ci-C 4 alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, / ⁇ ?r/-buryl, pentyl, 2-pentyI, isopentyl, neopentyl, hexyl, 2-hexy!, 3-hexyl or 3-methylpentyI.
  • Co-C4alkyl refers to a single covalent bond (Co) or an alkylene group having 1, 2. 3 or 4 carbon atoms;
  • Co-C ⁇ alkyl refers to a single covalent bond or a CrQalkylene group.
  • Alkylene refers to a divalent alkyl group, as defined above.
  • C]-C 4 alkylene js an alkylene group having 1 , 2, 3 or 4 carbon atoms.
  • Alken ⁇ yl refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include Co-Cgalkenyl, Co-Cgalkenyl and Ca-
  • Alkynyl refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include
  • C 2 -C 8 alkynyl, C 2 -C ⁇ alkynyl and Ci-Qalkynyl groups which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • a “cycloaikyl” is a saturated or partially saturated cyclic group in which all ring members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and partially saturated variants thereof. Certain cycloaikyl groups are C 3 -C 8 cycloalkyl, in which the ring contains from 3 to S ring members, all of which are carbon.
  • a "(C 3 -CscycloalkyI)C 0 -C 4 alkyl” is a C 3 -C fi cyc!oall ⁇ vl group linked via a single covalent bond or a C]-C 4 alkylene group.
  • alkoxy is meant an alkyl group attached via an oxygen bridge.
  • Alkoxy groups include C
  • 2-penloxy, 3-pentoxy isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy are representative alkoxy groups.
  • alkylthio refers to an alkyl group as attached via a sulfur bridge (i.e., — S— alkyl).
  • Alkyithio groups include Ci-C 6 alkylthio and Q-C t alkylthio groups, which have from 1 to 6 or from i to 4 carbon atoms, respectively.
  • Alkylsulfinyl refers to groups of the formula -(SO)-alkyi, in which the sulfur atom is the point of attachment AIkyisulfinyI groups include Ci-C & alkylsulfmy] and CrQalkylsulfmyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • Alkylsulfonyl refers to groups of the formula -(S ⁇ 2 >-alkyl, in which the sulfur atom is the point of attachment Alkyisulfony! groups include Ci-Qjalkylsulfonyl and CrQalkyfsulfonyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms.
  • Alkanoyl groups include, for example, Cj- C s alkanoyl, Cj-Qalkanoyl and d-Gjalkanoyl groups, which have from 1 to 8, from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • alkyi ether refers to a linear or branched ether substituent Alkyl ether groups include C 2 -C 8 alkyl ether, C 2 -C 6 alkyl ether and ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively, A C 2 alkyl ether lias the structure -CHr-O-CH 3 .
  • Alkoxycarbonyl groups include C 1 -C 8 , Ci-Cj and C r Qalkoxycarbonyl groups, which have from I to S, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group.
  • alkylamino refers to a secondary or tertiary amine that has the general structure - " NH-aikyl or -N(alky!(alkyl), wherein each alky! is selected independently from alkyl, cycloalkyl and
  • (cycloalkyl)aikyl groups include, for example, mono- and di-(Ci-C8alky3)amino groups, in which each C
  • Alkylaminoalkyl refers to an alkyfamino group linked via an alky ⁇ ene group (;. ⁇ ? consult a group having the general structure -alkylene— NH-aikyl or -alkyiene-N(alkyl)(alkyl)) in which each alkyl is selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups.
  • Alkylaminoalkyl groups inc ⁇ ude for example, mono- and ⁇ i-(C i-C 3 alkyl)aminoC]-C 6 alkyl, mono- and di-(Cj- C 6 aIkyI)aminoC
  • "Mono- or di-(Cj- C6alkyl)aminoCo-C 4 alkyl” refers to a mono- or di-(C]-C6alkyl)amino group linked via a single covalent bond or a C r Qalkyiene group.
  • alkyl as used in the terms “alkylamino” and “alkylaminoalkyi” differs from the definition of "alkyf” used for all other a ⁇ kyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups (e.g., (GrC 7 cycloallcy1)C t rC fi alkyl).
  • cycloalkyl and (cycloalkyl)alkyl groups e.g., (GrC 7 cycloallcy1)C t rC fi alkyl.
  • C 6 alkyl)aminocarbonylCo-C 4 alkyr' refers to an aminocarbonyl group in which one or both hydrogens are replaced with an independently selected Ci-C ⁇ alkyl group, and which is linked via a single covalent bond or a C r C 4 alkylene group.
  • aminosulfonyl refers to a sulfonamide group (i.e., -SO 2 NH 2 ).
  • “Mono- or di-(C[- C6alkyl)aminosulfonylCo-C 4 .alkyI” refers to an aminosulfonyl group in which one or both hydrogens arc replaced with an independently selected C ⁇ -C 6 alkyl group, and which is linked via a single covalent bond or a C
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl is an alkyl group that is substituted with 1 or more independently chosen halogens (e.g., "C
  • haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1, 2,2,2 -tetrafluoro-l-trifluoromethyl-ethyl.
  • Typical haloalkyl groups are trifluoromethyl and dif ⁇ uoromethyl.
  • a "carbocycle” has from 1 to 3 fused, pendant or spiro rings, each of which has only carbon ring members and each of which may, but need not, be bridged by an alkylene moiety.
  • a carbocycle that has a single ring contains from 3 to 8 ring members (i.e., C 3 -C 8 carbocycles); rings having from 4 or 5 to 7 ring members (i.e., GpCvCarbocycles or Cs-Cycarbocyeles) are recited in certain embodiments.
  • Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members.
  • Carbocycles may be optionally substituted with a variety of substituents, as indicated.
  • a carbocycle may be a cycloalkyl group (i.e., each ring is saturated or partially saturated as described above) or an aryl group (Ie., at least one ring within the group is aromatic).
  • Representative aromatic carbocycles are phenyl, naphthyi, tetrahydronaphthyl and biphe ⁇ yl.
  • preferred carbocycles have a single ring., such as phenyl and C 3 - Cgcycloalkyl groups.
  • carbocycles recited herein are (C 3 -C]ocarbocyc1e)Co-C 4 alky! groups (i.e., groups in which a 3- to 10-membered carbocyclic group (which may be cycloalkyl or aryl) is linked via a single covalent bond or Q-dalkylene).
  • Phenyl groups linked via a single covalent bond or Ci-C 6 aikylene are designated phenyfC ⁇ -Cialkyl (e.g., benzyl, 1 -phenyl-ethyl, l ⁇ phenyl-propyl and 2-phenyl-ethyl).
  • a phenylCo-C 4 alkoxy group is a phenyl ring linked via an oxygen bridge or via an alkoxy group having from 1 to 4 carbon atoms (e.g., phenoxy or benzoxy). When substituted, it will be apparent that such groups may be substituted on the ring portion and/or on the alkylene portion of the group.
  • a "heterocycle” or “heterocyclic group” has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a heteroatom independently chosen from O, S and N, with the remaining ring atoms being carbon). Additional rings, if present, may be heterocyclic or carbocyclic.
  • a heterocyclic ring comprises I 5 2, 3 or 4 heteroatoms; within certain embodiments eacli heterocyclic ring has 1 or 2 heteroatoms per ring.
  • Each heterocyclic ring generally contains from 4 to 8 ring members (rings having from 4 or 5 to 7 ring members are recited in certain embodiments) and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members.
  • Certain heterocycles comprise a sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SOa.
  • Heterocycles may be optionally substituted with a variety of substituents, as indicated.
  • Certain heter ⁇ cycies are 4- to l O-membered and comprise one or two rings; in certain embodiments, such heterocycles are monocyclic (e.g., 4- to 8-membered,
  • heterocycies are heteroaryl groups (i.e., at least one ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6-membered heteroaryl (e.g., pyr ⁇ dyl or pyrimidyl).
  • heteroaryl encompasses groups that comprise a phenyl ring and a heterocycloalkyl ring, such as 2,3-dihydro-l,4-benzod ⁇ oxinyI and 1,3-benzodioxol-S-yI.
  • Other heterocycles are heterocycloalkyl groups (i.e., do not comprise an aromatic ring).
  • heterocycles may be linked by a single covalent bond or via an alkylene group, as indicated, for example, by the terms "(4- to 8-membered heterocycloalkyOQrG t alkyl” and "(4- to 10-membered heterocycle)C 0 -C 4 afkyL"
  • a “substituent,” as used herein, is a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • a “ring substituent” may be a moiety such as a halogen, alkyl group, haloalkyl group or other group discussed herein mat is covalently bonded to an atom (such as a carbon or nitrogen atom) that is a ring member.
  • substitution refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
  • Groups that are "optionally substituted” are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically 1, 2, 3, 4 or 5 positions, with one or more suitable groups ⁇ which may be the same or different).
  • Optional substitution is also indicated by the phrase “substituted with from 0 to X substituents," where X is the maximum number of possible subsLituents.
  • Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substituents).
  • Bi refers to the human Bj bradykinin receptor reported by Menke et ah
  • Bi agonist refers to a compound that binds Bj and induces signal transduction mediated by Bi. Such induction may be determined using the representative calcium mobilization assay provided in Example 7.
  • B 1 agonists include, for example, bradyktntn and kallidin (lysyl- bradykinin), as well as peptide portions or variants of bradykinin or kallidin that bind Bj and retain activity.
  • Representative Bi agonists include, but are not limited to, desArg 9 bradykinin and des Arg 1 °kai 1 idin.
  • a "B] antagonist" is a compound that detectably inhibits signal transduction mediated by B). Such inhibition may be determined using the representative calcium mobilization assay provided in
  • Bi antagonists have an IC50 of 5 ⁇ M or less in this assay, more preferably 2 ⁇ M or less, and stiJI more preferably 1 ⁇ M or less, 500 nM or less, 100 nM or Jess or 10 nM or less.
  • the Bi antagonist is specific for Bi (i.e., the ICso value in a similar assay performed using the B 2 receptor is greater than 2 ⁇ M and/or the IC50 ratio (B 2 /Bi) is at least 10. preferably 100, and more preferably at least 1000).
  • B 1 antagonists preferably have minimal agonist activity (i.e., induce an increase in the basal activity of Bi that is less than 5% of the increase that would be induced by one EC 5 0 of the peptide agonist desArg iO kallidin, and more preferably have no detectable agonist activity within the assay described in Example 7).
  • Bi antagonists for use as described herein are generally non-toxic. Bi antagonists include neutral antagonists and inverse agonists.
  • a "neutral antagonist" of Bi is a compound that inhibits the activity of Bi agonist (e.g., desArg' ⁇ aIlidin) at Bi, but does not significantly change the basal activity of the receptor (i.e., within a calcium mobilization assay as described in Example 7 performed in the absence of agonist, Bj activity is reduced by no more than 10%, more preferably by no more than 5%, and even more preferably by no more than 2%; most preferably, there is no detectable reduction in activity).
  • Neutral antagonists may, but need not, also inhibit the binding of agonist to Bi .
  • An "inverse agonist" of B 1 is a compound that reduces the activity of Bi below its basal actfvity level in the absence of activating concentrations of agonist.
  • Inverse agonists may also inhibit the activity of agonist at B 1 , and/or may inhibit binding of Bi agonist to Bi.
  • the reduction in basal activity of Bi produced by an inverse agonist may be determined from a calcium mobilization assay, such as the assay of Example 7.
  • a "therapeutically effective amount” is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., provides detectable relief from a condition being treated). Such benefit may be detected using any appropriate criteria.
  • a therapeutically effective amount or dose generally results in a concentration of compound in a body fluid (such as blood, plasma, serum, CSF 3 synovial fluid, lymph, cellular interstitial fluid, tears or urine) that is sufficient to result in detectable alteration in B r mediated signal transduction (using an assay provided herein).
  • the discernible patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending upon the indication for which the compound is administered. For the treatment of pain, a discernible patient benefit is generally apparent after administration of a single therapeutically effective dose, although further benefit may become apparent following repeated admin istrati ons .
  • a "patient” is any individual treated with an aryl sulfonyl helerocycle as provided herein.
  • Patients include humans, as well as other animals such as companion animals (e.g., dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to B] modulation or may be free of such symptom(s) (i.e., treatment may be prophylactic in a patient considered to be at risk for the development of such symptoms),
  • the present invention provides aryl sulfonyl hetcrocyclcs of Formula I that may be used in a variety of contexts, including in the treatment of conditions responsive to B 1 modulation, as described herein.
  • Such compounds may also be used within in vitro assays (e.g., assays for Bi activity), as probes for detection and localization of Bi and within assays to identify other Bj antagonists.
  • Ri within Formula I and other formulas provided herein, generally represents optional substituents of the phenyl ring.
  • R 4 , R 5 and R& groups include, for example, halogen, hydroxy, Ci-C 6 alkyl, Ci-Cshaloalkyl, Ci-C ⁇ alkoxy and Ci-Cehaloalkoxy.
  • R 3 is methyl or methoxy and R 4 and R 5 (if present) are each methyl; within other embodiments, R 4 and Re (if present) each represent a halogen, and R 5 is a halogen, methoxy, trifluoromethyl or methyl.
  • n is 1 and either (i) m is 1 and q is 1 or 2, or (ii) m is 2 and q is 1.
  • Such groups include, for example,
  • R 2 within certain compounds of Formula I and other Formulas provided herein, represents from 0 to 4 substituents independently chosen from Q-Caalkyl.
  • R 2 represents from 0 to 4 substituents independently chosen from Q-Caalkyl.
  • R 2 represents gem-dimethyl (e.g., the group designated i:: is
  • ⁇ — ⁇ is, for example, ⁇ S , wherein p is 0, I 5 2 or 3; Z is CR 7 R 8 or NR 9 ;
  • R 7 and Rg are independently chosen from: (i) hydrogen, hydroxy and cyano; and (ii) Ci-C ⁇ alkyl, C 2 - Cealkenyl, C 2 -CQalkynyl, C
  • R 7 and Rg are taken together to form a spiro 4- to 10-membered heterocycle that is substituted with from 0 to 2 substituents independently chosen from hydroxy, oxo, cyano and Ci-C ⁇ alkyl; and
  • R 9 is C]-C 6 alkyl, C 2 -Q;alkeny], C 2 -C 6 a!kynyl, mono- or di-(C ⁇ -C 6 alkyl)arninoCi-C 4 aIkyl, (C 3 -
  • the group — -/ may, optionally, be further substituted (e.g., with Cj-C 6 aJkyl or oxo) at one or
  • ring carbon atoms include, for example, .
  • Z is CR 7 Rg, where R 7 and R 8 are as described above.
  • Representative R 7 groups include, for example, hydrogen, hydroxy, cyano and Cj-C$alkyl;
  • representative Rg groups include, for example, C 2 -C6alkyl ether, mono- or di-(Ci-C6alkyI)aminoC 0 - C ⁇ alkyl, phenyl Co-C 4 alkyl and (4- to 8-membered heterocycloalkyl)C 0 -C 4 alkyl, each of which is substituted with from 0 to 2 substihie ⁇ ts independently chosen from hydroxy, halogen, oxo, cyano, Cj-C 4 aikyl and Q-C 4 alkoxy.
  • Rg is mono- or di-(Cp C 5 alkyl)aminoCo-C 4 aIkyl or (4- to 8-membered heterocycloalkyl)Co-C « ⁇ aIkyI that is optionally substituted with
  • R 7 and Rs are taken together to form a spiro 4- to 10- membered helerocycle that is substituted with from 0 to 2 substituents independently chosen from hydroxy, oxo, cyano and Ci-C ⁇ alkyl; for example,
  • ⁇ / ⁇ ifu is , within certain such compounds.
  • Z is NR9, whei'ein R 3 is as described above.
  • Representative R 9 groups include, for example, d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, mono- or di-(Cp C 6 aIkyl)aminoCi-C 1 alkyl, (C 3 -Ci 0 carbocycle)Co-C4alkyl and (4- to 10-membered heterocycle)Co-
  • R 9 is C
  • R A is hydrogen, C]-C 6 alkyl, C 2 -C6aikenyl, C 2 -
  • Representative R A groups include, for example, ether.
  • Representative R B groups include, for example, C 2 -C ⁇ > alkyl ether, mono- or di-(C 1 -C ⁇ alkyl)aminoC ⁇ -C 1
  • Formulas provided herein encompass non-racemic compounds and racemic mixtures.
  • certain compounds of Formula I satisfy Formula Ia or Formula Ib, and certain compounds of Formula II satisfy Formula Ha or Formula lib:
  • Formula ⁇ a Certain compounds provided herein further satisfy one or more of the following Formulas, in which s is an integer ranging from 1 to 4, R 0 and R D are independently hydrogen or Q-C d alkyl, and the remaining variables are as described above:
  • Formula XXVI Representative compounds provided herein include, but are not limited to, those specifically described in the Examples below. It will be apparent that the specific compounds recited herein are representative only, and are not intended to limit the scope of the present invention. Further, as noted above, all compounds of the present invention may be present as a free acid or base or as a pharmaceutically acceptable salt.
  • compounds provided herein are Bi modulators.
  • certain compounds provided herein display B] specificity.
  • B t modulator activity may be confirmed using a calcium mobilization assay, such as the assay described in Example 7, herein.
  • binding activity of the compounds provided herein to Bi may be confirmed using the representative assay described in Example 6, herein, or using an assay described by Fox ct ai.
  • Preferred B 1 modulators exhibit a K; within such an assay of 5 micromolar or less, more preferably 2 micromolar or less, I micromolar or iess, 500 nanomolar or less, 100 nanomolar or less or 10 nanomolar or less.
  • B] modulators provided herein may be confirmed using any of a variety of animal models including, but not limited to, those described in the following documents (each of which is hereby incorporated by reference for its disclosure of the recited animal model): Wood ct al. (2003) J. Med. Chem. 46: 1803-06 — carrageenan-indiiced mechanical pressure hyperalgesia;
  • compounds provided herein may be evaluated for certain pharmacological properties including, but not limited to, oral bioavailability (preferred compounds are orally bioavailable to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably less than 50 mg/kg, more preferably less than 30 mg/kg, even more preferably less than 10 mg/kg,, still more preferably less than 1 mg/kg and most preferably less than 0.1 mg/kg), toxicity (a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject), side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), serum protein binding and in vitro and in vivo half-life (a preferred compound exhibits an in vivo haif-life allowing for Q.
  • oral bioavailability preferred compounds are orally bioavailable to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably less than 50 mg/kg, more preferably less than 30 mg/kg, even more preferably less than 10 mg
  • I. D. dosing preferably T.I.D. dosing, more preferably B.I.D. dosing, and most preferably once-a- day dosing).
  • differential penetration of the blood brain barrier may be desirable. Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously). Serum protein binding may be predicted from albumin binding assays.
  • Compound half-life is inversely proportional to the frequency of dosage of a compound.
  • In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described herein.
  • preferred compounds provided herein are nontoxic. In general, the term
  • nontoxic as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United Stales Food and Drug Administration (“FDA") for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans).
  • FDA United Stales Food and Drug Administration
  • a highly preferred nontoxic compound generally satisfies one or more of the following criteria: (I) does not substantially inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial liver enlargement, or (4) does not cause substantial release of liver enzymes.
  • a compound that does not substantially inhibit cellular ATP production is a compound that satisfies the criteria set forth in Example 8, herein.
  • cells treated as described in Example 8 with 100 ⁇ M of such a compound exhibit ATP levels that are at least 50% of the ATP levels detected in untreated ceHs. In more highly preferred embodiments, such cells exhibit
  • ATP levels that are at feast 80% of the ATP levels detected in untreated cells.
  • a compound that does not significantly prolong heart QT intervals is a compound that does not result in a statistically significant prolongation of heart QT intervals (as determined by electrocardiography) in guinea pigs, miniptgs or dogs upon administration of a dose that yields a serum concentration equal to the EC JO or IC 50 for the compound.
  • a dose of 0.01, 0.05, 0.1 , 0.5, 1, 5, 10, 40 or 50 mg/kg administered parenterally or orally does not result in a statistically significant prolongation of heart QT intervals.
  • statically significant results varying from control at the ⁇ 0.1 level or more preferably at the p ⁇ 0.05 level of significance as measured using a standard parametric assay of statistical significance such as a student's T test.
  • a compound does not cause substantial liver enlargement if daily treatment of laboratory rodents (e.g., mice or rats) for 5-10 days with a dose that yields a serum concentration equai to the EC 5O or IC 5O for the compound results in an increase in liver to body weight ratio that is no more than 100% over matched controls. In more highly preferred embodiments, such doses do not cause liver enlargement of more than 75% or 50% over matched controls.
  • non-rodent mammals e.g., dogs
  • such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls.
  • Preferred doses within such assays include 0.01, 0.05. 0.1, 0.5, 1 , 5, 10, 40 or 50 mg/kg administered parenterally or orally.
  • a compound does not promote substantial release of liver enzymes if administration of twice the minimum dose mat yields a serum concentration equal to the EC 50 or IQo for the compound does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 100% over matched mock-treated controls.
  • such doses do not elevate such serum levels by more than 75% or 50% over matched controls.
  • a compound does not promote substantial release of liver enzymes if, in an in vitro hepatocyte assay, concentrations (in culture media or other such solutions that are contacted and incubated with hepatocytes in vitro) that are equal to the EC 50 or IC 5 0 for the compound do not cause detectable release of any of such liver enzymes into culture medium above baseline levels seen in media from matched mock-treated control cells.
  • certain preferred compounds do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP 1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to die ECso or IC50 for the compound.
  • microsomal cytochrome P450 enzyme activities such as CYP 1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to die ECso or IC50 for the compound.
  • Certain preferred compounds are not clastogcnic (e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) at a concentration equal the ECso or IC 5 0 for the compound.
  • certain preferred compounds do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations.
  • compounds provided herein may be isotopically-labeled or radiolabeled.
  • such compounds may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be present in the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 11 C, ' 3 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P 5 35 S, 18 F and 36 Cl.
  • substitution with heavy isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by T. Greene, are well known. Compounds and intermediates requiring protection/deprotection will be readily apparent.
  • a compound provided herein may contain one or more asymmetric carbon atoms, so that the compound can exist in different stereoisomer ⁇ forms.
  • Such forms can be, for example, racemates or optically active forms.
  • All stereoisomers arc encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (i.e., optically active forms).
  • Standard methods for preparing single enantiomers include asymmetric synthesis and 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 HPLC column.
  • Compounds may be radiolabeled by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
  • Each radioisotope is preferably carbon (e.g., 14 C), hydrogen (e.g., 3 H), sulfur (e.g., 35 S) or iodine (e.g., 125 I).
  • Tritium labeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifiuoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas using the compound as substrate.
  • certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
  • Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • compositions comprising one or more aryl sulfonyl heterocycles provided herein, together with at least one physiologically acceptable carrier or excipient.
  • Pharmaceutical compositions may comprise, for example, one or more of water, buffers ⁇ e.g., sodium bicarbonate, neutral buffered saline or phosphate buffered saline), ethanoi, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose, starch, matmitol or dextrans), proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
  • buffers ⁇ e.g., sodium bicarbonate, neutral buffered saline or phosphate buffered saline
  • ethanoi mineral oil
  • vegetable oil dimethylsulfoxide
  • carbohydrates e.g., glucose, mannose, sucrose, starch
  • compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.
  • compositions suitable for oral use are preferred. Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • pharmaceutical compositions may be formulated as a lyophilizate.
  • Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations.
  • Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc). Tablets may be formed using standard techniques, including diy granulation, direct compression and wet granulation. The tablets may be uncoated or they may be coated by known techniques.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
  • an inert solid diluent e.g., calcium carbonate, calcium phosphate or kaolin
  • an oil medium e.g., peanut oil, liquid paraffin or olive oil
  • Aqueous suspensions contain the active material(s) in admixture with suitable excipients, such as suspending agents (e.g., sodium carboxymethylccliulosc, mcthylccllulosc, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate.
  • suspending agents e.g., sodium carboxymethylccliulosc, mcthylccllulosc, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia
  • dispersing or wetting agents e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide
  • Aqueous suspensions may also comprise one or more preservatives, such as ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and/or one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations.
  • Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., a suspending agent
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
  • compositions may also be formulated as oil-in-water emulsions.
  • the oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums (e.g., gam acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monoleate) and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethyJene sorbitan monoleate).
  • An emulsion may also comprise one or more sweetening and/or flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components.
  • Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery.
  • Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acyiglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphi ⁇ golipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin
  • glycols e.g., butylene, isoprene
  • a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers., moisturizers and sustained release materials.
  • stabilizing agents such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers., moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions. nanoparticles or nanocapsules.
  • a topical formulation may be prepared in any of a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions.
  • the physical appearance and viscosity of such pharmaceutically acceptable forms can be governed by the presence and amount of emulsifier(s) and viscosity adjusters) present in the formulation.
  • Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity.
  • These formulations may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers.
  • Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate.
  • Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate.
  • a gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaternimns, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethy lcel lulose, carbomer or ammoniated glycyrrhizinate.
  • Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • nonionic, amphoteric, ionic and anionic surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • one or more of d ⁇ methicone copolyol, poiysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations.
  • Suitable preservatives include, but are not limited to.
  • moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopenta ⁇ oate and mineral oils.
  • Suitable fragrances and colors include, but are not limited to, FD&C Red No.
  • Suitable additional ingredients that may be included a topical formulation include, but arc not limited to, abrasives, absorbents, anti-caking agents, anti- foam ⁇ ng agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
  • a suitable topical vehicle for formulation of a gel is: hydroxypropylceliulose
  • a suitable topical vehicle for formulation as a foam is: cetyi alcohol (1.1 %); stearyl alcohol (0.5%; QuaternJum 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percents are by weight.
  • Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing.
  • a pharmaceutical composition may be prepared as a sterile injectable aqueous or oleaginous suspension.
  • the compound(s) provided herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • Such a composition may be formulated according to the known art using suitable dispersing, wetting and/or suspending agents such as those mentioned above.
  • suitable dispersing, wetting and/or suspending agents such as those mentioned above.
  • suitable vehicles and solvents that may be employed are water, 1,3-butanedioI,
  • sterile, fixed oils may be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
  • compositions may also be formulated as suppositories (e.g., for rectal administration).
  • Sucli compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichiorodifiuoroniethane or trichlorofluoromethane).
  • a conventional propellant e.g., dichiorodifiuoroniethane or trichlorofluoromethane.
  • compositions may be formulated for release at a pre-determined rate.
  • Instantaneous release may be achieved, for example, via sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract).
  • Controlled release formulations i.e., formulations such as a capsule, tablet or coated tablet that slows and/or delays release of active ingredient ⁇ s) following administration
  • a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and thereby provides a delayed action or a sustained action over a longer period.
  • One type of controlled-release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate.
  • the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least S hours, and more preferably at least 12 hours.
  • blood e.g., plasma
  • Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release.
  • the amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation;, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controlled-release coating.
  • the release rate can be varied using methods well known in the art, including (a) varying the thickness or composition of coating, (b) altering the amount or manner of addition of plasticizer in a coating,, (c) including additional ingredients, such as release-modifying agents, (d) altering the composition, particle size or particle shape of the matrix, and (e) providing one or more passageways through the coating.
  • the amount of modulator contained within a sustained release formulation depends upon, for example, the method of administration (e.g., the site of implantation), the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • the matrix material which itself may or may not serve a controlled-release function, is generally any material that supports the active ingredient(s).
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Active mgredient(s) may be combined with matrix material prior to formation of the dosage form (e.g., a tablet).
  • active ingredient(s) may be coated on the surface of a particle, granule, sphere, microsphere, bead or pellet that comprises the matrix material. Such coating may be achieved by conventional means, such as by dissolving the active ingredient(s) in water or other suitable solvent and spraying.
  • additional ingredients arc added prior to coating (e.g., to assist binding of the active ingredient(s) to the matrix material or to color the solution).
  • the matrix may then be coated with a barrier agent prior to application of controlled-release coating. Multiple coated matrix units may, if desired, be encapsulated to generate the final dosage form.
  • a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ⁇ ngredient(s) at a controlled rate in aqueous medium).
  • the controlled release coating should be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert and tack-free.
  • Coatings that regulate release of the modulator include pH-independent coatings, pH-dependent coatings (which may be used to release modulator in the stomach) and enteric coatings (which allow the formulation to pass intact through the stomach and into the small intestine, where the coating dissolves and the contents are absorbed by the body).
  • pH dependent coatings include, for example, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid ester copolymers and zein.
  • the coating is a hydrophobic material, preferably used in an amount effective to slow the hydration of the gelling agent following administration.
  • Suitable hydrophobic materials include alkyl celluloses (e.g., ethylcellulose or carboxymethylcellulose), cellulose ethers, cellulose esters, acrylic polymers (e.g., poly(acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacryiate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate.
  • methacrylic acid alkamide copolymer ⁇ oly(methyl methacryiate), polyacrylamide, ammonio methacryiate copolymers, aminoalkyl methacryiate copolymer, poly(methacrylic acid anhydride) and grycidyl methacryiate copolymers) and mixtures of the foregoing.
  • Representative aqueous dispersions of ethylcellulose include, for example, AQUACOAT ⁇ (FMC Corp., Philadelphia, PA) and SURELEASE® (Colorcon, Inc., West Point, PA), both of which can be applied to the substrate according to the manufacturer's instructions.
  • Acrylic polymers include, for example, the various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which may be used singly or in combination depending on the desired release profile, according to the manufacturer's instructions.
  • the physical properties of coatings that comprise an aqueous dispersion of a hydrophobic material may be improved by the addition or one or more plasttcizers.
  • Suitable plasticizers for alkyl celluloses include, for example, dibutyl sebacate, diethyl phthalate, friethyl citrate, trib ⁇ tyl citrate and triacetin.
  • Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as tricthyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
  • citric acid esters such as tricthyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
  • Controlled-release coatings are generally applied using conventional techniques, such as by spraying in the form of an aqueous dispersion.
  • the coating may comprise pores or channels or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic material that is dissolved, extracted or leached from the coating in the environment of use.
  • pore-forming materials include hydrophilic polymers, such as hydroxyalkylcelluloses ⁇ e.g., hydroxypropylmethylceilulose), cellulose ethers, synthetic water-soluble polymers ⁇ e.g., polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and polyethylene oxide), water-soluble polydextrose, saccharides and polysaccharides and alkali metal salts.
  • a controlled release coating may include one or more orifices, which may be formed my methods such as those described in US Patent Nos. 3,845,770; 4,034,758; 4,077,407; 4,088,864; 4,783,337 and 5,071,607. Controlled-release may also be achieved through the use of transdermal patches, using conventional technology ⁇ see, e.g., US Patent No. 4,668,232).
  • controlled release formulations and components thereof, may be found, for example, in US Patent Nos. 4,572,833; 4,587,117; 4,606,909; 4,610,870; 4,684,516; 4,777,049;
  • a compound provided herein may be conveniently added to food or drinking water ⁇ e.g., for administration to non-human animals including companion animals (such as dogs and cats) and livestock).
  • Animal feed and drinking water compositions may be formulated so that, the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to feed or drinking water.
  • Aryl sulfonyl heterocycles(s) provided herein are generally administered in a therapeutically effective amount.
  • Preferred systemic doses are no higher than 50 mg per kilogram of body weight per day ⁇ e.g., ranging from about 0.001 mg to about 50 mg per kilogram of body weight per day), with oral doses generally being about 5-20 fold higher than intravenous doses ⁇ e.g., ranging from 0.01 to 40 mg per kilogram of body weight per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage unit will vary depending, for example, upon the patient being treated and the particular mode of administration. Dosage units will generally contain from about 10 ⁇ g to about 500 rng of an active ingredient Optimal dosages may be established using routine testing, and procedures that are well known in the art.
  • compositions provided herein may, but need not, further comprise one or more additional pharmaceutical agents, such as an anti-inflammatory agent or analgesic.
  • Anti-inflammatory agents include, for example, non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and cyclooxygenase-2 (COX-2) specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, leflunomide, cycJosporine A, IM gold, minocycline, azathioprine, tumor necrosis factor (TNF) receptor antagonists, soluble TNF alpha receptor (etanercept), anti-TNF alpha antibodies (e.g., infliximab and adalimumab), anti-C5 antibodies, interleukin-1 (IL-I) receptor antagonists (e.g., anakinra or IL-I trap), IL-18 binding protein, CTLA4- Ig (e.g., abatacept), anti-human IL-6 receptor monoclonal antibody (e.g., tocilizumab), LFA-3-lg fusion proteins (e.g.
  • NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen or naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodofac, fenoprofen calcium, ketoprof.en, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.
  • COX cyclooxyge ⁇ ase
  • NSAlDs further include salicylates such as acetylsalicylic acid or aspirin, sodium salicylate, choline and magnesium salicylates, and salsalate, as well as corticosteroids such as cortisone, dexamethasone, methyl prednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.
  • salicylates such as acetylsalicylic acid or aspirin
  • sodium salicylate sodium salicylate
  • choline and magnesium salicylates sodium salicylate
  • salsalate sodium salicylate
  • corticosteroids such as cortisone, dexamethasone, methyl prednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.
  • analgesics for use in combination with B 1 modulators provided herein are also antiinflammatory agents, and are listed above.
  • Other such medications are analgesic agents, including narcotic agents which typically act at one or more opioid receptor subtypes (e.g., ⁇ , K and/or ⁇ ), preferably as agonists or partial agonists.
  • opioid receptor subtypes e.g., ⁇ , K and/or ⁇
  • Such agents include opiates, opiate derivatives and opioids, as well as pharmaceutically acceptable salts and hydrates thereof.
  • Specific examples of narcotic analgesics include, within preferred embodiments, alfentanil, aiphaprodine, anileridine, bezitramide, buprenorphine, butorphanol.
  • narcotic analgesic agents include acetorphine, acetyldihydrocodeine, acetylmethadol, allylprodine, afphracetylmethadol, alphameprodine, alphamethadol, bcnzethidine, benzyhno ⁇ hi ⁇ e, betacetyimethadol, betameprodine, betamethadol, betaprodine, clonitazene, codeine methylbromide, codeine-N-oxide, cyprenorphine, desomo ⁇ hine, dextronrtoramide, diampromide, diethylthiambutene, dihydromorphine, dime ⁇ oxadol, dimepheptanol, dimethylthiamubutene, dioxaphetyl butyrate, dipipanone, drotebanol, ethanoi, ethylmethyl
  • analgesic agents include, for example acetaminophen
  • NR2B antagonists capsaicin receptor antagonists: anti-migraine agents; anticonvulsants such as oxcarbazepine and carbamazeptne; antidepressants (such as TCAs, SSJR-Is, SNRIs, substance P antagonists, etc.); spinal blocks; pentazocine/naloxone; meperidine; Jevo ⁇ hanol; bupreno ⁇ hine; hydromorphone; fentanyl; sufentanyl; oxycodone; oxycodone/acetaminophen, nalbuphine and oxymo ⁇ hone.
  • analgesic agents include CB2-receptor agonists, such as AM1241, capsaicin receptor antagonists and compounds that bind to the ⁇ 2 ⁇ subunit of voltage-gated cafcium channels, such as gabapentin and pregabalin.
  • Representative anti-migraine agents for use in combination with a Bi modulator provided herein include CGRP antagonists, capsaicin receptor antagonists, ergotamines and 5-HTi agonists, such as sumatripan, naratriptan, zolmatriptan and rizatriptan.
  • compositions may be packaged for treating conditions responsive to B 1 modulation (e.g., treatment of pain, inflammation or other disorder(s) recited herein).
  • Packaged pharmaceutical preparations generally comprise a container holding a therapeutically effective amount of a pharmaceutical composition as described above and instructions (e.g., labeling) indicating that the composition is to be used for treating a condition responsive to Bi modulation in a patient (e.g., pain or other disorder as indicated herein).
  • a packaged pharmaceutical preparation comprises one or more aryl sulfonyl heterocycles provided herein and one or more additional agents in the same package, either in separate containers within the package or in the same container (i.e., as a mixture).
  • Preferred mixtures are fo ⁇ nulated for oral administration (e.g., as pills, capsules, tablets or the like).
  • the package comprises a label bearing indicia indicating that the components are to be taken together for the treatment of pain.
  • the present invention provides methods for treating a condition responsive to Bi modulation in a patient.
  • the patient may be afflicted with such a condition, or may be free of symptoms but considered at risk for developing such a condition.
  • a condition is "responsive to Bj modulation" if the condition or symptom(s) thereof are alleviated, attenuated, delayed or otherwise improved by modulation of Bi activity.
  • such methods comprise administering to the patient a therapeutically effective amount of at least one compound as provided herein.
  • Conditions responsive to B] modulation include, for example pain; inflammation including neuroinfiammation (such as atherosclerosis), inflammation associated with airway diseases (e.g., asthma, including allergic asthma, exercise-induced branch oconstriction, occupational asthma, and other non-allergic asthmas), and inflammatory skin disorders (e.g., psoriasis and eczema)); respiratory disorders including bronchoconstrictio ⁇ , asthma, chronic obstructive pulmonary disease (e.g., emphysema), chronic cough (including ACE-inhibitor cough), adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis and vasomotor rhinitis; vascular edema (including diabetes- related vascular disease); and epilepsy.
  • inflammation including neuroinfiammation (such as atherosclerosis), inflammation associated with airway diseases (e.g., asthma, including allergic asthma, exercise-induced branch oconstriction, occupational asthma, and other non-allergic
  • Other conditions responsive to Bi modulation include diabetes (e.g., type Il or non insulin dependent, as well as diabetic vascuiopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and symptoms associated with insulitis), seizure disorders (e.g., epilepsy), multiple sclerosis, liver disease, cardiovascular disorders (e.g., atherosclerosis, congestive heart failure and myocardial infarction), neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) rheumatoid arthritis, infection, cancer, cranial trauma, rhinitis, septic shock, endotoxic and pancreatic shock, anaphylaxis, inflammatory bowel disease, irritable bowel syndrome, pancreatitis, cystitis, uveitis, vascular permeability, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder, cerebral edema, vasodilation, hypotension associated with sepsis,
  • Pain that may be treated using the Bi modulators provided herein includes, for example, acute, chronic, inflammatory, and neuropathic pain.
  • Specific pain indications that may be treated as described herein include, but are not limited to, bone and joint pain (e.g., pain associated with osteoarthritis or rheumatoid arthritis; various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, oral neuropathic pain, phantom limb pain, post-mastectomy pain, peripheral neuropathy, traumatic neuropathy, painful polyneuropathy, myofascial pain syndromes, MS-related neuropathy, HIV or AIDS-related neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflux disease (GERD) : , irritable bowel syndrome, inflammatory bowel disease, pan
  • cervicobrachial neuralgia cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, m ⁇ granous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia.
  • Headache including headaches involving peripheral nerve activity may also be treated as described herein.
  • Such headache pain includes, for example, sinus, cluster (i.e., migranous neuralgia) and tension headaches, migraine, temporomandibular pain and maxillary sinus pain.
  • migraine headaches may be prevented by administration of a compound provided herein as soon as a pre-migrainous aura is experienced by the patient.
  • Further pain conditions that can be treated as described herein include Charcot's pains, ear pain, muscle pain, eye pain, orofacial pain (e.g., odontalgia), repetitive motion pain, carpel tunnel syndrome, acute and chronic back pain (e.g., lower back pain), gout, scar pain, hemorrhoidal pain, dyspeptic pains, angina, nerve root pain, "non-painful” neuropathies, complex regional pain syndrome ⁇ homotopic pain and heterotopic pain - including pain associated with carcinoma, often referred to as cancer-associated pain (e.g., in patients with bone cancer), pain (and inflammation) associated with venom exposure (e.g., due to snake bite, spider bite, or insect sting) and trauma- associated pain (e.g., post-surgical pain, episiotomy pain, pain from cuts, musculoskeletal pain, bruises and broken bones, and bum pain, especially primary hyperalgesia associated therewith). Additional pain conditions that may be treated as described herein include pain associated
  • pain treated with B 1 modulators provided herein is inflammatory pain, acute pain, dental pain, back pain, surgical pain, headache, neuropathic pain or pain from osteoarthritis or trauma.
  • compounds provided herein may be administered alone or in combination with, one or more additional agents that are suitable for treating the disorder of interest.
  • the compound(s) and additional agent(s) may be present in the same pharmaceutical composition, or may be administered separately in either order.
  • Representative anti-inflammatory agents and analgesics for use in combination therapy include those indicated above.
  • B) modulators provided herein may be used within combination therapy for the treatment of conditions involving pain and/or inflammatory components.
  • Such conditions include, for example, autoimmune disorders and pathologic autoimmune responses known to have an inflammatory component including, but not limited to, arthritis (especially rheumatoid arthritis), psoriasis, Crohn's disease, lupus erythematosus, irritable bowel syndrome, tissue graft rejection, and hyperacute rejection of transplanted organs.
  • Other such conditions include trauma (e.g., injury to the head or spinal cord), cardio- and cerebro-vascular disease and certain infectious diseases.
  • a B) modulator is administered to a patient along with an additional analgesic and/or anli-Jnflammatory agent.
  • the Bi modulator and additional analgesic and/or anti-inflammatory agent may be present in the same pharmaceutical composition, or may be administered separately in either order.
  • Administration to the patient can be by way of any means discussed above, including oral, topical, nasal or transdermal admin ⁇ stration, or intravenous, intramuscular, subcutaneous, intrathecal, epidural, imracerebroventricular or like injection. Oral administration is preferred in certain embodiments (e.g., formulated as pills, capsules, tablets or the like).
  • Treatment regimens may vary depending on the compound used and the particular condition to be treated. In general, a dosage regimen of 4 times daily or less is preferred, with 1 or 2 times daily particularly preferred. It will be understood, however, that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, the time of administration, the route of administration, the rate of excretion, any drug combination and the severity of the particular disease undergoing therapy. Dosages are generally as described above; in general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.
  • Suitable dosages for B] modulators are generally as described above. Dosages and methods of administration of any additional agent(s) (e.g., anti-inflammatory and/or analgesic agents) can be found, for example, in the manufacturer's instructions or in the Physician's Desk Reference. In certain embodiments, combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect (i.e., a decrease in the minimum therapeutically effective amount). Thus, preferably, the dosage of additional agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of the agent without combination with a compound of Formula I.
  • any additional agent(s) e.g., anti-inflammatory and/or analgesic agents
  • combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect (i.e., a decrease in the minimum therapeutically effective amount).
  • the dosage of additional agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of
  • this dose is less than 3 A, even more preferably less than Vz, and highly preferably less than VA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the agent(s) when administered without combination administration as described herein. It will be apparent that the dose of compound as provided herein needed to achieve the desired effect may similarly be affected by the dose and potency of the additional agent.
  • the present invention provides a variety of non-pharmaceutical in vitro and in vivo uses for the compounds provided herein.
  • such compounds may be labeled and used as probes for the detection and localization of B] (in samples such as cell preparations or tissue sections, preparations or fractions thereof).
  • compounds provided herein that comprise a suitable reactive group such as an aryl carbonyl, nitro or azide group
  • compounds provided herein may be used in photoaffinity labeling studies of receptor binding sites.
  • compounds provided herein may be used as positive controls in assays for receptor activity, as standards for determining the ability of a candidate agent to bind to B]s or as radiotracers for positron emission tomography
  • SPECT single photon emission computerized tomography
  • SPECT single photon emission computerized tomography
  • SPECT single photon emission computerized tomography
  • a compound may be labeled using any of a variety of well known techniques (e.g., radiolabeled with a radionuclide such as tritium, as described herein), and incubated with a sample for a suitable incubation time (e.g., determined by first assaying a time course of binding).
  • Detection assays including receptor autoradiography (receptor mapping) of B
  • Mass spectroscopy data in the following Examples is Electrospray MS 5 obtained in positive ion mode using a Micromass Time-of-FHght LCT (Micromass, Beverly MA), equipped with a Waters 600 pump (Waters Corp.; M ⁇ lford, MA), Waters 996 photodiode array detector, and a Gilson 215 autosarapler (Gilson, Inc.; Middleton, W ⁇ ). MassLynx (Advanced Chemistry Development, Inc; Toronto, Canada) version 4.0 software with OpenLynx Global ServerTM, OpenLynxTM and AutoLynxTM processing is used for data collection and analysis.
  • Sample volume of 1 microliter is injected onto a 50x4.6mm Chromolith SpeedROD RP- 18e column (Merck KGaA, Darmstadt, Germany), and eluted using a 2-phase linear gradient at a flow rate of 6 ml/min. Sample is detected using total absorbaiice count over the 220 ⁇ 340nm UV range.
  • the elution conditions are: Mobile Phase A - 95% water, 5% MeOH with 0.05% TFA; Mobile Phase B - 5% water, 95% MeOH with 0.025% TFA.
  • the following gradient is used: 0-0.5 min 10-I00%B, hold at 100%B to 1.2 min, return to 10%B at 1.21 min. Inject to inject cycle is 2.15 rain.
  • the reaction mixture is washed three times with 50 mL water and once with 50 mL brine.
  • the organic phase is dried over MgSO 4 , filtered, and then concentrated in vacuo.
  • the product is purified by flash chromatography eluting with 8/2 hexanes/EtOAc, followed by 1/1 hexanes/EtOAc to afford the title compound.
  • Ethyl 4-(4-methoxy-2,6-dimelhylphenylsulfony.)-morphoiinyl-3-carboxyIate (476 mg, 1.33 mrnol) is dissolved in 10 mL dry THF.
  • a solution of DIBAL (4 mL of a 1 M THF solution) is added and the reaction mixture is stirred at rt for ! hr.
  • Another 4 mL of DIBAL solution is then added and stirring is continued for another hour. The reaction is quenched by careful addition of solid
  • DlBAL reduction product is dissolved in 5 mL dry DMA at room temperature.
  • Sodium hydride is added (63 mg of a 60% oil dispersion) followed by /t?r/-butyl bromoacetate (0.22 mL, 1.5 mmol).
  • the reaction mixture is stirred at room temperature for 15 h.
  • the reaction mixture is diluted with 20 mL
  • Step 4. 1 -(4-(3-(Dimethylamino)propyl)piperazm-3 -y!-2-((4-(4-methoxy ⁇ 2,6- dimethy]phenylsuifonyJ)morpholin-3-yl)methoxy)ethanone
  • the organic phase is applied to a Ig SCX cartridge and eluted with 5 mL MeOH to remove non-basic by-products followed by 5 mL 2N NH 3 in MeOH to elute the title compound. Removal of solvent affords the title compound as a white foam.
  • reaction mixture is quenched by addition of solid Na 2 SO 4 - IOH 2 O.
  • the reaction mixture is filtered through Celite and concentrated in vacuo to afford (R)-(4-(4-methoxy-2,6- dimethy3 ⁇ henylsulfonyl)-6,6-dimethyImorpholin-3-yi)methanol.
  • This compound without further purification, is dissolved in 10 mL DMA at rt. Potassium iodide (20 mg) and sodium hydride (140 mg of a 60% oil dispersion) are added, followed by bromo acetate (0.48 mL, 3.2 mmol).
  • the reaction mixture is diluted with 5 mL EtOAc and washed with 1 mL IN NaOH.
  • the organic phase is applied to a 1O g silica SPE cartridge and eluted with 10 int. RtOAc to remove non-poiar impurities, followed by 10 mL 10/1/1 EtOAc/MeOH/TEA to elute the title compound.
  • the solvent is removed in vacuo to afford the title compound.
  • the starting materials may be varied and additional steps employed to produce other aryl sulfony! heterocycles, including the following:
  • Step 1 [4-(4-Methoxy-2 :i 6-dimethylphenyl)suIfony!]thJomorpholine-3-carboxylic acid ethyl ester
  • thiomorpholine-3-carboxylic acid ethyl ester 2.0 g, 11.4 mmol
  • diisopropylethylamine 2.9S niL 3 17.1 mmol
  • 4-methoxy-2. 6-dimethylphe ⁇ ylsulfonyl chloride The mixture is stirred at rt overnight. The reaction mixture is washed with aq.
  • Step 6 1 -[4"(3 ⁇ Dimethylaminopropyl)piperazi.n-l -yi]-2-[ ⁇ -(4- ⁇ nethoxy-2 5 6-dimethylbenzene ⁇ sulfonyi)piperazin-2-ylmethoxy]ethanone
  • TFA (0.5 mL) is added in one portion to a solution of 3- ⁇ 2-[4-(3- d ⁇ iethylaminopropyl)piperazin-l-yl]-2-oxoethoxymethyl ⁇ -4-(4-methoxy-2,6-dimethyJ- benzenesulfonyl)piperazine-l-carboxylic acid tert-b ⁇ tyl ester (69 mg, 110 ⁇ mol) and CH 2 CI 2 (0.5 mL). After 1.5 h, the volatiles are removed under reduced pressure. The residue is dissolved in 1 M aqueous NaOH (10 mL) and then extracted with EtOAc (2 x 25 mL).
  • CDCI 3 CDCI 3 ) ⁇ : 6.62 (s, 1.3H), 6.60 (s, 0.7H), 4.03-4.15 (m, 3H), 4.13 (s, IH), 4.10 (s, 2H), 3.96 (m, IH),
  • the reaction mixture is poured into CH 2 Ch (150 mL) and 1 M aqueous NaOH (15 mL). The layers are separated and the aqueous layer is extracted with CH 2 CK (50 mL). The combined organic layers are washed with brine (50 mL), dried over Na 2 SO ⁇ filtered, and concentrated. Purification by flash column chromatography (19:1 CH 2 CkMeOH to 1% NH 4 OH in 19:1 CH 2 C ⁇ MeOH, 30 g SiO 2 ) affords the title compound as a pale orange oil.
  • the starting materials may be varied and additional steps employed to produce other aryi sulfonyl heterocycles.
  • Compounds listed in Table ID arc prepared using such methods. ⁇ H compounds in Table III exhibit an IC 5 O determined as described in Example 7 that is 5 micromolar or less.
  • Mass spectroscopy (MS) data is provided as M+l, with retention times (Ret time) shown in minutes.
  • This sulfonamide is dissolved in 15 mL toluene.
  • An aqueous 35% NaOH solution (30 mL) is added followed by tetrabutylammon ⁇ um chloride (500 mg).
  • Bromo-terf-butyl acetate (2.2 mL) is added and the two phase mixture is stirred vigorously at rt for 2 hours.
  • the aqueous phase is removed and the organic phase is dried over Na2SO 4 , filtered, and concentrated.
  • This ester is dissolved in 7 niL TFA and stirred 20 rain at rt. The solvent is removed and the residue dissolved in EtOAc. The product is extracted into IN NaOH. The aqueous phase is adjusted to pH ⁇ 3 with 6N HC ⁇ and the product extracted into EtOAc. The organic phase is dried over Na 2 SO 4 , filtered and concentrated to afford the title compound.
  • the starting materials may be varied and additional steps employed to produce other aryl sulfonyl heterocycles.
  • Compounds listed in Tables IV and V are prepared using such methods.
  • AU compounds in Tables IV and V exhibit an IC 50 determined as described in Example 7 that is 5 micromolar or less.
  • Mass spectroscopy (MS) data is provided as M+l, with retention times (Ret time) shown in minutes.
  • This Example illustrates the preparation of Bptransfected cells for use in Bj binding and modulation assays (Examples 6 and 7).
  • Cynomolgus macaque lung total RNA is isolated as described by Chomzynsk ⁇ et a!. (1987) Anal. Biochem. 162 ⁇ - S6 ⁇ S9.
  • a cDNA encoding Bi is cloned from the totaf RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) with the following oligonucleotides:
  • Primer 1 GGCGCTAGCCACCATGGCATCCTGGCCCCCTC (SEQ ID NO:!)
  • Primer 2 AGCCGTCCCAGATCTGAAC (SEQ ID NO:2)
  • Primer 3 GATCTGGGACGGCTTGGATG (SEQ ID NO:3)
  • Primer 4 CGGAGCTCTTAATTCCGCCAGAAAAGTTGGA (SEQ TD NO:4)
  • Primer pairs 1 & 2 and 3 & 4 are used to generate overlapping cDNA fragments corresponding to the entire protein coding sequence of cynomolgus macaque Bi cDNA are isolated and linked to form the full-length coding sequence (GenBank Accession Number AY788905).
  • the construct is cloned into pcDNA 3.1 (Invitrogen, Carlsbad, CA) and transfected into Chinese hamster ovary (CHO) cells using Lipofectamine (Invitrogen)., resulting in cynomolgus macaque Bi-expressing CHO cells.
  • the construct is cloned into pBAKPAK9 (Clontech, Mountain View, CA) and transfected into Sf9 cells to generate clonal baculovirus stocks.
  • Clonal cell lines stably expressing the cynomolgus macaque Bi receptor are selected in G418.
  • a single clonal line that exhibits high levels of receptor expression is chosen for use in binding and calcium mobilization assays (Examples 6 and 7).
  • Clonal baculovirus stocks are used to infect Sf9 cells such that the infected cells express high levels of recombinant Bj receptors. These cells are used in radioligand binding assays (Example 6).
  • This Example illustrates a representative Bj receptor binding assay that may be used to determine the binding affinity of compounds for Bi.
  • IMR-90 cells which endogenously express human Bi, are seeded into 24 well plates at 65,000 cells per well, cultured overnight, and then treated for 3 h with 0.2 ng/mL interleukin-1 beta to induce B 1 expression (Menke, et al. (1994) J. Biol Chem. 269:21583-86).
  • CHO cells stably expressing rat Bi are seeded into 24 well plates at 200,000 cells per well and cultured overnight. The cells are then washed 3 times with phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • binding buffer 50 mM Tris 7.4, 0.14 mg/mL, bacitracin, and 1 mg/mL BSA
  • DMSO concentration 1% by volume; some wells receive DMSO only, and some wells receive DMSO plus 10 ⁇ M desArg'°Kallidin to define non-specific binding. All wells then receive 0.3 nM (final concentration) [3H]-desArg I0 Kallidin. The plates are allowed to sit for 2 h at room temperature. Cells are then washed three times, and lysed with. 400 ⁇ l Ultima Gold scintillation fluid (PerkinElmer; Boston, MA; 20 rnin incubation). The fluid is then transferred to counting vials counted in a Packard liquid scintillation counter (PerkinElmer).
  • Sf9 cells infected with a baculovirus carrying the coding sequence for cynomolgus macaque B] are harvested by centrifugation and frozen at -SO 0 C. Pellets are subsequently resuspended on ice in Tris buffered saline (TDS; 50 mM Tris (pli 7.4), 120 mM NaCl), and cells arc homogenized using a polytron for 30 seconds. The crude membrane fraction is collected by centrifugation at 20,000 rpm. Membranes are washed two times with TBS and collected by centrifugation each time.
  • TDS Tris buffered saline
  • Protein content of the membranes is determined after the last wash and the concentration is adjusted to 0.7 ⁇ g/uL with binding buffer (50 mM Tris 7.4, 0.14 mg/mL bacitracin, and 1,0 mg/mL BSA)-
  • binding buffer 50 mM Tris 7.4, 0.14 mg/mL bacitracin, and 1,0 mg/mL BSA
  • Some wells receive DMSO only, and some wells receive DMSO plus I O ⁇ M desArg ! °KaHidin to define non-specific binding.
  • the 96 well plates are allowed to sit for 2 h at room temperature.
  • Membrane proteins are then harvested by filtration onto GF/C filtermats (PerkinElmer) pre-soaked for 1 hr in 0.5 % polyethylenimine. AfteF filtration, filters are dried and then counted in a Beta pfate counter. The number of counts present in the scintillation fluid is plotted as a function of antagonist compound concentration and fitted to a logistical equation using SigmaPlot (Systat Software, Point Richmond, CA) to determine each compound's IC 50 and K; (e.g., as described by Szallasi, et al (1993) J. Pharmacol. Exp. Ther. 266:675-83).
  • This Example illustrates representative caicium mobilization assays for use in evaluating test compounds for agonist and antagonist activity.
  • Cynomolgus macaque Bj-expressing CHO cells (Example 5) are plated in a 96 well plate. The cells are cultured for 1 day, after which culture media is emptied from the plate and replaced with 50 ⁇ l of KRH (Krebs-Ringer HEPES buffer: 25 mM HEPES 5 5 mM KCI, 0.96 mM NaH 2 PO4 7 1 mM MgSO 4 , 2 mM CaCl 2 , 5 mM glucose, 1 mM probenecid, pH 7.4) supplemented with the calcium- sensitive fluorescent dye Fluo4-AM (5 ⁇ g/ml; Teflabs, Austin, TX).
  • KRH Kerat-Ringer HEPES buffer: 25 mM HEPES 5 5 mM KCI, 0.96 mM NaH 2 PO4 7 1 mM MgSO 4 , 2 mM CaCl 2 , 5 mM glucose, 1 mM probenecid, pH 7.4
  • the cells are then incubated at 37 0 C in an environment containing 5% CO2. After the 1 hour incubation, the dye solution is removed from the plate, the- plate is washed once with KRH, and 100 ⁇ L KRH is added. DETERMINATION OF B I AGONIST ACTIVITY
  • y is the maximum fluorescence signal
  • x is the concentration of the Bi agonist
  • a is the E mnx
  • b corresponds to the EC 50 value
  • c is the Hill coefficient.
  • this assay is also used to assess B) agonist activity of the test compound.
  • test compounds are added to the cell plate prepared as described above in 100 ⁇ L KRH + 2% DMSO, such that the final volume in each well is 200 microliters and the final DMSO concentration is 1%.
  • the EC 50 concentration of desArg' 0 Kailidin is then added to each well of plates containing test compound to determine the extent to which each test compound inhibits an agonist-induced B] response.
  • the maximum fluorescent response is plotted as a function of test compound concentration in order to determine the IC 50 (concentration required to inhibit 50% of the effect of agonist) for each compound at B
  • Antagonists of B 1 decrease this response by at least about 20%, preferably by at least about 50%, and most preferably by at least 80%, as compared to matched control (i.e., cells treated with dcsArg'°Kal]idin at the EC 50 concentration in the absence of test compound), at a concentration of 10 micrornolar or less, preferably 1 micromolar or less.
  • matched control i.e., cells treated with dcsArg'°Kal]idin at the EC 50 concentration in the absence of test compound
  • the data is analyzed as follows. First, the average maximum relative fluorescent unit (RFU) response from negative control wells (no agonist) is subtracted from the maximum response detected for each of the other experimental wells. Second, average maximum RFU response is calculated for the positive control wells (agonist wells). Then, percent inhibition for each compound tested is calculated using the equation:
  • the % inhibition data is plotted as a function of test compound concentration and test compound IC 50 is determined using a linear regression in which x is ln(conc ⁇ ntration of test compound) and y is ln(percent inhibition/(100 - percent inhibition). Data with a percent inhibition that is greater than 90% or less than 15% are rejected and are not used in the regression.
  • the IC50 is
  • This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) ceil cytotoxicity assay.
  • test compound 1 ⁇ L is added to each well of a clear bottom 96-weIJ plate (Packard, Meriden, CT) to give final concentration of compound in the assay of 10 ⁇ M, 100 ⁇ M or 200 ⁇ M. Solvent without test compound is added to control wells.
  • MDCK cells ATCC no. CCL-34 (American Type Culture Collection, Manassas, VA), are maintained in sterile conditions following the instructions in the ATCC production information sheet. Confluent MDCK cells are trypsinized, harvested, and diluted to a concentration of 0.1 x I O 6 cells/mL with warm (37°C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30-
  • ATP-LlTE-M Luminescent ATP detection kit is generally used according to the manufacturer's instructions to measure ATP production in treated and untreated MDCK cells. PACKARD ATP
  • LITE-M reagents are allowed to equilibrate to room temperature. Once equilibrated, the lyophilized substrate solution is reconstituted in 5.5 mL of substrate buffer solution (from kit). Lyophilized ATP standard solution is reconstituted in deionized water to give a 10 mM stock. For the five control wells, 10 ⁇ L of serially diluted PACKARD standard is added to each of the standard curve control wells to yield a final concentration in each subsequent well of 200 nM, 100 ⁇ M, 50 nM, 25 11M, and
  • PACICARD substrate solution 50 ⁇ L is added to all wells, which are then covered, and the plates are shaken at approximately 700 rpm on a suitable shaker for 2 min.
  • a white PACKARD sticker is attached to the bottom of each plate and samples are dark adapted by wrapping plates in foil and placing in the dark for 10 mii ⁇ Luminescence is then measured at 22°C using a luminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or
  • ATP levels in cells treated with test compound(s) are compared to the levels determined for untreated cells. Ceils treated with 10 ⁇ M of a preferred test compound exhibit ATP levels that are at least 80%, preferably at least 90%, of the untreated cells. When a 100 ⁇ M concentration of the test compound is used, cells treated with preferred test compounds exhibit ATP levels that are at least 50%, preferably at least

Abstract

Compounds of Formula (I) are provided in which the variables are as described herein. Such compounds may be used to modulate bradykinin receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions responsive to B1 modulation in humans, domesticated companion animals and livestock animals, including inflammation and pain. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies and various in vitro assays.

Description

ARYL SULFONYL HETEROCYCLES
FIELD OF THE INVENTION
This invention relates generally to aryl sulfonyl heterocycles, and to the use of such compounds to treat conditions responsive to bradykinin receptor-1 (B]) modulation. The invention further relates to the use of such compounds as reagents for the identification of other agents that bind to B], and as probes for the detection and localization of Bj.
BACKGROUND OF THE INVENTION Millions of people throughout the world are incapacitated by pain. Existing treatments for pain are, unfortunately, not completely effective, and typically have undesirable side effects. Nonsteroidal anti-inflammatory drugs are only moderately effective against pain, and have serious renal and gastrointestinal side effects at high doses. Opiates, such as morphine, are potent analgesics, but their usefulness is limited because of adverse side effects, such as physical addictiveness and withdrawal properties, as well as respiratory depression, mood changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting, and alterations in the endocrine and autonomic nervous systems. There is thus a need for effective agents for the treatment of pain.
Bradykinin (BK) is a nonapeptide that functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and pain. The effects of BK are mediated by specific G protein-coupled BK receptors, of which there are at least two distinct subtypes termed B| and B2. The B2 receptor is expressed constitutive Iy in a variety of tissues. In contrast, the Bi receptor is inducibly expressed in response to pathophysiological conditions such as inflammation, pain, trauma, bacterial infection, burns and shock. Accordingly, Bi is a particularly attractive drug target for these and other conditions, and agents that act at this receptor may be targeted specifically to injured tissues, with minimal effects in norma! tissues. In addition, compounds that bind Lo Bi and/or modulate the activity of Bi also find use as research tools.
There is thus a need in the art for small molecule modulators of Bj activity. The present invention fulfills this need and provides further related advantages.
SUMMARY OF THE INVENTION The present invention provides aryl sulfonyl heterocycles that satisfy Formula I, or are a pharmaceutically acceptable salt, solvate or ester of such a compound: O Formula I
Figure imgf000003_0001
Within Formula I: n is O or 1; if n is 0, then m is 1 and q is O or 1 ; if n is 1, then either (i) m is 1 and q is 1 or 2 or (i) q is 1 and m is 1 or 2; X is NR3, O, S, SO or SO3;
Y is -0-CH2-, -N(R1O)-CH2-, -CH2-CH2-, -CH=CH-, -CH2-O-CH2-, -CH2-CH2-CH2- Or -O-CH2-CH2-; R1 represents from O to 5 ring substituents; preferably such substituents are independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl and -COOH; (ii) C,-C6alkyl, C2-C6aikenyl, C2-C6alkynyl. (C3-C8cycloaIkyl)Co-C4alkyl- CrC6alkoxy, C1-
Cβalkylthio, Ci-Cβalkylsuffinyl, C|-C6aikoxycarbonyl,
Figure imgf000003_0002
mono- or di-(C1-C6alkyi)aminoC0-C1jaiky3:, mono- or di-(Ci-C6alkyl)aminosulfonylCo-C4alkyl, mono- or di-(C!-CcalkyI)aminocarbonylC0-C4aikyl, and (4- to 8-membered heterocycloalkyl)C0- C4alkyl; each of which is substituted with from O to 6 substituents independently chosen from halogen, hydroxy, cyano and amino; and
(iii) groups that are taken together to form a fused carbocyclic ring that is substituted with from O to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, Cj- Qalkyl, Cj-Cβhaloalkyl, C]-C6alkoxy, and mono- or di-(CrC6aIkyl)aminoC0-C4alkyl; R2 represents from O to 4 substituents; preferably any such substituents are independently chosen from oxo, hydroxy and C[-C3alkyl;
R3 is hydrogen or a substituent such as CrCsalkyl or CpCgalkanoyl; Rio is hydrogen or a substituent such as Ci-Gjalkyl;
RA is hydrogen or a substituent such as d-Cβalkyl, C2-Cήalkenyl, C2-C6alkynyl, (C3-Cscycloalkyl)C0- C4alkyl, Co-C-ealkyl ether, or mono- or
Figure imgf000003_0003
each of which is optionally substituted with hydroxy, amino or oxo; and
RB is a substituent such as C,-Cόalkyl, Ca-Qalkenyl, C2-C6alkyriyl, (C3-C3cyc!oalkyl)Co-C4a]kyJ, C2- Cβalkyl ether, mono- or di-(CrC6alkyl)aminoCi-C4alkyl3 or (4- to 7-membered heterocyc!oalkyl)Co-C4alkyl. each of whicli is optionally substituted and each of which is preferably substituted with from 0 to 6 substituents independently chosen from: (i) amino, halogen, hydroxy, cyano and oxo; and
(ii) Ci-Cgalkyl, (C3-Cscycloalkyl)Co-C4alkyl, Ci-C6alkoxy, phenylCo-Gjalkyl and (5- or 6- membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from amino, cyano, halogen, hydroxy, CrC6alkyl, (C3- Cscycloalkyl)Co-C4aIkyI, Ci-C6haloalkyl, Cj-Cβalkoxy, Ci-CgaikoxycarbonyJ, mono- or di- (Ci-Cήalkyl)amino, phenylCo-Qafkyl and phenyl Co-C4alkoxy; or RA and RB are taken together to form a 4- to 7-membered heterocycloalkyl that is optionally substituted and is preferably substituted with from 0 to 4 siibstitiients independently chosen from:
(i) hydroxy, oxo, cyano and amino; and (iϊ) CrQalkyl, C1-QaIkOXy, mono- or di-(Ci-C(jalkyl)aminoCo-C4alkyl, (C3-C[ocarbocycle)Cu-
C4alkyl and (4- to 10-metnbered heterocycle)Co-C}alkyI; and
(iii) substituents that are taken together to form a spiro C^Ciocarbocycle or a spiro 4- to 10- mcrøbercd hetcrocyclc; each of which (ii) and (iii) is optionally substituted and is preferably substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, oxo, cyano, Ci-C^alkyl, C]-C6a1koxy, (C3-Ci 0carbocycle)Co-C4aIkyl and (4- to lθ-membered heterocycle)C<>-C4alkyI.
Within further aspects, aiyl sulfony! heterocycles of Formula 1 further satisfy formula 11:
O Formula II
Figure imgf000004_0001
or are a pharmaceutically acceptable salt, solvate or ester of such a compound. Within Formula II:
Figure imgf000004_0002
represents a 4- to 7-membered, N-linked heterocycloalkyl that is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from: (i) hydroxy, oxo, cyano and amino; (ii) CpCealkyl, Ci-C6aikoxy, mono- or di-(Ci-C6a!kyl)aminoCo-C4alkyl, (C3-Ci ocarbocycle)Co-
C4alkyl and (4- to 10-membered heterocycle)Co-C4alkyl; and (iii) substituents that are taken together to form a spiro C-rdocarbocycfe or a spiro 4- to 10- membered heterocycle; each of which (ii) and (iii) is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, oxo, cyano, Ci-C6alkyl, Ci-C<>alkoxy, (C3-Ciocarbocycle)Co-C4alkyl and (4- to
10-membered heterocycle)C0-C4alkyl; and the remaining variables are as described for Formula I.
Within certain aspects, aryl sulfonyl heterocycles of Formula 1, and other Formulas provided herein, are B1 modulators and exhibit a K,- of no greater than 5 micrornolar, 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in me B1 binding assay provided in Example 6, herein, and/or have an EC5<> or IC50 value of no greater than 5 micromolar, 2 micromolar, 1 micromolar, 500 nanomolar, ΪG0 nanomolar, 50 nanomolar or i0 nanomolar in an assay for determination of B3 agonist or antagonist activity as provided in Example 7, herein.
In certain embodiments, aryl sulfonyl heterocycles of Formula I are B] antagonists; preferably such antagonists exhibit no detectable B1 agonist activity.
Within certain aspects, aryl sulfonyl heterocycles of Formula I are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).
The present invention further provides, within other aspects, pharmaceutical compositions comprising at least one aryl sulfonyl heterocycle of Formula I in combination with a physiologically acceptable carrier or excipieπt.
Methods are further provided for inhibiting agonist-induced B1 activity. Within certain such aspects, the inhibition takes place in vitro. Such methods comprise contacting a Bi receptor with at least one Bj antagonist as described herein;, under conditions and in an amount or concentration sufficient to detectably inhibit agonist-induced B1 activity. Within other such aspects, the Bj receptor is in a patient. Such methods comprise contacting cells expressing a Bi receptor in a patient with at least one B] antagonist as described herein in an amount or concentration that would be sufficient to detectably inhibit agonist-induced Bi activity in cells expressing a cloned Bi receptor in vitro.
The present invention further provides methods for treating a condition responsive to Bi receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one aryl sulfonyl heterocycle of Formula I.
Within other aspects, methods are provided for treating pain in a patient, comprising administering to a patient suffering from (or at risk for) pain a therapeutically effective amount of at least one aryl sulfonyl heterocycle of Formula I. Pain conditions that may be treated include, but are not limited to, inflammatory pain, acute pain, dental pain, back pain, surgical pain, headache, neuropathic pain, and pain associated with osteoarthritis or trauma.
Within further aspects, the present invention provides methods for determining the presence or absence of Bi in a sample, comprising: (a) contacting a sample with an aryl sulfonyl heterocycle of Formula I under conditions that permit binding of the compound to Bi; and (b) detecting a signal indicative of a level of the compound bound to Bt- In yet another aspect, the present invention provides methods of preparing the compounds disclosed herein, including the intermediates.
These and other aspects of the present invention will become apparent upon reference to the following detailed description.
DETAILED DESCRIPTION As noted above, the present invention provides aryl sulfonyl heterocycles. Such compounds may be used in vitro or in vivo in a variety of contexts, as described herein. TERMINOLOGY
Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. If a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautorner, but rather is intended to encompass all tautomeric forms. Certain compounds are described herein using a general formula that includes variables {e.g., X, RA, q). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence.
The term "aryl sulfonyl heterocycles" encompasses all compounds of Formula I, and includes pharmaceutically acceptable salts, solvates and esters of such compounds.
A "pharmaceutically acceptable salt" of a compound recited herein is an acid or base salt that is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutically acceptable anions for use in salt formation include, but are not limited to, acetate, 2-acetoxybenzoate, ascorbate, benzoate, bicarbonate, bϊtartrate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochloride, diphosphate, edetate, estoiate (ethylsuccinate), formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycoϋylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phenylacetate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamate, sulfanilate, sulfate, sulfonates including besylate (benzenesulfonate), camsylate (camphorsulfonate), edisylate (ethane-1 ,2-disuifbnate), esylate (ethanesulfonate) 2-hydroxyethyIsuIfonate, mesylate (methanesulfonate), triflate (trifiuoromethanesulfonate) and tosylate (p-tolπenesιt3fonate), tannate, tartrate, teoclate and triethiodide. Similarly, pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaiue, choline, diethanolamine, ethylenediamine, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile, is preferred.
Tt will be apparent that each compound provided herein may, but need not, be formulated as a solvate (e.g., a hydrate) or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention. Also provided herein are prodrugs of the compounds provided herein. A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group mat, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, or sulfhydryl group, respectively- Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
As used herein, the term "aikyl" refers to a straight or branched chain saturated aliphatic hydrocarbon. Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-Cgftlkyl), from 1 to 6 carbon atoms (Cι-C6alky!) and from I to 4 carbon atoms (Ci-C4alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, /<?r/-buryl, pentyl, 2-pentyI, isopentyl, neopentyl, hexyl, 2-hexy!, 3-hexyl or 3-methylpentyI. "Co-C4alkyl" refers to a single covalent bond (Co) or an alkylene group having 1, 2. 3 or 4 carbon atoms; "Co-Cβalkyl" refers to a single covalent bond or a CrQalkylene group..
"Alkylene" refers to a divalent alkyl group, as defined above. C]-C4alkylene js an alkylene group having 1 , 2, 3 or 4 carbon atoms.
"Alkeπyl" refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include Co-Cgalkenyl, Co-Cgalkenyl and Ca-
C4alkenyl groups, which have from 2 to S, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, allyl or isopropeny!. "Alkynyl" refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include
C2-C8alkynyl, C2-Cβalkynyl and Ci-Qalkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
A "cycloaikyl" is a saturated or partially saturated cyclic group in which all ring members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and partially saturated variants thereof. Certain cycloaikyl groups are C3-C8cycloalkyl, in which the ring contains from 3 to S ring members, all of which are carbon. A "(C3-CscycloalkyI)C0-C4alkyl" is a C3-Cficyc!oallςvl group linked via a single covalent bond or a C]-C4alkylene group.
By "alkoxy," as used herein, is meant an alkyl group attached via an oxygen bridge. Alkoxy groups include C|-C6alkoxy and C1-C4BIkOXy groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively. Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-bυtoxy, tert-butoxy, n- pentoxy. 2-penloxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy are representative alkoxy groups.
Similarly, "alkylthio" refers to an alkyl group as attached via a sulfur bridge (i.e., — S— alkyl). Alkyithio groups include Ci-C6alkylthio and Q-Ctalkylthio groups, which have from 1 to 6 or from i to 4 carbon atoms, respectively.
The term "oxo,11 as used herein refers to an oxygen substituent of a carbon atom that results in the formation of a carbonyl group (C=O). An oxo group that is a substituent of a nonaromatic carbon atom results in a conversion of -CH2- to -CC=O)-. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to -CC=O)- and may result in a loss of aromaticity.
"Alkylsulfinyl" refers to groups of the formula -(SO)-alkyi, in which the sulfur atom is the point of attachment AIkyisulfinyI groups include Ci-C&alkylsulfmy] and CrQalkylsulfmyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
"Alkylsulfonyl" refers to groups of the formula -(Sθ2>-alkyl, in which the sulfur atom is the point of attachment Alkyisulfony! groups include Ci-Qjalkylsulfonyl and CrQalkyfsulfonyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
The term "alkanoyl" refers to an acyl group (e.g., -<C=O)-aIkyl)5 in which carbon atoms arc in a linear or branched alkyl arrangement and where attachment is through the carbon of the keto group. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C^alkanoyl group is an acetyl group having the formula -(C=O)CH3; "Cialkanoyl" refers to -(C=O)H. Alkanoyl groups include, for example, Cj- Csalkanoyl, Cj-Qalkanoyl and d-Gjalkanoyl groups, which have from 1 to 8, from 1 to 6 or from 1 to 4 carbon atoms, respectively.
Similarly, "alkyi ether" refers to a linear or branched ether substituent Alkyl ether groups include C2-C8alkyl ether, C2-C6alkyl ether and
Figure imgf000008_0001
ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively, A C2alkyl ether lias the structure -CHr-O-CH3.
The term "alkoxycarbonyl" refers to an alkoxy group linked via a carbonyl (i.e., a group having the general structure -C(=O)-O-alkyl). Alkoxycarbonyl groups include C1-C8, Ci-Cj and Cr Qalkoxycarbonyl groups, which have from I to S, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group. "C1 alkoxycarbonyl" refers to -CC=O)-O-CI-I3.
"Afkylamino" refers to a secondary or tertiary amine that has the general structure -"NH-aikyl or -N(alky!)(alkyl), wherein each alky! is selected independently from alkyl, cycloalkyl and
(cycloalkyl)aikyl groups. Such groups include, for example, mono- and di-(Ci-C8alky3)amino groups, in which each C|-C8alky! may be the same or different, as well as mono- and di-(C]-C6alkyl)amino groups and mono- and di-(Ci-C4alkyl)amino groups.
"Aikylaminoalkyl" refers to an alkyfamino group linked via an alkyϊene group (;.<?„ a group having the general structure -alkylene— NH-aikyl or -alkyiene-N(alkyl)(alkyl)) in which each alkyl is selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Alkylaminoalkyl groups incϊude, for example, mono- and άi-(C i-C3alkyl)aminoC]-C6alkyl, mono- and di-(Cj- C6aIkyI)aminoC|-C6alkyi and mono- and di-(Ci-C6alkyl)aminoC1-C4alkyI. "Mono- or di-(Cj- C6alkyl)aminoCo-C4alkyl" refers to a mono- or di-(C]-C6alkyl)amino group linked via a single covalent bond or a CrQalkyiene group. The following are representative alkylaminoaikyl groups:
Figure imgf000009_0001
It wiH be apparent that the definition of "alkyl" as used in the terms "alkylamino" and "alkylaminoalkyi" differs from the definition of "alkyf" used for all other aϊkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups (e.g., (GrC7cycloallcy1)CtrCfialkyl). The term "aminocarbonyl" refers to an amide group (i.e., -C(=O)NH2). "Mono- or di-(Cj-
C6alkyl)aminocarbonylCo-C4alkyr' refers to an aminocarbonyl group in which one or both hydrogens are replaced with an independently selected Ci-Cβalkyl group, and which is linked via a single covalent bond or a CrC4alkylene group.
The term "aminosulfonyl" refers to a sulfonamide group (i.e., -SO2NH2). "Mono- or di-(C[- C6alkyl)aminosulfonylCo-C4.alkyI" refers to an aminosulfonyl group in which one or both hydrogens arc replaced with an independently selected Cι-C6alkyl group, and which is linked via a single covalent bond or a C|-C4alkyleπe group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
A "haloalkyl" is an alkyl group that is substituted with 1 or more independently chosen halogens (e.g., "C|-C3haloalkyl" groups have from 1 to 8 carbon atoms; "Ci-C6haloalkyl" groups have from 1 to 6 carbon atoms). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1, 2,2,2 -tetrafluoro-l-trifluoromethyl-ethyl. Typical haloalkyl groups are trifluoromethyl and difϊuoromethyl. A dash ("— ") that is not between two letters or numbers is used to indicate a point of attachment for a substituent. For example, — C(=O)NH2 is attached through the carbon atom.
A "carbocycle" has from 1 to 3 fused, pendant or spiro rings, each of which has only carbon ring members and each of which may, but need not, be bridged by an alkylene moiety. Typically, a carbocycle that has a single ring contains from 3 to 8 ring members (i.e., C3-C8carbocycles); rings having from 4 or 5 to 7 ring members (i.e., GpCvCarbocycles or Cs-Cycarbocyeles) are recited in certain embodiments. Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Carbocycles may be optionally substituted with a variety of substituents, as indicated. Unless otherwise specified, a carbocycle may be a cycloalkyl group (i.e., each ring is saturated or partially saturated as described above) or an aryl group (Ie., at least one ring within the group is aromatic). Representative aromatic carbocycles are phenyl, naphthyi, tetrahydronaphthyl and bipheπyl. In certain embodiments preferred carbocycles have a single ring., such as phenyl and C3- Cgcycloalkyl groups.
Certain carbocycles recited herein are (C3-C]ocarbocyc1e)Co-C4alky! groups (i.e., groups in which a 3- to 10-membered carbocyclic group (which may be cycloalkyl or aryl) is linked via a single covalent bond or Q-dalkylene). Phenyl groups linked via a single covalent bond or Ci-C6aikylene are designated phenyfCø-Cialkyl (e.g., benzyl, 1 -phenyl-ethyl, l~phenyl-propyl and 2-phenyl-ethyl).
A phenylCo-C4alkoxy group is a phenyl ring linked via an oxygen bridge or via an alkoxy group having from 1 to 4 carbon atoms (e.g., phenoxy or benzoxy). When substituted, it will be apparent that such groups may be substituted on the ring portion and/or on the alkylene portion of the group. A "heterocycle" or "heterocyclic group" has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a heteroatom independently chosen from O, S and N, with the remaining ring atoms being carbon). Additional rings, if present, may be heterocyclic or carbocyclic. Typically, a heterocyclic ring comprises I5 2, 3 or 4 heteroatoms; within certain embodiments eacli heterocyclic ring has 1 or 2 heteroatoms per ring. Each heterocyclic ring generally contains from 4 to 8 ring members (rings having from 4 or 5 to 7 ring members are recited in certain embodiments) and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain heterocycles comprise a sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SOa. Heterocycles may be optionally substituted with a variety of substituents, as indicated. Certain heterαcycies are 4- to l O-membered and comprise one or two rings; in certain embodiments, such heterocycles are monocyclic (e.g., 4- to 8-membered,
5- to 7-membered, 4- to 7-membered> or 5- or ό-membered).
Certain heterocycies are heteroaryl groups (i.e., at least one ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6-membered heteroaryl (e.g., pyrϊdyl or pyrimidyl). For heteroaiyl groups containing multiple rings, it will be apparent that the aromatic ring and the heterocycle may, but need not, be the same; for example, the term "heteroaryl" encompasses groups that comprise a phenyl ring and a heterocycloalkyl ring, such as 2,3-dihydro-l,4-benzodϊoxinyI and 1,3-benzodioxol-S-yI. Other heterocycles are heterocycloalkyl groups (i.e., do not comprise an aromatic ring). Certain heterocycles may be linked by a single covalent bond or via an alkylene group, as indicated, for example, by the terms "(4- to 8-membered heterocycloalkyOQrGtalkyl" and "(4- to 10-membered heterocycle)C0-C4afkyL"
A "substituent," as used herein, is a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, haloalkyl group or other group discussed herein mat is covalently bonded to an atom (such as a carbon or nitrogen atom) that is a ring member. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
Groups that are "optionally substituted" are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically 1, 2, 3, 4 or 5 positions, with one or more suitable groups {which may be the same or different). Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible subsLituents. Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substituents). "Bi," as used herein, refers to the human Bj bradykinin receptor reported by Menke et ah
(1994) J. Biol. Chem. 269:21583-21586, as well as allelic variants thereof and homoiogues thereof found in other species (e.g., GenBank Accession Number AAX14712 for Macaca fascicularis).
The term "Bi agonist" refers to a compound that binds Bj and induces signal transduction mediated by Bi. Such induction may be determined using the representative calcium mobilization assay provided in Example 7. B1 agonists include, for example, bradyktntn and kallidin (lysyl- bradykinin), as well as peptide portions or variants of bradykinin or kallidin that bind Bj and retain activity. Representative Bi agonists include, but are not limited to, desArg9bradykinin and des Arg1 °kai 1 idin.
A "B] antagonist" is a compound that detectably inhibits signal transduction mediated by B). Such inhibition may be determined using the representative calcium mobilization assay provided in
Example 7. Preferred Bi antagonists have an IC50 of 5 μM or less in this assay, more preferably 2 μM or less, and stiJI more preferably 1 μM or less, 500 nM or less, 100 nM or Jess or 10 nM or less. In certain embodiments, the Bi antagonist is specific for Bi (i.e., the ICso value in a similar assay performed using the B2 receptor is greater than 2 μM and/or the IC50 ratio (B2/Bi) is at least 10. preferably 100, and more preferably at least 1000). B1 antagonists preferably have minimal agonist activity (i.e., induce an increase in the basal activity of Bi that is less than 5% of the increase that would be induced by one EC50 of the peptide agonist desArgiOkallidin, and more preferably have no detectable agonist activity within the assay described in Example 7). Bi antagonists for use as described herein are generally non-toxic. Bi antagonists include neutral antagonists and inverse agonists.
A "neutral antagonist" of Bi is a compound that inhibits the activity of Bi agonist (e.g., desArg'\aIlidin) at Bi, but does not significantly change the basal activity of the receptor (i.e., within a calcium mobilization assay as described in Example 7 performed in the absence of agonist, Bj activity is reduced by no more than 10%, more preferably by no more than 5%, and even more preferably by no more than 2%; most preferably, there is no detectable reduction in activity). Neutral antagonists may, but need not, also inhibit the binding of agonist to Bi . An "inverse agonist" of B1 is a compound that reduces the activity of Bi below its basal actfvity level in the absence of activating concentrations of agonist. Inverse agonists may also inhibit the activity of agonist at B1, and/or may inhibit binding of Bi agonist to Bi. The reduction in basal activity of Bi produced by an inverse agonist may be determined from a calcium mobilization assay, such as the assay of Example 7.
A "therapeutically effective amount" (or dose) is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., provides detectable relief from a condition being treated). Such benefit may be detected using any appropriate criteria. A therapeutically effective amount or dose generally results in a concentration of compound in a body fluid (such as blood, plasma, serum, CSF3 synovial fluid, lymph, cellular interstitial fluid, tears or urine) that is sufficient to result in detectable alteration in Brmediated signal transduction (using an assay provided herein). The discernible patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending upon the indication for which the compound is administered. For the treatment of pain, a discernible patient benefit is generally apparent after administration of a single therapeutically effective dose, although further benefit may become apparent following repeated admin istrati ons .
A "patient" is any individual treated with an aryl sulfonyl helerocycle as provided herein.
Patients include humans, as well as other animals such as companion animals (e.g., dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to B] modulation or may be free of such symptom(s) (i.e., treatment may be prophylactic in a patient considered to be at risk for the development of such symptoms),
B1 MODULATORS
As noted above, the present invention provides aryl sulfonyl hetcrocyclcs of Formula I that may be used in a variety of contexts, including in the treatment of conditions responsive to B1 modulation, as described herein. Such compounds may also be used within in vitro assays (e.g., assays for Bi activity), as probes for detection and localization of Bi and within assays to identify other Bj antagonists.
Ri, within Formula I and other formulas provided herein, generally represents optional substituents of the phenyl ring. Within certain compounds, the group designated:
Figure imgf000012_0001
each represent one substituent independently chosen from Ri. Representative R4, R5 and R& groups include, for example, halogen, hydroxy, Ci-C6alkyl, Ci-Cshaloalkyl, Ci-Cβalkoxy and Ci-Cehaloalkoxy. Within certain embodiments, R3 is methyl or methoxy and R4 and R5 (if present) are each methyl; within other embodiments, R4 and Re (if present) each represent a halogen, and R5 is a halogen, methoxy, trifluoromethyl or methyl.
Within certain embodiments of Formula T, and other formulas provided herein, n is 0, m is 1 and q is 0 or 1. In such embodiments, the group designated:
Figure imgf000013_0001
Within other embodiments, n is 1 and either (i) m is 1 and q is 1 or 2, or (ii) m is 2 and q is 1. In such embodiments, the group designated:
Figure imgf000013_0002
, o orr . Such groups include, for
Figure imgf000013_0004
R2, within certain compounds of Formula I and other Formulas provided herein, represents from 0 to 4 substituents independently chosen from Q-Caalkyl. For example, in certain compounds,
R2 represents gem-dimethyl (e.g., the group designated i::
Figure imgf000013_0005
is
As noted above, the variable "Y" is -0-CH2-, -N(R,o)-CH2-, -CH2-CH2-, -CH=CH-, -CH2-O- CH2-, -CH2-CH2-CH2- or -0-CH2-CH2-. It will be apparent that the orientation of such groups within Formula I is retained; for example, when Y is -O-CH2-, then the compound satisfies Formula III:
Formula HI
Figure imgf000013_0006
Certain compounds of Formula I further satisfy Formula II, as described above. Within certain embodiments of Formula II, the group designated: ^—^ is, for example, ^S , wherein p is 0, I5 2 or 3; Z is CR7R8 or NR9;
R7 and Rg are independently chosen from: (i) hydrogen, hydroxy and cyano; and (ii) Ci-Cβalkyl, C2- Cealkenyl, C2-CQalkynyl, C|-C6alkoxy, mono- or di-(Ci-C6alky])aminoC0-C4alkyl, (C3-
C8cycloallcyl)Co-C4alkyl and (4- to 8-membered heterocycloalky^Co-C^alkyl, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, oxo and C)-C6alkyi; or
R7 and Rg are taken together to form a spiro 4- to 10-membered heterocycle that is substituted with from 0 to 2 substituents independently chosen from hydroxy, oxo, cyano and Ci-Cβalkyl; and
R9 is C]-C6alkyl, C2-Q;alkeny], C2-C6a!kynyl, mono- or di-(Cι-C6alkyl)arninoCi-C4aIkyl, (C3-
C]ocarbocycIe)Co~C4alkyl or (4- to 10-membered heterocyc^Co-QalkyJ, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, oxo and d-Q-aikyl.
The group — -/ may, optionally, be further substituted (e.g., with Cj-C6aJkyl or oxo) at one or
more ring carbon atoms. Representative
Figure imgf000014_0001
groups include, for example, .
Within certain embodiments, Z is CR7Rg, where R7 and R8 are as described above. Representative R7 groups include, for example, hydrogen, hydroxy, cyano and Cj-C$alkyl; representative Rg groups include, for example, C2-C6alkyl ether, mono- or di-(Ci-C6alkyI)aminoC0- C^alkyl, phenyl Co-C4alkyl and (4- to 8-membered heterocycloalkyl)C0-C4alkyl, each of which is substituted with from 0 to 2 substihieπts independently chosen from hydroxy, halogen, oxo, cyano, Cj-C4aikyl and Q-C4alkoxy. Within certain such compounds, Rg is mono- or di-(Cp C5alkyl)aminoCo-C4aIkyl or (4- to 8-membered heterocycloalkyl)Co-C«ιaIkyI that is optionally substituted with
Figure imgf000014_0002
Alternatively, R7 and Rs are taken together to form a spiro 4- to 10- membered helerocycle that is substituted with from 0 to 2 substituents independently chosen from hydroxy, oxo, cyano and Ci-Cβalkyl; for example,
</λifu is
Figure imgf000014_0003
, within certain such compounds.
With further embodiments, Z is NR9, whei'ein R3 is as described above. Representative R9 groups include, for example, d-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, mono- or di-(Cp C6aIkyl)aminoCi-C1alkyl, (C3-Ci0carbocycle)Co-C4alkyl and (4- to 10-membered heterocycle)Co-
C4alkyl, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, oxo and Ci-Cβalkyl. Within certain such compounds, R9 is C|-C6aIkyL, mono- or di-(Ci-C6alkyl)aminoCrC4alkyI or (5- to 7-membered heterocycle)C0-C4alkyI} each of which is substituted with from 0 to 2 sυbstituents independently chosen from halogen, hydroxy, cyano, oxo and C]-C6alkyl. Within certain compounds of Formula I, RA is hydrogen, C]-C6alkyl, C2-C6aikenyl, C2-
C6alkynyl, (C3-C8cycloalkyl)Co-Qalky], C2'C6alkyl ether, or mono- or
Figure imgf000015_0001
C4alkyl; and RB is d-Cgalkyl, C2-C6aikenyl, C2-C6aIkynyL (C3-C3eycIoalky])Co-C4aiky!, QrC6alkyl ether, mono- or di-tCi-CgalkyOaminoCrQaikyl, or (5- or 6-membered heterocycloalkyl)C0-C4alkyl, each of which is substituted with from 0 to 6 substituents independently chosen from: (i) amino, halogen, hydroxy, cyano and oxo; and (ii) Ci-C6alkyi, {Ca-CgcycloalkyrjCo-Qalkyl, Ci-Csalkoxy, phenylC0-C4alkyl and (5- or 6-membered heterocycle)Co-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from amino, cyano, halogen, hydroxy, d-C6aIkyl, (C3- C8cycloalkyl)Co-C4aIkyl, Ci-Qhaloalkyl, C)-C6alkoxya Cj-Cealkoxycarbonyl, mono- or di-(Ci- C6aikyl)amino, ρhenylCo-C4alkyl and phenylCo-C4alkoxy. Representative RA groups include, for example,
Figure imgf000015_0002
ether. Representative RB groups include, for example, C2-Cι>alkyl ether, mono- or di-(C1-C≤alkyl)aminoCι-C1|alkyL and (5- or 6-membered heterocycloalkyl)C0-C4alkyi, each of which is optionally substituted.
As noted above, Formulas provided herein encompass non-racemic compounds and racemic mixtures. For example, certain compounds of Formula I satisfy Formula Ia or Formula Ib, and certain compounds of Formula II satisfy Formula Ha or Formula lib:
Figure imgf000015_0003
Formula Ia
Figure imgf000015_0005
Formula ϊϊa
Figure imgf000015_0004
Certain compounds provided herein further satisfy one or more of the following Formulas, in which s is an integer ranging from 1 to 4, R0 and RD are independently hydrogen or Q-Cdalkyl, and the remaining variables are as described above:
Figure imgf000016_0001
Formul"a IV Formula V Foiinula VI
Figure imgf000016_0002
Formula VlI Formula VIII Formula IX
Figure imgf000016_0003
Formula X Formula Xl Foπnula XII
Figure imgf000016_0005
Figure imgf000016_0004
Formula XV
Figure imgf000017_0001
Formula XVI Formula XVII Formula XVIII
Figure imgf000017_0002
Formula XIX Formula XX Foπnula XXI
Figure imgf000017_0003
Formula XXII Formula XXIII
Figure imgf000017_0004
FormuEa XXlV Formula XXV
Figure imgf000017_0005
Formula XXVI Representative compounds provided herein include, but are not limited to, those specifically described in the Examples below. It will be apparent that the specific compounds recited herein are representative only, and are not intended to limit the scope of the present invention. Further, as noted above, all compounds of the present invention may be present as a free acid or base or as a pharmaceutically acceptable salt.
As noted above, within certain aspects, compounds provided herein are Bi modulators. In addition, certain compounds provided herein display B] specificity. Bt modulator activity may be confirmed using a calcium mobilization assay, such as the assay described in Example 7, herein.
If desired, binding activity of the compounds provided herein to Bi may be confirmed using the representative assay described in Example 6, herein, or using an assay described by Fox ct ai.
(2005) Br. J. Pharmacol. 744:889-99. Preferred B1 modulators exhibit a K; within such an assay of 5 micromolar or less, more preferably 2 micromolar or less, I micromolar or iess, 500 nanomolar or less, 100 nanomolar or less or 10 nanomolar or less.
In vivo activity of B] modulators provided herein may be confirmed using any of a variety of animal models including, but not limited to, those described in the following documents (each of which is hereby incorporated by reference for its disclosure of the recited animal model): Wood ct al. (2003) J. Med. Chem. 46: 1803-06 — carrageenan-indiiced mechanical pressure hyperalgesia;
Conley et al. (2005) Eur, J. Pharmacol. 527:44-51 — thermal antinociception and carrageenan-induced mechanical pressure hypersensitivity;
Gougat et al. (2004) /. Pharmacol. Exper. Thercφ. 309:661-669 - UV irradiation-induced thermal hyperalgesia and chronic constriction of the sciatic nerve-induced neuropathy and in ischemia- induced injury;
Fox et al. (2005) Br. J. Pharmacol. /44:889-99 — complete Freund's adjuvant-induced mechanical pressure hypersensitivity;
Gabra et al. (2005) J. Neuropathol. Exp. Neurol. 64:782-89 - diabetes-induced peripheral neuropathic pain; Pesquero et al. (2000) Proc. Natl. Acad. ScL USA 97:8140-45 - carrageenan-induced pleurisy
(inflammation around the lung); Lawson et al. (2005) Eur. J. Pharmacol. 574:69-78 — diabetes-induced vascular disease; Hirata et a (2003) Eur. J. Pharmacol 474:255-60 - ACE inhibitor-induced cough; Mazzuferi et al. (2005) Neuroscience. 735:979-86 — neuronal hyperexcitabilϊty in epilepsy.
If desired, compounds provided herein may be evaluated for certain pharmacological properties including, but not limited to, oral bioavailability (preferred compounds are orally bioavailable to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably less than 50 mg/kg, more preferably less than 30 mg/kg, even more preferably less than 10 mg/kg,, still more preferably less than 1 mg/kg and most preferably less than 0.1 mg/kg), toxicity (a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject), side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), serum protein binding and in vitro and in vivo half-life (a preferred compound exhibits an in vivo haif-life allowing for Q. I. D. dosing, preferably T.I.D. dosing, more preferably B.I.D. dosing, and most preferably once-a- day dosing). In addition, differential penetration of the blood brain barrier may be desirable. Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously). Serum protein binding may be predicted from albumin binding assays. Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described herein. As noted above, preferred compounds provided herein are nontoxic. In general, the term
"nontoxic" as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United Stales Food and Drug Administration ("FDA") for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans). In addition, a highly preferred nontoxic compound generally satisfies one or more of the following criteria: (I) does not substantially inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial liver enlargement, or (4) does not cause substantial release of liver enzymes.
As used herein, a compound that does not substantially inhibit cellular ATP production is a compound that satisfies the criteria set forth in Example 8, herein. In other words, cells treated as described in Example 8 with 100 μM of such a compound exhibit ATP levels that are at least 50% of the ATP levels detected in untreated ceHs. In more highly preferred embodiments, such cells exhibit
ATP levels that are at feast 80% of the ATP levels detected in untreated cells.
A compound that does not significantly prolong heart QT intervals is a compound that does not result in a statistically significant prolongation of heart QT intervals (as determined by electrocardiography) in guinea pigs, miniptgs or dogs upon administration of a dose that yields a serum concentration equal to the ECJO or IC50 for the compound. In certain preferred embodiments, a dose of 0.01, 0.05, 0.1 , 0.5, 1, 5, 10, 40 or 50 mg/kg administered parenterally or orally does not result in a statistically significant prolongation of heart QT intervals. By "statistically significant" is meant results varying from control at the ρ<0.1 level or more preferably at the p<0.05 level of significance as measured using a standard parametric assay of statistical significance such as a student's T test. A compound does not cause substantial liver enlargement if daily treatment of laboratory rodents (e.g., mice or rats) for 5-10 days with a dose that yields a serum concentration equai to the EC5O or IC5O for the compound results in an increase in liver to body weight ratio that is no more than 100% over matched controls. In more highly preferred embodiments, such doses do not cause liver enlargement of more than 75% or 50% over matched controls. If non-rodent mammals (e.g., dogs) are used, such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls. Preferred doses within such assays include 0.01, 0.05. 0.1, 0.5, 1 , 5, 10, 40 or 50 mg/kg administered parenterally or orally. Similarly, a compound does not promote substantial release of liver enzymes if administration of twice the minimum dose mat yields a serum concentration equal to the EC50 or IQo for the compound does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 100% over matched mock-treated controls. In more highly preferred embodiments, such doses do not elevate such serum levels by more than 75% or 50% over matched controls. Alternatively, a compound does not promote substantial release of liver enzymes if, in an in vitro hepatocyte assay, concentrations (in culture media or other such solutions that are contacted and incubated with hepatocytes in vitro) that are equal to the EC50 or IC50 for the compound do not cause detectable release of any of such liver enzymes into culture medium above baseline levels seen in media from matched mock-treated control cells. In more highly preferred embodiments, there is no detectable release of any of such liver enzymes into culture medium above baseline levels when such compound concentrations are five-fold, and preferably len-fold the ECso or IC50 for the compound.
In other embodiments, certain preferred compounds do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP 1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to die ECso or IC50 for the compound.
Certain preferred compounds are not clastogcnic (e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) at a concentration equal the ECso or IC50 for the compound. In other embodiments, certain preferred compounds do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations.
For detection purposes, as discussed in more detail below, compounds provided herein may be isotopically-labeled or radiolabeled. For example, such compounds may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 11C, '3C, 14C, 15N, 18O, 17O, 31P, 32P5 35S, 18F and 36Cl. In addition, substitution with heavy isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
PREPARATION OF BI MODULATORS
Compounds provided herein may generally be prepared using standard synthetic methods. In general, starting materials are commercially available from suppliers such as Sigma-AIdrich Corp. (St,
Louis, MO), or may be synthesized from commercially available precursors using established protocols. By way of example, a synthetic route similar to that shown in any of the following
Schemes may be used, together with synthetic methods known in the ail of synthetic organic chemistry, or variations thereon appreciated by those skilled in the art. It will be apparent that the reagents and synthetic transformations in the following Schemes can be readily modified to produce additional compounds of Formula I. Each variable in the following Schemes refers to any group consistent with the description of the compounds provided herein.
When a protecting group is required, an optional deprotection step may be employed. Suitable protecting groups and methodology for protection and deprotection, such as those described in Protecting Groups in Organic Synthesis by T. Greene, are well known. Compounds and intermediates requiring protection/deprotection will be readily apparent.
Certain abbreviations used in the following Schemes and in the Examples include; Ac2O acetic anhydride
AIBN 2,2'-Azobis(2-rnethylpropionitrile) BOC t-butoxycarbonyl
BOP benzotfiazol-l-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate
DEBAL diisobutylaluminium hydride DMA N, TV-dimethyl acetamide
DMAP N,JV-dimethyl-4-ami»opyridine DMC 2-ch!oro-I.3-dimethyltmidazolinium chloride
DMF dimethylformamide
DMSO dimethylsulfoxide Et ethyl
EtOH ethaπol EtOAc ethyl acetate h hour(s)
1H NMR proton nuclear magnetic resonance iPr isopropy!
LC-MS liquid chromatography/mass spectrometry Me methyl
MHz megahertz
M+l mass + l ram rmnute(s)
MS mass spectrometry n-BuLi n-butyl lithium
NMO N-methylmorphoIine N-oxide δ chemical shift rt room temperature
Ph phenyl
SCX strong cation exchange
SPE solid phase extraction tBu fert-butyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TPAP tetra-n-propylammonium perruthenate
Scheme 1
Figure imgf000022_0001
Scheme 2
1) HCI, BOH 1) DiBAL 2 2)) AArrSSOO22CCii 2) BrCH2CO2IBu
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
Scheme 3
Figure imgf000023_0004
Scheme 4
ne
Figure imgf000024_0001
Scheme 5
Figure imgf000025_0001
NaH, DMF BrCH2CO2Et
Figure imgf000025_0002
Figure imgf000025_0003
Scheme 6
Figure imgf000025_0004
Scheme 7
Figure imgf000026_0001
In certain embodiments, a compound provided herein may contain one or more asymmetric carbon atoms, so that the compound can exist in different stereoisomer^ forms. Such forms can be, for example, racemates or optically active forms. As noted above, all stereoisomers arc encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (i.e., optically active forms). Standard methods for preparing single enantiomers include asymmetric synthesis and 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 HPLC column.
Compounds may be radiolabeled by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. Each radioisotope is preferably carbon (e.g., 14C), hydrogen (e.g., 3H), sulfur (e.g., 35S) or iodine (e.g., 125I). Tritium labeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifiuoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas using the compound as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate. Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. PHARMACEUTICAL COMPOSITIONS
The present invention also provides pharmaceutical compositions comprising one or more aryl sulfonyl heterocycles provided herein, together with at least one physiologically acceptable carrier or excipient. Pharmaceutical compositions may comprise, for example, one or more of water, buffers {e.g., sodium bicarbonate, neutral buffered saline or phosphate buffered saline), ethanoi, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose, starch, matmitol or dextrans), proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. In addition, other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein. Pharmaceutical compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions suitable for oral use are preferred. Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, pharmaceutical compositions may be formulated as a lyophilizate.
Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc). Tablets may be formed using standard techniques, including diy granulation, direct compression and wet granulation. The tablets may be uncoated or they may be coated by known techniques.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
Aqueous suspensions contain the active material(s) in admixture with suitable excipients, such as suspending agents (e.g., sodium carboxymethylccliulosc, mcthylccllulosc, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate. condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as poiyoxyethylene sorbitol monooleate., or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate). Aqueous suspensions may also comprise one or more preservatives, such as ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and/or one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions may also be formulated as oil-in-water emulsions. The oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums (e.g., gam acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monoleate) and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethyJene sorbitan monoleate). An emulsion may also comprise one or more sweetening and/or flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acyiglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphiπgolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers., moisturizers and sustained release materials. Examples of such components are described in Martindale— The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Remington: Tfie Science and Practice of Pharmacy, 21st ed,, Lippincott Williams & Wilkins, Philadelphia, PA (2005). Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions. nanoparticles or nanocapsules.
A topical formulation may be prepared in any of a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions. The physical appearance and viscosity of such pharmaceutically acceptable forms can be governed by the presence and amount of emulsifier(s) and viscosity adjusters) present in the formulation. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate.
Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. A gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaternimns, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethy lcel lulose, carbomer or ammoniated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dϊmethicone copolyol, poiysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations. Suitable preservatives include, but are not limited to. antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl galiate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentaπoate and mineral oils. Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that may be included a topical formulation include, but arc not limited to, abrasives, absorbents, anti-caking agents, anti- foamϊng agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
An example of a suitable topical vehicle for formulation of a gel is: hydroxypropylceliulose
(2.1%); 70/30 isopropyl alcohol/water (90.9%); propylene glycol (5.1%); and Polysorbate 80 (1.9%).
.An example of a suitable topical vehicle for formulation as a foam is: cetyi alcohol (1.1 %); stearyl alcohol (0.5%; QuaternJum 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All percents are by weight.
Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing.
A pharmaceutical composition may be prepared as a sterile injectable aqueous or oleaginous suspension. The compound(s) provided herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Such a composition may be formulated according to the known art using suitable dispersing, wetting and/or suspending agents such as those mentioned above. Among the acceptable vehicles and solvents that may be employed are water, 1,3-butanedioI,
Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
Pharmaceutical compositions may also be formulated as suppositories (e.g., for rectal administration). Sucli compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichiorodifiuoroniethane or trichlorofluoromethane).
Pharmaceutical compositions may be formulated for release at a pre-determined rate.
Instantaneous release may be achieved, for example, via sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract). Controlled release formulations (i.e., formulations such as a capsule, tablet or coated tablet that slows and/or delays release of active ingredient{s) following administration) may be administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at a target site. In general, a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and thereby provides a delayed action or a sustained action over a longer period. One type of controlled-release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate.
Preferably, the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least S hours, and more preferably at least 12 hours. Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation;, the rate and expected duration of release and the nature of the condition to be treated or prevented.
Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controlled-release coating. The release rate can be varied using methods well known in the art, including (a) varying the thickness or composition of coating, (b) altering the amount or manner of addition of plasticizer in a coating,, (c) including additional ingredients, such as release-modifying agents, (d) altering the composition, particle size or particle shape of the matrix, and (e) providing one or more passageways through the coating. The amount of modulator contained within a sustained release formulation depends upon, for example, the method of administration (e.g., the site of implantation), the rate and expected duration of release and the nature of the condition to be treated or prevented. The matrix material, which itself may or may not serve a controlled-release function, is generally any material that supports the active ingredient(s). For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. Active mgredient(s) may be combined with matrix material prior to formation of the dosage form (e.g., a tablet). Alternatively, or in addition, active ingredient(s) may be coated on the surface of a particle, granule, sphere, microsphere, bead or pellet that comprises the matrix material. Such coating may be achieved by conventional means, such as by dissolving the active ingredient(s) in water or other suitable solvent and spraying. Optionally, additional ingredients arc added prior to coating (e.g., to assist binding of the active ingredient(s) to the matrix material or to color the solution). -The matrix may then be coated with a barrier agent prior to application of controlled-release coating. Multiple coated matrix units may, if desired, be encapsulated to generate the final dosage form.
In certain embodiments, a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ϊngredient(s) at a controlled rate in aqueous medium). The controlled release coating should be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert and tack-free. Coatings that regulate release of the modulator include pH-independent coatings, pH-dependent coatings (which may be used to release modulator in the stomach) and enteric coatings (which allow the formulation to pass intact through the stomach and into the small intestine, where the coating dissolves and the contents are absorbed by the body). It wiϊl be apparent that multiple coatings may be employed (e.g., to allow release of a portion υf the dose in the stomach and a portion further along the gastrointestinal tract). For example, a portion of active ingredient(s) may be coated over an enteric coating, and thereby released in the stomach, while the remainder of active ingredient(s) in the matrix core is protected by the enteric coating and released further down the Gl tract. pH dependent coatings include, for example, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid ester copolymers and zein.
In certain embodiments, the coating is a hydrophobic material, preferably used in an amount effective to slow the hydration of the gelling agent following administration. Suitable hydrophobic materials include alkyl celluloses (e.g., ethylcellulose or carboxymethylcellulose), cellulose ethers, cellulose esters, acrylic polymers (e.g., poly(acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacryiate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate. methacrylic acid alkamide copolymer, ρoly(methyl methacryiate), polyacrylamide, ammonio methacryiate copolymers, aminoalkyl methacryiate copolymer, poly(methacrylic acid anhydride) and grycidyl methacryiate copolymers) and mixtures of the foregoing. Representative aqueous dispersions of ethylcellulose include, for example, AQUACOAT© (FMC Corp., Philadelphia, PA) and SURELEASE® (Colorcon, Inc., West Point, PA), both of which can be applied to the substrate according to the manufacturer's instructions. Representative acrylic polymers include, for example, the various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which may be used singly or in combination depending on the desired release profile, according to the manufacturer's instructions. The physical properties of coatings that comprise an aqueous dispersion of a hydrophobic material may be improved by the addition or one or more plasttcizers. Suitable plasticizers for alkyl celluloses include, for example, dibutyl sebacate, diethyl phthalate, friethyl citrate, tribυtyl citrate and triacetin. Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as tricthyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
Controlled-release coatings are generally applied using conventional techniques, such as by spraying in the form of an aqueous dispersion. If desired, the coating may comprise pores or channels or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic material that is dissolved, extracted or leached from the coating in the environment of use. Certain such pore-forming materials include hydrophilic polymers, such as hydroxyalkylcelluloses {e.g., hydroxypropylmethylceilulose), cellulose ethers, synthetic water-soluble polymers {e.g., polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and polyethylene oxide), water-soluble polydextrose, saccharides and polysaccharides and alkali metal salts. Alternatively, or in addition, a controlled release coating may include one or more orifices, which may be formed my methods such as those described in US Patent Nos. 3,845,770; 4,034,758; 4,077,407; 4,088,864; 4,783,337 and 5,071,607. Controlled-release may also be achieved through the use of transdermal patches, using conventional technology {see, e.g., US Patent No. 4,668,232).
Further examples of controlled release formulations, and components thereof, may be found, for example, in US Patent Nos. 4,572,833; 4,587,117; 4,606,909; 4,610,870; 4,684,516; 4,777,049;
4,994,276; 4,996,058; 5, 128,143; 5,202,128; 5,376,384; 5,384,133; 5,445,829; 5,510,1 19; 5,618,560;
5,643,604; 5,891,474; 5,958,456; 6,039,980; 6,143,353; 6,126,969; 6,156,342; 6,197,34-7; 6,387,394;
6,399,096; 6,437,000; 6,447,796; 6,475,493; 6,491,950; 6,524,615; 6,838,094; 6,905,709; 6,923,984;
6,923,988; and 6,911,217; each of which is hereby incorporated by reference for its teaching of the preparation of controlled release dosage forms.
In addition, to or together with the above modes of administration, a compound provided herein may be conveniently added to food or drinking water {e.g., for administration to non-human animals including companion animals (such as dogs and cats) and livestock). Animal feed and drinking water compositions may be formulated so that, the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to feed or drinking water.
Aryl sulfonyl heterocycles(s) provided herein are generally administered in a therapeutically effective amount. Preferred systemic doses are no higher than 50 mg per kilogram of body weight per day {e.g., ranging from about 0.001 mg to about 50 mg per kilogram of body weight per day), with oral doses generally being about 5-20 fold higher than intravenous doses {e.g., ranging from 0.01 to 40 mg per kilogram of body weight per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage unit will vary depending, for example, upon the patient being treated and the particular mode of administration. Dosage units will generally contain from about 10 μg to about 500 rng of an active ingredient Optimal dosages may be established using routine testing, and procedures that are well known in the art.
Pharmaceutical compositions provided herein may, but need not, further comprise one or more additional pharmaceutical agents, such as an anti-inflammatory agent or analgesic.
Anti-inflammatory agents include, for example, non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and cyclooxygenase-2 (COX-2) specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, leflunomide, cycJosporine A, IM gold, minocycline, azathioprine, tumor necrosis factor (TNF) receptor antagonists, soluble TNF alpha receptor (etanercept), anti-TNF alpha antibodies (e.g., infliximab and adalimumab), anti-C5 antibodies, interleukin-1 (IL-I) receptor antagonists (e.g., anakinra or IL-I trap), IL-18 binding protein, CTLA4- Ig (e.g., abatacept), anti-human IL-6 receptor monoclonal antibody (e.g., tocilizumab), LFA-3-lg fusion proteins (e.g., aiefacept), LFA-I antagonists, anti-VLA4 monoantibody (e.g., natalizumab), anti-CDl Ia monoclonal antibody, anti-CD20 monoclonal antibody (e.g., rituximab), anti-IL-I2 monoclonal antibody, anti-IL-15 monoclonal antibody, CDP 484, CDP 870, chemokine receptor antagonists, selective iNOS inhibitors, p3δ kinase inhibitors, integrin antagonists, angiogenesis inhibitors, and TMI-I dual inhibitors. Further anti-inflammatory agents include meioxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib.
NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen or naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodofac, fenoprofen calcium, ketoprof.en, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. One class of NSAIDs consists of compounds that inhibit cyclooxygeπase (COX) enzymes; such compounds include celecoxib and rofecoxib. NSAlDs further include salicylates such as acetylsalicylic acid or aspirin, sodium salicylate, choline and magnesium salicylates, and salsalate, as well as corticosteroids such as cortisone, dexamethasone, methyl prednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.
Certain analgesics for use in combination with B1 modulators provided herein are also antiinflammatory agents, and are listed above. Other such medications are analgesic agents, including narcotic agents which typically act at one or more opioid receptor subtypes (e.g., μ, K and/or δ), preferably as agonists or partial agonists. Such agents include opiates, opiate derivatives and opioids, as well as pharmaceutically acceptable salts and hydrates thereof. Specific examples of narcotic analgesics include, within preferred embodiments, alfentanil, aiphaprodine, anileridine, bezitramide, buprenorphine, butorphanol. codeine, diacetyldihydromorphine, diacetylmorphine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphane, levorphanol, meperidine, metazocine, methadone, methorphan, metopon, morphine, nalbuphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, paregoric, pentazocine, pethidine, phenazocine, piminodine, propoxyphene, racemethorphan, racemorphaπ, sulfentanyl, thebaine and phaπnaceutically acceptable salts and hydrates of the foregoing agents.
Other examples of narcotic analgesic agents include acetorphine, acetyldihydrocodeine, acetylmethadol, allylprodine, afphracetylmethadol, alphameprodine, alphamethadol, bcnzethidine, benzyhnoφhiπe, betacetyimethadol, betameprodine, betamethadol, betaprodine, clonitazene, codeine methylbromide, codeine-N-oxide, cyprenorphine, desomoφhine, dextronrtoramide, diampromide, diethylthiambutene, dihydromorphine, dimeπoxadol, dimepheptanol, dimethylthiamubutene, dioxaphetyl butyrate, dipipanone, drotebanol, ethanoi, ethylmethylthiambutene, etonitazene, etorphine, etoxeridine, furethidine, hydromorphinol, hydroxypethidine, ketobemidone, levomoramide, levophenacylmorphan, methyldesorphine, methyidihydromoφhine, morpheridine, morphine, methylpromide, morphine methylsulfbnate, moφhine-N-oxide, myrophin, naloxone, naltyhexone, nicocodeine, nicomorphine, noracymethadol, norlevorphanol, normethadone, norraorphine, norpipanone, pentazocaine, phenadoxone, phenampromide, phenomorphan, phenoperidine, piritramide, pholcodine, proheptazoine, properidine, propiran, racemorarnide, thebacon, trimeperidine and the pharmaceutically acceptable sails and hydrates thereof.
Further specific representative analgesic agents include, for example acetaminophen
(paracetamol); aspirin and other NSAIDs described above; NR2B antagonists; capsaicin receptor antagonists: anti-migraine agents; anticonvulsants such as oxcarbazepine and carbamazeptne; antidepressants (such as TCAs, SSJR-Is, SNRIs, substance P antagonists, etc.); spinal blocks; pentazocine/naloxone; meperidine; Jevoφhanol; buprenoφhine; hydromorphone; fentanyl; sufentanyl; oxycodone; oxycodone/acetaminophen, nalbuphine and oxymoφhone. Still further analgesic agents include CB2-receptor agonists, such as AM1241, capsaicin receptor antagonists and compounds that bind to the α2δ subunit of voltage-gated cafcium channels, such as gabapentin and pregabalin.
Representative anti-migraine agents for use in combination with a Bi modulator provided herein include CGRP antagonists, capsaicin receptor antagonists, ergotamines and 5-HTi agonists, such as sumatripan, naratriptan, zolmatriptan and rizatriptan.
Pharmaceutical compositions may be packaged for treating conditions responsive to B1 modulation (e.g., treatment of pain, inflammation or other disorder(s) recited herein). Packaged pharmaceutical preparations generally comprise a container holding a therapeutically effective amount of a pharmaceutical composition as described above and instructions (e.g., labeling) indicating that the composition is to be used for treating a condition responsive to Bi modulation in a patient (e.g., pain or other disorder as indicated herein). In certain embodiments, a packaged pharmaceutical preparation comprises one or more aryl sulfonyl heterocycles provided herein and one or more additional agents in the same package, either in separate containers within the package or in the same container (i.e., as a mixture). Preferred mixtures are foπnulated for oral administration (e.g., as pills, capsules, tablets or the like). In certain embodiments, the package comprises a label bearing indicia indicating that the components are to be taken together for the treatment of pain.
METHODS OF USK
Within certain aspects, the present invention provides methods for treating a condition responsive to Bi modulation in a patient. The patient may be afflicted with such a condition, or may be free of symptoms but considered at risk for developing such a condition. A condition is "responsive to Bj modulation" if the condition or symptom(s) thereof are alleviated, attenuated, delayed or otherwise improved by modulation of Bi activity. In general, such methods comprise administering to the patient a therapeutically effective amount of at least one compound as provided herein.
Conditions responsive to B] modulation include, for example pain; inflammation including neuroinfiammation (such as atherosclerosis), inflammation associated with airway diseases (e.g., asthma, including allergic asthma, exercise-induced branch oconstriction, occupational asthma, and other non-allergic asthmas), and inflammatory skin disorders (e.g., psoriasis and eczema)); respiratory disorders including bronchoconstrictioπ, asthma, chronic obstructive pulmonary disease (e.g., emphysema), chronic cough (including ACE-inhibitor cough), adult respiratory distress syndrome, bronchitis, pneumonia, allergic rhinitis and vasomotor rhinitis; vascular edema (including diabetes- related vascular disease); and epilepsy.
Other conditions responsive to Bi modulation include diabetes (e.g., type Il or non insulin dependent, as well as diabetic vascuiopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and symptoms associated with insulitis), seizure disorders (e.g., epilepsy), multiple sclerosis, liver disease, cardiovascular disorders (e.g., atherosclerosis, congestive heart failure and myocardial infarction), neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) rheumatoid arthritis, infection, cancer, cranial trauma, rhinitis, septic shock, endotoxic and pancreatic shock, anaphylaxis, inflammatory bowel disease, irritable bowel syndrome, pancreatitis, cystitis, uveitis, vascular permeability, gingivitis, osteoporosis, benign prostatic hyperplasia, hyperactive bladder, cerebral edema, vasodilation, hypotension associated with sepsis, edema resulting from trauma associated with burns, sprains or fracture, cerebral edema, angiodema, Crohn's disease and ulcerative colitis. B| modulators may aiso be used as smooth muscle relaxants for treating spasms of the gastrointestinal tract of uterus. In certain embodiments, the condition responsive to Bi modulation is pain or inflammation.
Pain that may be treated using the Bi modulators provided herein includes, for example, acute, chronic, inflammatory, and neuropathic pain. Specific pain indications that may be treated as described herein include, but are not limited to, bone and joint pain (e.g., pain associated with osteoarthritis or rheumatoid arthritis; various neuropathic pain syndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome, fibromyalgia, oral neuropathic pain, phantom limb pain, post-mastectomy pain, peripheral neuropathy, traumatic neuropathy, painful polyneuropathy, myofascial pain syndromes, MS-related neuropathy, HIV or AIDS-related neuropathy, and chemotherapy-induced and other iatrogenic neuropathies); visceral pain, (such as that associated with gastroesophageal reflux disease (GERD):, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, renal colic, interstitial cystitis, intestinal gas, gynecological disorders (e.g., menstrual pain, dysmenorrhoea, pain associated with cystitis, labor pain, chronic peivic pain, vulvodynia, chronic prostitis, and endometriosis), heart pain and abdominal pain, and urologicai disorders); dental pain (e.g., toothache, denture pain, nerve root pain, pain resulting from periodontal disease, and pain due to dental surgery including operative and post-operative pain); stump pain; meralgia paresthetica; burning-mouth syndrome; pain associated with nerve and root damage, including as pain associated with peripheral nerve disorders (e.g., nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies including bilateral peripheral neuropathy, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis), causalgia, neuritis (including, for example, sciatic neuritis, peripheral neuritis, polyneuritis, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis and ϋombault's neuritis), neuronitis, neuralgias (e.g.r those mentioned above, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, mϊgranous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia. Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia and vidian neuralgia); surgery-related pain; musculoskeletal pain; central nervous system pain (e.g., pain due to brain stem damage, sciatica, and ankylosing spondylitis); and spinal pain, including spinal cord injury-related pain.
Headache, including headaches involving peripheral nerve activity may also be treated as described herein. Such headache pain includes, for example, sinus, cluster (i.e., migranous neuralgia) and tension headaches, migraine, temporomandibular pain and maxillary sinus pain. For example, migraine headaches may be prevented by administration of a compound provided herein as soon as a pre-migrainous aura is experienced by the patient.
Further pain conditions that can be treated as described herein include Charcot's pains, ear pain, muscle pain, eye pain, orofacial pain (e.g., odontalgia), repetitive motion pain, carpel tunnel syndrome, acute and chronic back pain (e.g., lower back pain), gout, scar pain, hemorrhoidal pain, dyspeptic pains, angina, nerve root pain, "non-painful" neuropathies, complex regional pain syndrome^ homotopic pain and heterotopic pain - including pain associated with carcinoma, often referred to as cancer-associated pain (e.g., in patients with bone cancer), pain (and inflammation) associated with venom exposure (e.g., due to snake bite, spider bite, or insect sting) and trauma- associated pain (e.g., post-surgical pain, episiotomy pain, pain from cuts, musculoskeletal pain, bruises and broken bones, and bum pain, especially primary hyperalgesia associated therewith). Additional pain conditions that may be treated as described herein include pain associated with autoimmune diseases or immunodeficiency disorders, hot flashes, burns, sunburn, and pain that results from exposure to heat, cold or external chemical stimuli.
In certain embodiments, pain treated with B1 modulators provided herein is inflammatory pain, acute pain, dental pain, back pain, surgical pain, headache, neuropathic pain or pain from osteoarthritis or trauma.
It will be apparent that compounds provided herein may be administered alone or in combination with, one or more additional agents that are suitable for treating the disorder of interest. Within such combination therapy, the compound(s) and additional agent(s) may be present in the same pharmaceutical composition, or may be administered separately in either order. Representative anti-inflammatory agents and analgesics for use in combination therapy include those indicated above. Within other aspects, B) modulators provided herein may be used within combination therapy for the treatment of conditions involving pain and/or inflammatory components. Such conditions include, for example, autoimmune disorders and pathologic autoimmune responses known to have an inflammatory component including, but not limited to, arthritis (especially rheumatoid arthritis), psoriasis, Crohn's disease, lupus erythematosus, irritable bowel syndrome, tissue graft rejection, and hyperacute rejection of transplanted organs. Other such conditions include trauma (e.g., injury to the head or spinal cord), cardio- and cerebro-vascular disease and certain infectious diseases. Within such combination therapy, a B) modulator is administered to a patient along with an additional analgesic and/or anli-Jnflammatory agent. The Bi modulator and additional analgesic and/or anti-inflammatory agent may be present in the same pharmaceutical composition, or may be administered separately in either order.
Administration to the patient can be by way of any means discussed above, including oral, topical, nasal or transdermal admin ϊstration, or intravenous, intramuscular, subcutaneous, intrathecal, epidural, imracerebroventricular or like injection. Oral administration is preferred in certain embodiments (e.g., formulated as pills, capsules, tablets or the like).
Treatment regimens may vary depending on the compound used and the particular condition to be treated. In general, a dosage regimen of 4 times daily or less is preferred, with 1 or 2 times daily particularly preferred. It will be understood, however, that the specific dose and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, the time of administration, the route of administration, the rate of excretion, any drug combination and the severity of the particular disease undergoing therapy. Dosages are generally as described above; in general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.
Suitable dosages for B] modulators (either alone or within such combination therapy) are generally as described above. Dosages and methods of administration of any additional agent(s) (e.g., anti-inflammatory and/or analgesic agents) can be found, for example, in the manufacturer's instructions or in the Physician's Desk Reference. In certain embodiments,, combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect (i.e., a decrease in the minimum therapeutically effective amount). Thus, preferably, the dosage of additional agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of the agent without combination with a compound of Formula I. More preferably this dose is less than 3A, even more preferably less than Vz, and highly preferably less than VA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the agent(s) when administered without combination administration as described herein. It will be apparent that the dose of compound as provided herein needed to achieve the desired effect may similarly be affected by the dose and potency of the additional agent.
Within separate aspects, the present invention provides a variety of non-pharmaceutical in vitro and in vivo uses for the compounds provided herein. For example, such compounds may be labeled and used as probes for the detection and localization of B] (in samples such as cell preparations or tissue sections, preparations or fractions thereof). In addition, compounds provided herein that comprise a suitable reactive group (such as an aryl carbonyl, nitro or azide group) may be used in photoaffinity labeling studies of receptor binding sites. In addition, compounds provided herein may be used as positive controls in assays for receptor activity, as standards for determining the ability of a candidate agent to bind to B]s or as radiotracers for positron emission tomography
(PET) imaging or for single photon emission computerized tomography (SPECT). Such methods can be used to characterize Bi receptors in living subjects. For example, a compound may be labeled using any of a variety of well known techniques (e.g., radiolabeled with a radionuclide such as tritium, as described herein), and incubated with a sample for a suitable incubation time (e.g., determined by first assaying a time course of binding). Following incubation, unbound compound is removed (e.g., by washing), and bound compound detected using any method suitable for the label employed (e.g., autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be used to delect luminescent groups and fluorescent groups). As a control, a matched sample containing labeled compound and a greater (e.g., 10-fold greater) amount of unlabeled compound may be processed in the same manner. A greater amount of detectable label remaining in the test sample than in the control indicates the presence of Bi in the sample. Detection assays, including receptor autoradiography (receptor mapping) of B| in cultured cells or tissue samples may be performed as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology
(1998) John Wiley & Sons, New York. The following Examples are offered by way of illustration and not by way of limitation.
Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification. Using routine modifications, the starting materials may be varied and additional steps employed to produce other compounds provided herein.
EXAMPLES
Mass spectroscopy data in the following Examples is Electrospray MS5 obtained in positive ion mode using a Micromass Time-of-FHght LCT (Micromass, Beverly MA), equipped with a Waters 600 pump (Waters Corp.; Mϊlford, MA), Waters 996 photodiode array detector, and a Gilson 215 autosarapler (Gilson, Inc.; Middleton, Wϊ). MassLynx (Advanced Chemistry Development, Inc; Toronto, Canada) version 4.0 software with OpenLynx Global Server™, OpenLynx™ and AutoLynx™ processing is used for data collection and analysis. MS conditions are as follows: capillary voltage = 3.5 kV; cone voltage = 30 V, desolvation and source temperature = 35O0C and 1200C, respectively; mass range = 181-750 with a scan time of 0.22 seconds and an interscan delay of 0.05 min.
Sample volume of 1 microliter is injected onto a 50x4.6mm Chromolith SpeedROD RP- 18e column (Merck KGaA, Darmstadt, Germany), and eluted using a 2-phase linear gradient at a flow rate of 6 ml/min. Sample is detected using total absorbaiice count over the 220~340nm UV range. The elution conditions are: Mobile Phase A - 95% water, 5% MeOH with 0.05% TFA; Mobile Phase B - 5% water, 95% MeOH with 0.025% TFA. The following gradient is used: 0-0.5 min 10-I00%B, hold at 100%B to 1.2 min, return to 10%B at 1.21 min. Inject to inject cycle is 2.15 rain.
EXAMPLE 1. SYNTHESIS OF REPRESENTATIVE ARYL SULFONYL HETEROCYCLES
A. l-(4-(3 -(DIMETHYLAMINO)PROPYL)PIPERAZIN- 1 -YL)-2-((4-(4-METTIOXY-2,6- DIMETHYLPHENYLSULFONYL)MORPHOLIN-3-YL)METHOXY)ETHANONE
Figure imgf000040_0001
Step 1. Ethyl 4-(4-methoxy-2,6-diraethylphenylsulfonyl)-morphoIinyl-3-carboxylate
Figure imgf000041_0001
To a solution of N-BOC-rnorpholine-S-carboxylic acid (980 mg, 4.2mraol) is added 5 mL of a solution of 2M HCl in ether. The mixture is stirred at reflux for 15 hours, cooled to rt, and the solvent removed in vacuo. The resulting product is dissolved in 15 mL pyridine. 2,6-Dimethyl-4- methoxyphenylsulfonyl chloride (1.2 g, 5 mmol) and DMAP (15 mg) are added. The reaction mixture is stirred at 50 0C for 5 h, cooled to rt, diluted with 1.00 mL EtOAc, and transferred to a separatory funnel. The reaction mixture is washed three times with 50 mL water and once with 50 mL brine. The organic phase is dried over MgSO4, filtered, and then concentrated in vacuo. The product is purified by flash chromatography eluting with 8/2 hexanes/EtOAc, followed by 1/1 hexanes/EtOAc to afford the title compound.
Step 2. r<2rr-Butyi 2-((4-(4-methoxy-2,6-dimethylphenylsuIfonyI)morpholin-3-yl)methoxy)acetate'
Figure imgf000041_0002
Ethyl 4-(4-methoxy-2,6-dimelhylphenylsulfony.)-morphoiinyl-3-carboxyIate (476 mg, 1.33 mrnol) is dissolved in 10 mL dry THF. A solution of DIBAL (4 mL of a 1 M THF solution) is added and the reaction mixture is stirred at rt for ! hr. Another 4 mL of DIBAL solution is then added and stirring is continued for another hour. The reaction is quenched by careful addition of solid
Na2SO4' I OH2O. The reaction mixture is filtered through Ceiite then concentrated in vacuo. The
DlBAL reduction product is dissolved in 5 mL dry DMA at room temperature. Sodium hydride is added (63 mg of a 60% oil dispersion) followed by /t?r/-butyl bromoacetate (0.22 mL, 1.5 mmol). The reaction mixture is stirred at room temperature for 15 h. The reaction mixture is diluted with 20 mL
EtOAc3 and then washed successively with saturated NH4Cl, IN NaOH, H2O, and brine. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The product is purified by column chromatography eluting with 8/2 hexanes/EtOAc, followed by 6/4 hexanes/EtOAc to afford the title compound. Step 3. 2-{(4-(4-Methoxy-2,6-dimetliylphenylsu3foπyl)moφholin-3-yl)methoxy)acetic acid
Figure imgf000042_0001
tert~Buty\ 2-((4-(4-methoxy-2,6-dimethylphenylsulfonyI)morpholin-3-yl)methoxy)acetate (454 mg, 1 -06 mmol) is dissolved in 5 mL dioxane. HCl (1.2 mL of a 2M HCI in dioxane solution) is added and the reaction mixture is stirred 15 h at 60 0C. The reaction mixture is cooled to rt and concentrated in vacuo. The product is purified by flash chromatography eluting with 6/4 hexanes/EtOAc followed by EtOAc to afford the title compound;
Step 4. 1 -(4-(3-(Dimethylamino)propyl)piperazm-3 -y!)-2-((4-(4-methoxy~2,6- dimethy]phenylsuifonyJ)morpholin-3-yl)methoxy)ethanone
Figure imgf000042_0002
To a solution of 2-((4-(4-metlioxy-236-dimethylphenyJsulfonyl)moiphoiin-3- yl)methoxy)acetϊc acid (0.3 mL of a 0.2M solution of acid in DMA) is added 4-(3- (dimethylammo)propyl)piperazine (0.3 mL of a 0.2M solution in toluene) followed by BOP (100 mg, 0.23 mmol) followed by TEA (0. I mL). The reaction mixture is stirred at 60 αC for 4 hours. The reaction mixture is cooled to room temperature, diluted with 1 mL RtOAc, and washed with 2 mL H2O. The organic phase is applied to a Ig SCX cartridge and eluted with 5 mL MeOH to remove non-basic by-products followed by 5 mL 2N NH3 in MeOH to elute the title compound. Removal of solvent affords the title compound as a white foam. 1H NMR (400 MHz, CDC13) δ: 6.63 (s, 2H), 4.11 (s, 2H)5 4.05 (d, IH), 3.94 (t, IH), 3.81 (s, 3H), 3.77 (m, 2H), 3.73 (m, 2H), 3.57-3.60 (m, 4H), 3.40- 3.42 (m, 4H), 3.22 (dt, IH), 3.12 (dd, IH)5 2.60 (s, 6H), 2.34-2.44 (m, 6H), 2.29 (t, 2H), 2.21 (s, 6H), 1.65 (m, 2H). LC-MS m/z (M+H): 527.29. B. (R)-2-((4-(4-METHOXY-2,6-DIMEΗIYLPIIENYLSULFONYL)-6,6-DlMETHYLMORPHOLIN-3- YL)METHOXY)-l-(4-( 1 -METHYLPIPERΪDIN-4- YL)PIPERAZIN-1 -YL)ETHANONE
Figure imgf000043_0001
Step 1. (S)-Methyi 6,6-dimethylrnorphoiine-3-carboxylate
Figure imgf000043_0002
(S)-Methyl 2-(benzy!amino)-3-hy -droxypropanoate (27.4 g, 131 mmol) is combined with 3- bromo-2-methylpropene (25 mL, 248 mmol), K2CO3 (45 g, 327 πimol), and Kl (4.3 g, 26 mmol) in 300 mL acetonitrile. The reaction mixture is stirred at rt for 3 days. Iodine (66 g, 262 mmol) is added and the reaction mixture is stirred an additional 2 h at rt. The reaction mixture is diluted with 300 mL ether and transferred to a separatory funnel. The solution is washed twice successively with 200 mL IN Na2SO3, once with 200 mL saturated NaHCOa5 and once with 200 mL brine. The organic phase is dried over MgSO^, filtered and concentrated in vacuo. The product is purified by flash chromatography, eluting with 9/1 hexanes/EtOAc to afford (3S)-methyI 4-benzyl-6-(iodomethyl)-6- mϋthyimorpholine-3-carboxylate as a 5/1 mixture of diastereomers. This mixture of diastereomers is combined with tributyltin hydride (73 mL, 272 mmol) in 400 mL refiuxing toluene. AIBN (1 g, 6 mmol) dissolved in 40 mL toluene is added dropwise. After 2 h reflux, the reaction mixture is cooled to rt. Saturated aqueous KF solution (800 mL) is added and the resulting heterogeneous mixture is filtered through Celite and the solid washed with EtOAc. The combined solutions are transferred to a separatory funnel and washed twice with 200 mL saturated KF, and then once with 20 mL brine. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The product is purified by flash chromatography eluting with 95/5 hexanes/EtOAc followed by EtOAc to afford (S)-methyl 4- benzyl-6,6-dimethylmorpholine-3-carboxylate as a clear oil. This oil is dissolved in a mixture of 200 mL MeOH and 20 mL acetic acid. Palladium hydroxide (5 g, 20 wt. % on carbon) is added and the reaction mixture hydrogenated on a Paar apparatus at 50 psi for 1O h. An additional 5 g of palladium hydroxide is added and the hydrogeπation is continued at 50 psi for another 25 h. The reaction mixture is filtered through Celite and concentrated in -vacuo to afford the title product. IH NMR (400 MHz, d-6-DMSO) d: 3.71-3.74 (m, I H)5 3.61-3.65 (m, I H), 3.61 (s, 3H), 3.36 (m, IH), 2.65 (d, IH)5 2.46 (d, I H), 1.1 1 (s, 3H)5 1.09 (s, 3H).
Step 2. (R)~2-{(4 -(4-Methoxy-2,6-dimethylpheny lsulfonyl)-6,6-dimethylmorpholin-3 - yl)methoxy)acetic acid
Figure imgf000044_0001
(S)-Methyl 6,6-dimethylmorpholine-3-carboxylate (2.3 g, 13 mraol) is dissolved in 50 mL pyridine. 2,6~Dimethyl~4-τnethoxyphenylsu]fonyl chloride (3.1 g, 13 mmol) and DMAP (15 mg) are added. The reaction mixture is stirred at 50 0C for 5 h. The reaction mixture is cooled to rt, diluted with 100 mL EtOAc, and transferred to a separatory funnel. The reaction mixture is washed three times with 50 mL water and once with 50 mL brine. The organic phase is dried over MgSO4, Filtered, then concentrated in vacuo. The product is purified by flash chromatography eluting with 8/2 hexanes/EtOAc followed by I/I hexanes/EtOAc to afford (S)-methyl 4-(4-methoxy-2,6- dτmerhy1phenylsuf fonyl)-636-dimethy!moφho!ine-3-carhoxylate. This compound is. dissolved in 8 mL of dry THF at 0 0C. DIBAL (8 rnL of a IM solution in THF) is added and the reaction mixture stirred 30 min at 0 0C. An additional 1 mL DlBAL solution is added and stirring is continued for 30 min. The reaction mixture is quenched by addition of solid Na2SO4- IOH2O. The reaction mixture is filtered through Celite and concentrated in vacuo to afford (R)-(4-(4-methoxy-2,6- dimethy3ρhenylsulfonyl)-6,6-dimethyImorpholin-3-yi)methanol. This compound, without further purification, is dissolved in 10 mL DMA at rt. Potassium iodide (20 mg) and sodium hydride (140 mg of a 60% oil dispersion) are added, followed by bromo
Figure imgf000044_0002
acetate (0.48 mL, 3.2 mmol). The reaction mixture is stirred for 2 days, and then diluted with 50 mL EtOAc, transferred to a separatory funnel, and washed once with 20 mL water and once with 20 mL brine. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The product is purified by flash chromatography eluting with 9/1 hexanes/EtOAc to afford (R)-tø-f-butyl 2-((4~(4-mcthoxy-2,6- dimethyIphenylsulfonyl)-6,6-dimethylmorpholin-3-yi)methoxy)acetate. This compound is dissolved in 3 mL of 4 M HCI in dioxane. and stirred at 500C for 3 h. The reaction mixture is cooied to rt and concentrated in vacuo. The product is purified by flash chromatography, eluting with 1/1 hexanes/EtOAc to afford the title compound. LC-MS m/∑ (M+Kfa): 424.73. Step 3. (R)-2-((4-(4 -Methoxy-2,6-dimethylphenyIsulfonyl)-6,6-dimethylmorpholin-3 ~yl)methoxy)- 1 - (4-(l-methylpiperidin-4-yl)piperazin-l-y!)ethanone
Figure imgf000045_0001
To a solution of (R)-2-((4- -(4-jmvethoxy-2,6-dimethylphenylsuIfoiiyl)-6:ι6-dimethylmθφholin- 3-yl)methoxy)acetic acid (1 itiL of a 0.2 M solution in 95/5 EtOAc/TEA) is added isobutylchloroformate (1 raL of a 0.2 M solution in toluene). The reaction mixture is stirred at rt for S min. I-(l-Methylpϊperidin-4-yi)piperazine (1.2mL of a 0.2M solution in toluene) is added and the reaction mixture is stirred 90 min at rt. The reaction mixture is diluted with 5 mL EtOAc and washed with 1 mL IN NaOH. The organic phase is applied to a 1O g silica SPE cartridge and eluted with 10 int. RtOAc to remove non-poiar impurities, followed by 10 mL 10/1/1 EtOAc/MeOH/TEA to elute the title compound. The solvent is removed in vacuo to afford the title compound. 1H NMR (400 MHz, CDCl3) S: 6.62 (s, 2H), 4.04 (s, 2H)5 3.93 (dd, IH), 3.84-3.86 (m, IH), 3.81 (s, 3H), 3.76 (d, IH), 3.70 (m, 3H)5 3.56 (m, 3H), 3.47 (m, 1 H)3 3.39 (m, 2H), 2.99 <dd, 2H), 2.90 (d, 2H)5 2.60 (a, 6H), 2.52 (m, 4H), 2.25 (s, 3H), 1.95 (t, 2H), 1.75 (d, 2H), 1.56 (m, 2H), 1.15 (s, 3H), 1.11 (s, 3H). LC-MS m/z (M+H): 567.17.
C. ADDITIONAL ARYL SULFONYL HETEROCΎCLES
Using routine modifications, the starting materials may be varied and additional steps employed to produce other aryl sulfony! heterocycles, including the following:
I. (R)-2-((4-(4-Methoxy-236-dimethylphenylsulfonyl)-6-6-dimethy!moφholm-3-yl)methoxy)-l-(4- (3-(piperidin- 1 -yl)propyl)ρiperazin- 1 -yl)ethanone
Figure imgf000045_0002
1H NMR {400 MHz, CDC13) δ: 6.62 (s, 2H), 4.04 (s, 2H), 3.93 (dd, IH), 3.85 (d, I H), 3.82 (s, 3H), 3.77 (d. IH), 3.71 (m, IH)5 3.57 (m, 2H), 3.40 (m, 2H), 3.04 (d, IH), 2.96 (d, IH), 2.64 (d, 2H), 2.60 (s, 6H)5 2.33-2.44 (m, 10H), 1.70 (m, 2H), 1.60 (m, 4H), 1.44 (m, 2H), 1.15 (s, 3H), 1.12 (s, 3H). LC- MS m/z (M+H): 595.61. 2. (R)-2-((4-(4-Methoxy-2,6-diraethylphenyIsulfonyl)-6,6-dimethylmoτpholin-3-yl)methoxy)-l-(4- (3-(piperidin-l-yl)propyl)piperidin-l-yl)ethanone
Figure imgf000046_0001
1H NMR (400 MHz5 CDCB) δ: 6.62 (s, 2H)3 4.48 (d3 IH), 4.02 (s, 2H)5 3.93 (dd, IH), 3.85 (d, IH), 3.82 (s, 3H), 3.62-3.80 (m, 3H), 3.57 (m, IH), 3.51 (m, IH), 3.08 (t, IH), 2.95-3.02 (m, 2H)3 2.88 (d, IH), 2.66 (d, 2H)3 2.63 (s, 6H), 2.51. (m, IH)5 2.38 (m, 4H)5 2.28 (m, 2H), 1.70 (br d, 2H), 1.60 (m, 2H), 1.52 (m, 2H)3 1.43 (m, 2H), 1.24 (m, 2H)3 1.15 (s, 6H), 1.13 (m, 2H), 1.06 (m, 2H). LC-MS m/z (M+H): 594.25.
Compounds listed in Table I are prepared using methods illustrated above. All compounds in Table I exhibit an IC50 determined as described in Example 7 that is 5 micromolar or less. Mass spectroscopy (MS) data is provided as M+l, with retention times (Ret time) shown in minutes.
Table I Representative Aryl Suifonyl Heterocycles
Ret Compound Name Time MS
1
Figure imgf000046_0002
L T 5 484"35
L 15 470J4
Figure imgf000046_0003
Compound Name MS
1.16 472.35
1.15 484.37
1.15 472.36
Figure imgf000047_0001
1.15 484.37
1.15 470.35
Figure imgf000047_0002
Ret
Compound Name Time MS
1.14 470.37
Figure imgf000048_0001
Figure imgf000048_0002
1.15 486.39
Figure imgf000048_0003
NrN-diethyI- 1 -[({(3 S)-4-
[(4-methoxy-2,6- dimethylphenyj)sulfonyl]m orpholin-3- 1.16 512.43 yl} methoxy)acetyl]piperidi n-4-amine
Figure imgf000048_0004
Ret
Compound Name Time MS
1.16 498.42
Figure imgf000049_0001
)- -
1.16 496.41 ]m
Figure imgf000049_0002
Ret
Compound Name Time MS
Figure imgf000050_0001
N-(cyclopropylmethyl)- 1 -
[({(3S)-4-[(4-methoxy-2,6- dimethy1phenyl)sulfony]]m orpholin-3- 1.18 552.50 yl}methoxy)acetyl]-N- propylpiperidin-4-amine
Figure imgf000050_0002
1.17 540.51
1.15 510.44
Figure imgf000050_0003
Ret
Compound Time MS
1.16 524-46
1.17 528.46
1.16 569.54
Figure imgf000051_0001
N-isopropyl-N-(2-{4-
[({(3 S)-4-[(4-methoxy-2,6- dimethylρhenyl)sulfony]]m 2 orpholin-3- 1.15 569.54 yl}methoxy)acetyl]piperazi n- 1 -yl} ethyl)propan-2- araine
Figure imgf000051_0002
3 1.14 555.50
Figure imgf000051_0003
Ret
Compound Name Time MS
Figure imgf000052_0001
1.12 553.52 i
1.14 553.52 i
1.13 567.54
Figure imgf000052_0002
Ret
Compound Name Time MS
N,N-diethyI~3-{4-[({(3S)-
4-[(4-methoxy-2,6- dimetliylphenyl)suffonyl]m orphoIin-3- 1.12 555.54 y 1 } metlioxy)acety 1] piperazi n- 1 -y 1} propan- 1 -amine
Figure imgf000053_0001
1.12 553.53
l
Figure imgf000053_0002
Figure imgf000053_0003
1.14 539.50 i
1.1 512.4
I.I 547.4
Figure imgf000053_0004
Ret
Compound Name Time MS
1.1 512.4
1.1 508.1
,
1.1 507.1
Figure imgf000054_0001
Figure imgf000054_0002
Ret
Compound Name Time MS
N-(4-cyanopheny!)-2-
({(3R)-4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]-
6,6-dimethylmorpholin-3- 1.2 516.2 yl}metlioxy)~N~ methylacetamide
Figure imgf000055_0001
1.2 548.1
1.2 509.1
1.1 611.1
1.1 558.2
Figure imgf000055_0002
Compound Name MS
1.1 645.
1.1 577.1
1.1 590.1
Figure imgf000056_0001
Figure imgf000056_0002
1.1 580.3
Figure imgf000056_0003
Ret
Compound arae Time MS
1.1 523.3
1.1 574.1
Figure imgf000057_0001
8-{[2,2-dimethyl-5-({2-[4-
( 1 -methylρϊperidin-4- yi)p iperazin- 1 -y l]-2- 1.0 560.2 oxoethoxy} methyl)moφho Iin-4-y!]sulfonyl} quinoline
Figure imgf000057_0002
I.I 570.2
Figure imgf000057_0003
1.1 537.2 piperaz i
Figure imgf000057_0004
Figure imgf000057_0005
Ret
Compound Time MS
Figure imgf000058_0001
1.1 528.2
Ll 514.2
1.1 528.2
Figure imgf000058_0002
Ret
Compound Name Time MS
3-{4-[2-({(3R)-4-[(4- methoxy-2,6- dimethy!phenyl)sulfonyi]-
73 6,6-dimethylmorpholin-3- 1.1 570.2 y ! } methoxy)acetyl]piρerazi n-l-yl} propyl acetate
4-{4-[2-({(3R)-4-[(4- methoxy-2,6- dimethylpheny])sulfonyl]-
74 6, 6-d imethy lmorphol in-3 - 1.2 584.2 yj } methoxy)acetyl]piperazϊ n-l-yi} butyl acetate
Figure imgf000059_0001
1.2 583.0
1.1 577.1
1.1 577.1
1 .3 5S7.1
Figure imgf000059_0002
Ret
Compound Name Time MS
1.2 577.2 i
1.1 573.3
1.1 577.2
Figure imgf000060_0001
N-[4-(4,5-dihydro-IH- imidazol-2-yl)benzyl]-2- ( {(3R)-4-[(4-methoxy~2,6-
82 dimethylphenyl)sulfonyl]- I.I 559.. 6,6-dimethylmorpholin-3- yl } methoxy)acetamide
Figure imgf000060_0002
83 1.2 583.2
84 1.1 543.2
Figure imgf000060_0003
Ret
Compound Name Time MS
85 1.2 587.2
Figure imgf000061_0001
N-l4-(S,5-dimethyl-l,4,5,6- tetrahy dropyr ira i d i n-2- yl)benzy]]-2-({(3 R)-4-[(4- methoxy-2,6-
86 dimethylphenyl)sulfonyl]- 1.2 615.3 6, 6-d I methy imoiphol in-3 - yl} methoxy)-N-
Figure imgf000061_0002
methylacetamide
87 1.2 520,3
Figure imgf000061_0003
N-[4-(4s5-dihydro-lH- imidazol-2-yl)benzyl]-N- isopropyI-2-({(3R)-4-[(4-
SS melhoj.y-2,6- 1.1 601.4 dimetliylpheniyl)sulfonyl]-
6,6-dimethylmoipholiπ-3- yl} methoxy)acetam lde
N-[4-{4,5-dϊhydro-lH- imidazoI-2-yl)benzyl]-2- ( {(3 R)-4-[(4-methoxy-2,6-
89 dimethyiphenyl)sulfonyl]- 1.1 601.4 6,6-dimethylmorpholin-3- yI}methoxy)-N- propylacetamide
Figure imgf000061_0004
-
90 1.2 587.1
Figure imgf000061_0005
Ret
Compound Name Time MS
2-({4-[(2-chloro-4- methoxypheny!)sulfonyl]-
6,6-dimethylmorpholin-3-
91 yl }methoxy)-N-[4-(4,5- 1.2 579.0 dihydro-lH-imidazoil-2- yl)benzyf]-N- methylacetamide
Figure imgf000062_0001
I]-
1.3 545
Figure imgf000062_0002
E. 93 3-{4-[{{4-[(4-METHOXY-256-DIMETHYLPHENYL)SULFO^rYL]THIOMORPHOLIN-3- YL}M94ETHOX Y)ACETYL] PIPERAZlN- 1 -YL)-N1JV-DIMH l H YLPROP AN-I-AMINE
Figure imgf000062_0003
EtNMe2-AIH3 THF/toluene
Figure imgf000062_0004
Figure imgf000062_0005
Step 1. [4-(4-Methoxy-2:i6-dimethylphenyl)suIfony!]thJomorpholine-3-carboxylic acid ethyl ester (I) To a solution of thiomorpholine-3-carboxylic acid ethyl ester (2.0 g, 11.4 mmol) in anhydrous CH2Cl2 (25 mL) under N2 at O CC is added diisopropylethylamine (2.9S niL3 17.1 mmol), followed by 4-methoxy-2. 6-dimethylpheπylsulfonyl chloride. The mixture is stirred at rt overnight. The reaction mixture is washed with aq. IN HCl and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by silica gel chromatography (hexane/EtOAc: 4/1) to afford compound I as a colorless oil. 1H NMR {400 MHz, CDCl3) & 6.62 (s, 2H)3 4.75 (1, IH)5 4.20 (q, 2H), 3.83 (m, III), 3.81 (s, 3H), 3.55 (m, IH), 3.15 (m, IH), 3.02 <m, IH), 2.90 (m, IH), 2.61 (s, 6H), 2.32 (m, IH), 1.25 (t, 3H). LC-MS m/z (M+H): 373.87.
Step 2. {4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]thiomoφhoIiπ-3-yl}-methanol (II)
To a solution of compound I (2.50 g. 6.7 mmol) in anhydrous THF (50 mL) under Nzat rt is added DIBAL (1M/THF, 33.5 mL, 33.5 mmol). After stirring for 2 h at rt, the reaction is quenched with Na2SO^ IOH2O, filtered through celite and concentrated under reduced pressure. The residue is dissolved in MeOH (50 mL), and treated with NaBH4 (190 mg, 5 mmol) at rt for 30 min. The reaction is quenched with Vi saturated NaHCO3, and MeOH is removed under reduced pressure. The residue is extracted with EtOAc. The organic layer is washed with IN NaOH and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by passing through a silica gel plug (hexane/EtOAc: 2/1) to afford compound II as a colorless oil. LC-MS m/z (M ( II): 332.00.
Step 3. {4-[(4-Methυxy-2,6-dimethylphenyl)sulfony!]thiomoφhoIin-3-ylmethoxy}-acctic acid tert- butyJ ester (III)
To a solution of compound II (1.84 g, 5.56 inmol) in anhydrous DMF (30 mL) at 0 °C is added NaH (60% in mineral oil, 0.27 g, 6.67 mmol), followed by tert-buty! bromoacetate (1.24 mL,
8.40 mmo!)- The mixture is then warmed to rt, and stirred overnight. The reaction mixture is diluted with EtOAc, washed with water (3x) and brine, dried over Na2Sd, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (hexane/EtOAc: 4/1) to afford compound in as a colorless oil. 1H NMR (400 MHz5 CDCI3) S: 6.62 (s, 2H), 4.17 (t, IH), 4.03 (m.
IH), 3.87 (m, 2H), 3.79-3.84 (m, 4H), 3.69 (m5 IH), 3.22 (m, I H), 3.09 (m, IH), 2.74-2.82 (m, 2H),
2.60 (s, 6H), 2.33 (m, IH), 1.46 (s, 9H). LC-MS m/z (M+Na): 468.03
Step 4. {[4-(4-Methoxy-2, 6-dimethylphenyl)sulfonyl]thiomoipholin-3-ylmethoxy}-acetic acid (IV)
Compound HI (1.42 g, 3.19 mmol) is treated with TFA (8 mL) at rt overnight. TFA is removed under reduced pressure. The residue is purified by flash chromatography (EtOAc/hexane:
1/1) to afford compound IV as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 6.66 (s, 2H), 4.46 (m, IH), 4.19-4.25 (m, 2H), 4.06 (m, IH), 3.83 (s, 3H), 3.81 (m, IH), 3.46 (m, IH), 3.27 (m. IH), 3.13
(m. IH), 2.62 (s. 6H), 2.55-2.59 (m, 211), 2.33 (m, IH). LC-MS m/z (M+H): 389.80
Step 5. 3-{4-[({4-[(4-Methoxy-2,6-dimethylphenyl)sulfonyl]thiomorphoIin-3-yl}methoxy)acetyl3 piperazin- 1 -yl}-Λζ JV-dimethylpropan- 1 -amine (V)
To a solution of compound IV (46.7 mg, 0.12 mmol) in anhydrous DMΛ (0.6 mL) is added dimethyl-(3-piperazin~l-yl-propyI>amine (0.1 mmol, 0.2 M in toluene), DMC (0.2 mmol, 0.2 M in anhydrous CH3CN) and TEA (0.25 mmol, IM in toluene). The mixture is heated at 50 0C for 3 h. The reaction mixture is cooled to rt, and concentrated under reduced pressure. The residue is partitioned between EtOAc and IN NaOH, organic layer is separated, loaded onto SCX cartridge (3 g of resin) which are pre- washed with MeOH (9 mL), and eluted with MeOH (2 x 9 mL) to remove non-basic impurities, and EtOAc/MeOH/TEA (5/5/2, 9 mL) to afford compound V as a colorless oil. 1H NMR (400 MHz, CDCi3) & 6.62 (s, 2H), 4.0I-4.I7 (m, 4H), 3.81 (s, 3H), 3.79 (m, IH)5 3.65 (m, I H), 3.55-3.61 (m, 2H)3 3.36-3.40 (rn. 2H)5 3.20 (in, IH), 3.08 (m, IH), 2.64-2.81 (m, 2H), 2.58 (s, 6H), 2.22-2.40 (m, 15H), 1.64-1.72 (m, 2H). LC-MS wfe (M+H): 543.15.
F. ADDITIONAL ARYL SULFONYL HETEROCYCLES
Using routine modifications of the methods illustrated above, the starting materials may be varied and additional steps employed to produce other aryl sulfonyl heterocycles. Compounds listed in Table II are prepared using such methods. All compounds in Tabic II exhibit an IC50 determined as described in Example 7 that is 5 micromolar or less. Mass spectroscopy (MS) data is provided as
M-H, with retention times (Ret time) are shown in minutes.
Table II
Representative Arvl Sulfonyl Heterocycles
Ret
Compound Name Time MS
Figure imgf000064_0001
Ret
Compound Name Time MS
96 1.18 474.40
Figure imgf000065_0001
Figure imgf000065_0002
100 1.17 500.43
101 1.17 486.41
Figure imgf000065_0003
Ret
Compound Name Time MS
1 _[( {4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]tlii ornoipholin-3- 1.16 486.42 yl } methoxy)acetyl ] -N, IV- d imethy lpyrro 1 i d in-3 -am ine
Figure imgf000066_0001
Figure imgf000066_0002
N-[2-(diethyiamino)ethyl]- 2-({4-[(4-methoxy-2,6- diraethylphenyi)sulfonyl]thi 1.19 502.50 omorpholin-3-yl}methoxy)- N-methylacetam ide
Figure imgf000066_0003
N.N-diethyI-1 -[( (4-[(4- methoxy-2,6- dimethylphenyl)sulfonyl]thi
N r. omorphoIin-3- 1.18 528.48 N yl} methoxy)acety l]piperidi n-4-am.ine
Figure imgf000066_0004
Ret
Compound Name Time MS
Figure imgf000067_0001
514.46
516.48
514.46
Figure imgf000067_0002
Ret
Compound Name Time MS
Figure imgf000068_0001
l.[({4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]thi omoφholin-3- 1.2 556.52 yl} methoxy)acetyl]-ΛζiV- dipropylρiperidin-4-amine
Figure imgf000068_0002
Ret
Compound Name Time MS
4-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]-
3-{[2-oxo-2~(4-pyrroϋdin-
120 1-ylpiperidin-ϊ- 1.18 526.47 yl)ethoxy]methyl}thiomoφ hoϋne
Figure imgf000069_0001
121 1.18 540.49
1] thi
122 - 1.2 544.49
123
124 1.2 585.57
i
125 1.18 585.57
Figure imgf000069_0002
Figure imgf000070_0001
Figure imgf000071_0001
EXAMPLE 2. SYNTHESIS OF REPRESENTATIVE ARYL SULFONYL HETRROCYCLES
A. 2-[4-ACETYL- 1 -(4-METOOXY^9O-DIMETHYLBENZENESULFONYL) PΪPERAZlN-2-YLMETHOXY]-l - [4-(3 -DIMETHYLAMINOPROPYL)P1PA2ΪN-1 -YL]ETHANONE
Figure imgf000072_0001
1. DIBAL
/Pr2NEt, CH2CI2 2. NaBH4
Figure imgf000072_0003
Figure imgf000072_0002
Figure imgf000072_0004
Step 1. 4-(4-Metboxy-2,6-dimethylbenzenesulfoπyl)piperazine-l,3-dicai-boxylic acid 1-tert-butyl ester 3-methyl ester
Figure imgf000073_0001
The title compound as a yellow oil is prepared as indicated above using piperazine-1,3- dicarboxylic acid l-tert-butyl ester 3-methyl ester. 1H-NMR (400 MHz, CDCl3) S: 6.63 (s, 2H), 4.53 (m, IH), 4.40 (m, IH), 4.11 (m, I H), 3.82 (s, 3H), 3.69 (s, 3H), 3.55 (m, IH)3 3.42 (m, IH), 3.17 (m, IH), 2.86 (m, IH), 2.61 (s, 6H), 1.43 (s, 9H). LC-MS m/z (M + Na+): 466.
Step 2. S-Hydroxymethyl^^-methoxy^ό-dimethylbenzenesulfonyOpiperazine-l-carboxyiic acid /ert-butyi ester
Figure imgf000073_0002
A 1.5 M solution of DIBAL in toluene (12.1 mL, 18.2 mmol) is added dropwise to a solution of 4-(4-methoxy-2,6-dimethylbenzenesulfony!)piperazinc-l,3-dicarboxylic acid 1 -ter/-butyl ester 3- methyl ester (3.22 g, 7.28 mrπol) and CH2CI2 (70 mL) at -78 0C under nitrogen. After stirring for 1 h at -78 0C, the bath is thawed to 0 0C over 1 h. The excess DIBAL is quenched with EtOAc, the cold bath is removed, and then a 15% solution of sodium potassium tartrate (80 mL) is added. The mixture is vigorously stirred overnight. The layers are separated and the aqueous layer is extracted with CH2CI2 (2 x 75 mL). The combined organics are dried over Na2SO4- filtered, and concentrated to afford a 3:1 ratio of aldehyde to alcohol as a pale, yellow oil. The erode mixture is dissolved in MeOH (35 mL). Sodium borohydride (275 mg, 7.27 mmol) is added portionwise over 5 min. After 30 min, brine (50 mL) is added. The volatiles are removed under reduced pressure. The aqueous residue is extracted with CH2CI2 (3 X 75 mL). The combined organic layers are dried over Na2SO4j filtered, and concentrated to a pale yellow foam. Purification by flash column chromatography (1:1 hexanes:EtOAc, 50 g SiO2) affords the title compound as a light yellow foam. 1H-NMR (400 MHz5 CDCl3) & 6.64 (s, 2H). 4.23 (m, IH), 3.94 (m, I H), 3.82 (s, 3H), 3.76 (m, IH), 3.52-3.67 (m, 2H), 3.43 (m, IH), 2.90-3.18 (m, 3H), 2.61 (s, 6H), 1.46 (s, 9H). LC-MS m/z (M + Na+): 438. Step 3. 3-Ethoxycarbonylmethoxymethyl-4-(4-methoxy-2:,6-dimethylbenzenesulfonyI)-piperazine- 1-carboxylic acid tert-butyl ester
Figure imgf000074_0001
A ! .0 M solution of potassium tert-butoxide in THF (6.4 mL, 6.4 mmol) is added to a solution of 3-hydroxymethyl-4-(4-methoxy-2,6-dϊrnethylbeπzenesulfonyJ)piperazine-l-carboxyIic acid tert- butyl ester (2.39 g, 5.77 mraol) and DMF (1.2 mL) at 0 0C under nitrogen. After 3 min, ethyl bromoacetate (830 μL, 7.5 mmol) is added. After 1 h, the cold bath is removed and the cloudy mixture is stirred at ambient temperature for 16 h. The reaction mixture is poured into 50% sat. aqueous NH4CI (150 mL). The solution is extracted with EtOAc (2 x 150 mL). The combined organic layers are washed with 50% sat. aqueous NH4Cl (150 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography (2: 1 hexanesrEtOAc to 1.5: 1 hexanesrEtOAc to 1 : 1 hexanes: EtOAc3 100 g SiO2) affords the title compound as a light yellow oil. 1H-NMR (400 MHz, CDCl3) & 6.63 (s, 2H)5 4.24 (m, IH), 4.19 (q, 2H), 3.96-4.01 (m, 211), 3.87 (m, IH), 3.82 (s, 3H), 3.58-3.75 (m, 2H), 3.41 (m, IH), 3.01-3.14 (m, 2H), 2.61 (s, 6H), 3.45 (s, 9H). LC-MS m/∑ (M + Na""): 523.
Step 4. 3-Carboxymethoxymethyl-4-(4-methoxy-2,6-dimelhylbenzenesulfonyi)piperazine- 1 - carboxylic acid tert-butyl ester
Figure imgf000074_0002
The title compound as a white foam is prepared as indicated above. 1H-NMR (400 MHz, CDCl3) & 6.63 (s, 2H), 3.90-4.26 (m, 5H), 3.83 (s, 3H), 3.61-3.82 (m, 3H), 2.94-3.22 (m, 3H), 2.62 (s, 6H), 1.44 (s, 9H). LC-MS m/z (M + Na+): 496. Step 5. 3-{2-[4-(3~Dimethylaminopropyl)piperazin-l-yl]-2-oxoethoxymethyl}-4-(4-methoxy-2,6- dimethylbenzenesulfonytypiperazine-l-carboxylic acid tert-buty] ester
Figure imgf000075_0001
The title compound as a light yellow oil is prepared as indicated above. 1H-NMR (400 MHz, CDCl3) δ: 6.62 (s, 2H), 4.19 (d, IH), 4.11 (d, IH), 4.10 (d, IH)5 3.86 (m, IH), 3.81 (s, 3H), 3.30-3.68 (m, 8H), 2.95-3.10 (m, 3H)3 2.55-2.63 <m, 2H), 2.59 (s, 6H), 2.32-2.46 (m, 4H), 2.29 <dd, 2H), 2.22 (s, 6H), 1.65 (quintet, 2H), 1.44 (s, 9H). LC-MS m/z (M+): 626.
Step 6. 1 -[4"(3~Dimethylaminopropyl)piperazi.n-l -yi]-2-[ \ -(4-τnethoxy-256-dimethylbenzene~ sulfonyi)piperazin-2-ylmethoxy]ethanone
Figure imgf000075_0002
TFA (0.5 mL) is added in one portion to a solution of 3-{2-[4-(3- dύτiethylaminopropyl)piperazin-l-yl]-2-oxoethoxymethyl}-4-(4-methoxy-2,6-dimethyJ- benzenesulfonyl)piperazine-l-carboxylic acid tert-bυtyl ester (69 mg, 110 μmol) and CH2CI2 (0.5 mL). After 1.5 h, the volatiles are removed under reduced pressure. The residue is dissolved in 1 M aqueous NaOH (10 mL) and then extracted with EtOAc (2 x 25 mL). The combined organic layers are dried over Na2SCj, filtered, and concentrated to afford the title compound as a yellow oil. 1H- NMR (400 MHz5 CDCi3) δ: 6.63 (s, 2H), 4.04-4.19 (m, 3H)5 3.79-3.86 (m, IH), 3.82 (s, 3H), 3.72 (dd, IH), 3.56-3.63 (m, 2H), 3.38-3.44 (m, 2H), 3.27 (d, IH), 3.08-3.19 (d, 2H), 2.85-2.95 (m, 2H), 2.67 (dd, I H), 2.61 (s, 6H), 2.30-2.45 (m, 8H), 2.25 (s, 6H)S 1.67 (quintet, 2H). LC-MS m/z (M+): 526. Step 7. 2-[4-Acetyl-I-(4-methox.y-2,6-dimethylbeπzenesuirony])piperazin-2-yhnetliιθxy]-l-[4-(3- dimethylaminopropyl)pipazin-l-yl]ethanone
Figure imgf000076_0001
Ac2O (IO μL, 100 μraol) is added to a solution of l-[4-(3-dimethylamino-propyI)piperazin-l- yl]-2-[l ~(4-methoxy-2.,6-dimethylbenzenesulfony{)ptperazin-2-ylmethoxy]ethanone (40 mg, 76 μmol), pyridine (0.4 mL), and CH2Cl2 (0.4 mL). After 2 h, the volatiles are removed under reduced pressure. The residue is dissolved in 1 M aqueous NaOH (3 mL) and then extracted with EtOAc (3 mL). The organϊcs are loaded onto two 0.5 g SCX columns. Each column is washed with MeOH (2 x
3 mL). Each column is then eluded with 5:5:2 EtOAc:MeOH:TEA (3 mL). Concentration of the organics under reduced pressure affords the title compound as a yellow oil. 1H-NMR (400 MHz,
CDCI3) δ: 6.62 (s, 1.3H), 6.60 (s, 0.7H), 4.03-4.15 (m, 3H), 4.13 (s, IH), 4.10 (s, 2H), 3.96 (m, IH),
3.72-3.84 (m, IH), 3.80 (s, 3H), 3.10-3.70 (m, 8H), 2.88-3.05 (m, IH), 2.58 (s, 6H)S 2.25-2.43 (m,
SH), 2.21 (s, 6H), 2.12 (s, 2H), 2.06 (s, IH), 1.64 (quintet, 2H). LC-MS m/z (M"): 568.
B. ^ -[4-(3-DϊlVIETHYLAMINOPROPYL)P]PERAZIN-l-YL]-2-[l-(4-METHOXY-2!,6-DIM•ETHYLBENZENE- SULFONYL)-4-METHYLPIPERAZIN-2-YLMETHOXY]ETHANONE
Figure imgf000077_0001
Step i, [l-^-Methoxy^β-dimethylbeπzenesulfonylJpiperazin^-ylmethoxyjacetic acid ethyl ester
Figure imgf000077_0002
TFA (20 mL) is added in one portion to a solution of 3-ethoxycarbonyl-methoxymethyI-4-(4- rnethoxy-2;,6-dimethylbcnzcncsulfonyi)piperazine-l-carboxy!ic acid iert-buty\ ester (1.93 g, 3.86 mmol) and CH2Ck (20 mL). After 1.5 h, the volatiles are removed under reduced pressure. The residue is dissolved in 1 M aqueous NaOH (75 mL) and then extracted with EtOAc (2 x 200 mL). The combined organic layers arc dried over Na2SO4- filtered, and concentrated to afford the title compound as a yellow-brown oil. 1H-NMR (400 MHz, CDCl3) δ: 6.64 (s, 2H), 4.04-4.26 (m, 5H), 3.72-3.88 (in, 2H), 3.82 (s, 3H)3 3.14-3.38 (m, 3H), 2.91-3.04 (m, 2H), 2.72 (m, IH), 2.62 (s, 6H)1
1.23-1.32 (m, 2H). LC-MS m/z (M + H+): 401. Step 2. [I-(4-Methoxy-2,6-dimethylbenzenesu!fony])-4-raethylpiperazin-2-yImethoxy]acetic acid ethyl ester
Figure imgf000078_0001
Sodium cyanoborohydride (1.1 g, I S mmol) is added to a solution of [l-(4-methoxy-2,6- dimethylbenzenesulfonyOpiperazin^-yimethoxylacetic acid ethyl ester (1.45 g, 3.62 mmol) and acGlonilrile (40 mL) cooled in a water bath. 37% Aqueous formaldehyde (10 mL) is added in one portion. After 5 min, glacial acetic acid (1.8 mL) is added in three poitions over 1.5 h. After 4 h, O.I M aqueous NaOH (15 mL) is added and the solution is stirred for 15 min. The reaction mixture is poured into CH2Ch (150 mL) and 1 M aqueous NaOH (15 mL). The layers are separated and the aqueous layer is extracted with CH2CK (50 mL). The combined organic layers are washed with brine (50 mL), dried over Na2SO^ filtered, and concentrated. Purification by flash column chromatography (19:1 CH2CkMeOH to 1% NH4OH in 19:1 CH2C^MeOH, 30 g SiO2) affords the title compound as a pale orange oil. 1H-NMR (400 MHz, CDCl3) & 6.63 (s, 2H)5 4.38 (s, 2H), 4.18 (q, 2H)1 3.85-4.08 (m, 3H), 3.82 (s, 3H), 3.72 (m, IH)5 2.90-3.52 (m, 5H), 2.61 (s, 6H), 2.32 (bs, 3H)5 1.28 (t, 3H). LC-
Figure imgf000078_0002
Step 3. [1 -(4-Methoxy-2,6-dimethylbenzenesulfonyl)-4-methylpiperazin-2-y Imethoxy]acetic acid
Figure imgf000078_0003
The title compound (as a yellow oil) is prepared as indicated above. 1H-NMR (400 MHz, CD3OD) S: 6.74 (s, 2H), 3.88 (m, IH), 3.82 (s, 3H)5 3.75 (s, 2H), 3.60 (an, IH)5 3.38 (m, IH)5 3,08- 3.27 (m} 3H)5 2.68 (m, IH), 2.59 (s, 6H)5 2.23 (s, 3H), 2.13 (dd5 IH), 1.92 (ddd, IH). LC-MS mh (M + H+): 387. Step 4. l-[4-(3-Dimethylaminopropyl)piperazin-l-yl]-2-[l -(4-methoxy~2,6-diτnethyIbenzene- suIfonyl)-4-methyIpiperazin-2-ylmethoxy]ethanone
Figure imgf000079_0001
The title compound (as a pale yellow oil) is prepared as Indicated above. 1H-NMR (400 MHz, CDCI3) & 6.60 (s, 2H), 4.07 (s, 2H), 3.84-3.96 (m, 2H)5 3.80 (s, 3H% 3.66 (dd, IH), 3.55-3.62 (m, 2H), 3.38-3.45 (m, 2H), 3.28 (m, IH), 3.14 (ddd, IH), 2.95 (d, IH), 2.64 (m. III), 2.59 (s, 6H), 2.28-2.43 <m, 8H), 2.24 (s, 6H), 2.21 (s, 3H), 2.1 1 (dd, IH), ] .92 (ddd, IH), 1.67 (quintet, 2H). LC- MS mh (M+): 540.
C. ADDITIONAL ARYL SULFONYL HETEROCYCLES
Using routine modifications of the methods illustrated above, the starting materials may be varied and additional steps employed to produce other aryi sulfonyl heterocycles. Compounds listed in Table ID arc prepared using such methods. ΛH compounds in Table III exhibit an IC5O determined as described in Example 7 that is 5 micromolar or less. Mass spectroscopy (MS) data is provided as M+l, with retention times (Ret time) shown in minutes.
Table HI Representative Arvl Sulfonvl Heterocvcles
Ret
Compound Name Time MS
Figure imgf000079_0002
Ret
Compound Name Time MS
1,08 497.20
I .I 497.21
1.11 525.24
-y I)- 1.11 511.23
1 '-[( { l-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]-4- 43 niethyIpipεrazin-2- 1.11 551.19 yl } methoxy)acetyl]-4-melhyf- l,4'-bipiperidinε
l-{ l-[({l-[{4-methoxy-2,6- dimethylphenyl)sulfony!J-4- 44 methyIpiperazin-2- I .ll 551.18 yl}methoxy)acetyl]piperidin-
4-yl}azepane
Figure imgf000080_0001
19 Ret
Compound Na Time MS
1.09 523.15
1.1 537.15
1.07 582.16
Figure imgf000081_0001
SO Ret
Compound Name Time MS
Figure imgf000082_0001
Ret
Compound Name Time MS
Figure imgf000083_0001
EXAMPLE 3. SYNTHESIS OF REPRESENTATIVE ARYL SULFONYL HETEROCYCLES
A. SYNTHESIS OF (S)-2-((l-(4-METHOXY-2a6-DIMETHYLPHENYLSULFONYL)PYRROLIDlN~2- YL)METHOXY)ACETIC ACID
Figure imgf000083_0002
To a mixture of (S)-2-hydroxymethylpyrrolidine (1.21 g) and TEA (I .21g) in 50 mL CH2CI2 is added 2,6-dimethyl-4-methoxysuIfonyl chloride (2.35 g). The reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is transferred to a separatory funnel and washed with
1.5 N HCl, and then with saturated NaHCOj. The organic phase is dried over MgSO4, filtered, and then concentrated to afford (S)-(l-(4-methoxy-2?6-dimethylphenyfsulfonyI)pyrrolidin-2-yl)methanol.
This sulfonamide is dissolved in 15 mL toluene. An aqueous 35% NaOH solution (30 mL) is added followed by tetrabutylammonϊum chloride (500 mg). Bromo-terf-butyl acetate (2.2 mL) is added and the two phase mixture is stirred vigorously at rt for 2 hours. The aqueous phase is removed and the organic phase is dried over Na2SO4, filtered, and concentrated. The product is purified by flash chromatography eluting with 85/15 hexanes/EtOAc to afford (S)-Ce rt-butyl 2-(( I -(4-methoxy- 2 , ό-dimethylpheny lsu lfonyl)pyrrolidin-2-yl)rnethoxy)acetate.
This ester is dissolved in 7 niL TFA and stirred 20 rain at rt. The solvent is removed and the residue dissolved in EtOAc. The product is extracted into IN NaOH. The aqueous phase is adjusted to pH~3 with 6N HCΪ and the product extracted into EtOAc. The organic phase is dried over Na2SO4, filtered and concentrated to afford the title compound. 400 MHz 1H NMR (CDCl3) δ; 1 1.72 (s, IH), 6.60 (s, 2H), 4.06 (m, IH)5 3.86 (s, 2H), 3.79 (s, 3H)3 3.40 (dd, IH), 3.31 (d, IH), 3.28 (m, IH), 3.05 (m, III), 2.61 (s, 6H), 2.00 (m, 2H), 1.86 (m, 2H). LC-MS m/z (M+H): 358.01
B. ADDΓΠONAL ARYL SULFONYL IIETEROCYCLES
Using routine modifications of the methods illustrated above, the starting materials may be varied and additional steps employed to produce other aryl sulfonyl heterocycles. Compounds listed in Tables IV and V are prepared using such methods. AU compounds in Tables IV and V exhibit an IC50 determined as described in Example 7 that is 5 micromolar or less. Mass spectroscopy (MS) data is provided as M+l, with retention times (Ret time) shown in minutes.
Table IV Representative Aryl Sulfonyl Heterocycles
Ret
Compound Name Time MS
160 lϊdin-2-
1.2 424.27
Figure imgf000084_0001
161 - 1.2 426.28
Figure imgf000084_0002
l-ethyl-4-({[(2S)-l-
162 (mesitylsulfonyI)pyrrotidin-2- 1.2 438.29 yljmethoxy} acetyi)piperazine
Figure imgf000084_0003
Ret
Compound Name Time MS
Figure imgf000085_0001
1.21 452.38
Figure imgf000085_0002
Figure imgf000085_0003
Ret
Compound Name Time MS
170 - 1.21 454.34
Figure imgf000086_0001
171 lidin-2- 1.23 466.34 erazme
Figure imgf000086_0002
l-isobutyi-4-({[(2S)-l-
172 (mesityIsulfonyl)pyrrolidin-2- 1.22 466.35 yl] methoxy } acety l)piperazine
l-cyclobutyl-4-({[(2S)-l-
173 (mesityIsuIfonyI)pyrroIidin-2- 1.22 464.34 y 1] methoxy} acety l)piperazine
Figure imgf000086_0003
Figure imgf000086_0004
1 -cyclopentyl-4-( { [(2S>1 -
176 x> (mesitylsulfonyl)pyrroHdin-2- 1.22 478.36 yl]methoxy } acety l)piperazine
Figure imgf000086_0005
O Ret
Compound Name Time MS
l-buiyl-4-({[(2S)-l- (mesitylsulfonyl)pyrroJidin-2-
177 yl]methoxy } acetyl)- 1 ,4- 1.22 480.37 diazepane
Figure imgf000087_0001
178 1.2 478.36
179 1.21 492.38
180 1.22 506.40
Figure imgf000087_0002
181 Hdin-2- eridin- 1.23 506.39
Figure imgf000087_0003
182 1.23 520.41
183 1.22 537.45
Figure imgf000087_0004
Ret
Compound Name Time MS
Figure imgf000088_0001
1.2 481.37
1.17 495.39
Figure imgf000088_0002
idin~2- 1 - 1.18 507.40
Figure imgf000088_0003
Figure imgf000088_0004
Figure imgf000089_0001
Ret
Compound Name Time MS
Figure imgf000090_0001
1.16 454.33 -
Figure imgf000090_0002
1 -[( {(2S)- 1 -[<4-methoxy-2,6- dϊmethylphenyl)sulfony]]pyrr olidin-2-y]}methoxy)acetylJ- 1.18 468.35 N, 7V-dimethylp iperid in-4- amine
l-isopropyl-4-[({(2S)-I-[(4- methoxy-2,6- dimethylphenyl)sulfonyfjpyπ" 1.18 468.35 olidin-2- yl} methoxy)acetyl]piperazine
2-({(2S)-l -[(4-methoxy-2,6- dimethy3phenyl)sulfonyl]pyiτ olidin-2-yI} methoxy)-N- 1.1 8 468.35 melhyl-N-(l-methy{piperidin- 4-yl)acetamide
l-[({(2S)-l-[(4-methoxy-2,6- dimethylphenyi)sulfonyl]pyrr 1.18 468.35 o!idin-2-yl}methox.y)acetyl]- 4-ρropyIpiperazine
Figure imgf000090_0003
Ret
Compound Najtie Time MS
I -isobutyf-4-[({(2S)-l -[(4- methoxy-2,6- dimethylphenyl)su]fonyl]pyiτ 1.19 482.37 oIidin-2- yl}methoxy)acetyl]piperazine
1 -cyclobutyl-4-[({(2S)-l-[(4- methoxy-2,6- d imethylρhenyl)sulfonyl]pyrr 1.19 480.35 olidiπ-2- y] }methoxy)acety]]piperazine
ΛζN-diethyl-l-[({(2S)-l-[(4- metlnoxy-2,6- dimethy .phenyl )su Ifony I ] pyrr oIidin-2- 1.18 482.37 yl } methoxy)acetyl]pyrrolϊdϊn-
3 -amine
Figure imgf000091_0001
484 34
494.37
Figure imgf000091_0002
l-butyl-4-[({(2S)-l-[(4- methoxy-2,6- dimethylphenyl)sulfony!3pyn" 1.2 496.38 olidin-2-yl} methoxy)acetyl]- 1,4-diazepane
l-[({(2S>l-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]pyπ- oHdin-2-yl}methoxy)acetyl]- 1.18 494.37 4-pyπ'θIidin-l -ylpiperidine
Figure imgf000091_0003
Ret
Compound Name Time MS
Figure imgf000092_0001
Compound MS
Figure imgf000093_0001
1.17 497.37
1.15 511.38
1.15 523.40
Figure imgf000093_0002
l-[({ l-[(4-methoxy-2,6- dimethylphenyl)sulfonyl]pyrr olidin-2-yl}methoxy)acetyO- 1.17 523.40 4-(2-pyrrol idin- 1 - ylethyl)piperazine
Figure imgf000093_0003
Ret
Compound Name Time MS
N,N-diethyl-2-{4-[({(2S)-l - [(4-methoxy-2,6- dimethy!phenyl)sυlfonyl]pyrr „ „ 4n yl} methoxy)acetyl]piperazin- 1 -yl}ethanamine
1 -[({(2S> I-[(4-πiethσxy-2>6- dimethylphenyl)sulfonyi]pyrr ol idin-2-yl } methoxy)acetyl] - 1.17 537.41 4-(2-piperidin-l - ylethy Opiperazine
Figure imgf000094_0001
Figure imgf000094_0002
l-[({(2S)-l-[(4-methoxy-2,6- dimethyiphenyl)sulfonyl]pyiτ 29 olidin-2-yI} methoxy)acetyi]- 1.15 537.41 4-[(l -methylpiperidin-3- yl)methyl]piperazine
Figure imgf000094_0003
Figure imgf000094_0004
N,N-dietliyl-3-{4-[({(2S)-l- [(4-methoxy-256- d i methy lphenyi)su I fony I] py rr 31 oiidin-2- 1.15 539.43 yl}tnetlioxy)acetyl]piρerazin- 1 -yl } pro pan- 1 -amine
H({(2S)-1 -[(4-methoxy-2,6- dimcthylphenyl)su lfonyl]pyrr 32 oHdin-2-y]}metnoxy)acetyl]- 1.15 551.43 4-(3-ρiρeridin-l- ylpropyl)piperazine
Figure imgf000094_0005
Ret
Compound Name Time MS
1.21 452.29
1.21 452.29
1.21 452.29
1.21 452.30
1.22 454.31
1.17 507.36
Figure imgf000095_0001
Table V Representative Arvi Sulfonvi Heterocycles
Ret
Compound Name Time MS
2-({{2S)- 1 -[(4-methoxy-2,ό- d im ethylpheny l)sulfony 1] py rr
239 olidin-2-yl}methoxy)-N-(l - 1.38 474.97 methyl-l- ρhenylethy!}acetamide
N-[l-ethyl-l-(3- meth oxyphenyi)propy iJ-2-
240 ({(2S)-l-[(4-methoxy-2s6- dimethylphenyl)su!fonyl]ρyrr ] .42 532.97 olidin-2- yl } methoxy)acetamide
N-(l-ethyl-l-phenylpropyl)-
2-({(2S)-l-[(4-methoxy-2,6-
241 d imethylphenyl)sulfoπyl] pyrr 1.43 502.99 olidin-2- yl } methoxy)acetamide
2-( {(2S> 1 -[(4-methoxy-2,6- d imethy lpheny l)su lfony] ] pyrr
242 olidin-2-yl}methoxy)-N-[ 1 - 1.39 504.96 (3 - meth oxypheny I)- 1 - methylethyljacetamide
2-(((2S)- 1 -[(4-methoxy-2,6-
243 dimethylphenyi)sulfonyl]pyrrol idin-2-yl}methoxy)-N-(3- 1.45 514.98 phenylcyclohexyl)acetamide
Figure imgf000096_0001
Figure imgf000096_0002
1.37 471.02
1.42 544.98
χ 33 5Q4 9g
1.43 529.02
1.28 498.00
1.25 524.00
Figure imgf000097_0001
Figure imgf000097_0002
252 1.35 550.95
253 1.32 546.99
Figure imgf000098_0001
l-[({(2S)-l-[(4-methoxy-2,6-
254 dimethylphenyl)sulfonyl]pyiτ olidiπ-2-y!} methoxy)acetyl]- 1.31 517.00 4-phenylpϊperidϊn-4-oI
l-[({(2S)-l-[(4-methoxy-2,6- dϊmethylphenyi)su!fonyl]pyrr
255 olidin-2-yi} methoxy)acetyl]- 1.34 526.00 4-phenylpipεridine-4- carbonitrϊle
Figure imgf000098_0002
EXAMPLE 4. ADDITIONAL REPRESENTATIVE COMPOUNDS
Using routine modifications, the starting materials may be varied and additional steps employed to produce other compounds provided herein. Compounds listed in Table Vf are prepared using such methods.
Table VI
2-[4-(4-Methoxy-2s6-dimethyI-benzenesuIfonyl)-
208 [ 1 ,4]oxazepan-3 -ylmethoxyl-l ~[4-( 1 -methyl- piperid in-4-y l)-pi perazin- 1 -y 1] -ethanone
Figure imgf000098_0003
2-[4-(4-Methoxy-2,6-dimethyl-benzenesulfony])-
209 [ 1.4]oxazepan-5 -ylm ethoxy ]- 1 - [4-( I -methy 1- piperidin-4-yl)~piperazin~ 1 -yl]-ethanone
2-[l-(4-Methoxy-2,6-dimethyl-benzenesuIfonyI)-
210 azetidin-2-ylmethoxy]-l -[4-(I -methyl-piperidάn-4-yl)- piperazin- 1 -yl]-ethanone
l-[4-(3-DimethyIamino-propyl)-piperazin-l-yIJ-2-[4-
21 1 (4-methoxy-2,6-dimethyl-benzenesuIfonyl)-
[ls4]oxazepan-3-ylmcthoxyl-ethanone
1 -[4-(3 -Di.methylamϊno-propyl)-piperazin-l -yl]-2-[4-
212 (4-methoxy-2;,6-dimetliyl-benzenesulfonyl)-
[I,4]oxazepan-5-ylmethoxyJ-ethanone
l-[4-(3-Dimethylamino-propyl)-piperazin-l-yl]-2-[l-
213 (4-melhoxy-2,6-dimethy]-benzenesulfonyI)-azetidinι- 2-ylmethoxyJ-ethanone
Figure imgf000099_0001
EXAMPLE 5. PREPARATION OF B,-TRANSFECTED CELLS
This Example illustrates the preparation of Bptransfected cells for use in Bj binding and modulation assays (Examples 6 and 7).
Cynomolgus macaque lung total RNA is isolated as described by Chomzynskϊ et a!. (1987) Anal. Biochem. 162Λ- S6Λ S9. A cDNA encoding Bi is cloned from the totaf RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) with the following oligonucleotides:
Primer 1: GGCGCTAGCCACCATGGCATCCTGGCCCCCTC (SEQ ID NO:!) Primer 2: AGCCGTCCCAGATCTGAAC (SEQ ID NO:2) Primer 3: GATCTGGGACGGCTTGGATG (SEQ ID NO:3) Primer 4: CGGAGCTCTTAATTCCGCCAGAAAAGTTGGA (SEQ TD NO:4) Primer pairs 1 & 2 and 3 & 4 are used to generate overlapping cDNA fragments corresponding to the entire protein coding sequence of cynomolgus macaque Bi cDNA are isolated and linked to form the full-length coding sequence (GenBank Accession Number AY788905). The construct is cloned into pcDNA 3.1 (Invitrogen, Carlsbad, CA) and transfected into Chinese hamster ovary (CHO) cells using Lipofectamine (Invitrogen)., resulting in cynomolgus macaque Bi-expressing CHO cells. Alternatively, the construct is cloned into pBAKPAK9 (Clontech, Mountain View, CA) and transfected into Sf9 cells to generate clonal baculovirus stocks. Clonal cell lines stably expressing the cynomolgus macaque Bi receptor are selected in G418. A single clonal line that exhibits high levels of receptor expression is chosen for use in binding and calcium mobilization assays (Examples 6 and 7). Clonal baculovirus stocks are used to infect Sf9 cells such that the infected cells express high levels of recombinant Bj receptors. These cells are used in radioligand binding assays (Example 6).
EXAMPLE 6. B, RECEPTOR BINDING ASSAYS
This Example illustrates a representative Bj receptor binding assay that may be used to determine the binding affinity of compounds for Bi.
A. [3 H]-DESARGI0KALLIDIN BINDIMG TO ΪNTACT JMR-90 CELLS OR CHO CELLS STABLY EXPRESSING
IMR-90 cells, which endogenously express human Bi, are seeded into 24 well plates at 65,000 cells per well, cultured overnight, and then treated for 3 h with 0.2 ng/mL interleukin-1 beta to induce B1 expression (Menke, et al. (1994) J. Biol Chem. 269:21583-86). CHO cells stably expressing rat Bi are seeded into 24 well plates at 200,000 cells per well and cultured overnight. The cells are then washed 3 times with phosphate buffered saline (PBS). One hundred fifty microliters of binding buffer (50 mM Tris 7.4, 0.14 mg/mL, bacitracin, and 1 mg/mL BSA) is added to each well. Various concentrations of test compound are added to each well from DMSO solutions such the final DMSO concentration is 1% by volume; some wells receive DMSO only, and some wells receive DMSO plus 10 μM desArg'°Kallidin to define non-specific binding. All wells then receive 0.3 nM (final concentration) [3H]-desArgI0Kallidin. The plates are allowed to sit for 2 h at room temperature. Cells are then washed three times, and lysed with. 400 μl Ultima Gold scintillation fluid (PerkinElmer; Boston, MA; 20 rnin incubation). The fluid is then transferred to counting vials counted in a Packard liquid scintillation counter (PerkinElmer). The number of counts present in the scintillation fluid is plotted as a function of antagonist compound concentration and fitted to a logistical equation using SigmaPiot (Systat Software, Point Richmond, CA) to determine each compound's IC50 and Kj {e.g., as described by Szallasi, et al. (1993) J. Pharmacol. Exp. Ther. 266:678-83). B. [3H]-DESARD10K-ALLIDIN BINDING TO MEMBRANE HOMOGENATES OF SF9 CELLS EXPRESSING CYNOMOLGUS MACAQUE BI
Sf9 cells infected with a baculovirus carrying the coding sequence for cynomolgus macaque B] are harvested by centrifugation and frozen at -SO 0C. Pellets are subsequently resuspended on ice in Tris buffered saline (TDS; 50 mM Tris (pli 7.4), 120 mM NaCl), and cells arc homogenized using a polytron for 30 seconds. The crude membrane fraction is collected by centrifugation at 20,000 rpm. Membranes are washed two times with TBS and collected by centrifugation each time. Protein content of the membranes is determined after the last wash and the concentration is adjusted to 0.7 μg/uL with binding buffer (50 mM Tris 7.4, 0.14 mg/mL bacitracin, and 1,0 mg/mL BSA)- To perform the binding assay, 150 microliters of membrane fraction is added to each well of a 96-weIl plate along with 50 μl [3H]-desArg'°Ka]lidin (0.3 iiM final) and test compound in DMSO (final DMSO concentration = 1%). Some wells receive DMSO only, and some wells receive DMSO plus I O μM desArg!°KaHidin to define non-specific binding. The 96 well plates are allowed to sit for 2 h at room temperature. Membrane proteins are then harvested by filtration onto GF/C filtermats (PerkinElmer) pre-soaked for 1 hr in 0.5 % polyethylenimine. AfteF filtration, filters are dried and then counted in a Beta pfate counter. The number of counts present in the scintillation fluid is plotted as a function of antagonist compound concentration and fitted to a logistical equation using SigmaPlot (Systat Software, Point Richmond, CA) to determine each compound's IC50 and K; (e.g., as described by Szallasi, et al (1993) J. Pharmacol. Exp. Ther. 266:675-83).
EXAMPLE 7. CALCIUM MOBILIZATION ASSAY
This Example illustrates representative caicium mobilization assays for use in evaluating test compounds for agonist and antagonist activity.
Cynomolgus macaque Bj-expressing CHO cells (Example 5) are plated in a 96 well plate. The cells are cultured for 1 day, after which culture media is emptied from the plate and replaced with 50 μl of KRH (Krebs-Ringer HEPES buffer: 25 mM HEPES5 5 mM KCI, 0.96 mM NaH2PO47 1 mM MgSO4, 2 mM CaCl2, 5 mM glucose, 1 mM probenecid, pH 7.4) supplemented with the calcium- sensitive fluorescent dye Fluo4-AM (5 μg/ml; Teflabs, Austin, TX). The cells are then incubated at 37 0C in an environment containing 5% CO2. After the 1 hour incubation, the dye solution is removed from the plate, the- plate is washed once with KRH, and 100 μL KRH is added. DETERMINATION OF B I AGONIST ACTIVITY
100 μL KRH + 2% DMSO is added to each well of celts, such that the final volume in each well is 200 microliters and the final DMSO concentration is 1%. Various concentrations of the Bi agonist desArgi0Kallidin are added. Addition of desArg10Kallidm elicits a fluorescent response as consequence of increased intracellular calcium. This response is measured with a FLIPR instrument (Molecular Devices, Sunnyvale, CA) and determined to be desArg'°Kallidin concentration dependent. A plot of maximum fluorescent response as a function of desArg10KalIigin is generated and an EC50 (concentration required to elicit a 50% of maximal response) for the response is determined using the equation: y=a*(l/(l+(b/x)c)) In this equation, y is the maximum fluorescence signal, x is the concentration of the Bi agonist, a is the Emnx, b corresponds to the EC50 value and c is the Hill coefficient.
By replacing the desArg'°Kallidin with a test compound, this assay is also used to assess B) agonist activity of the test compound.
DETERMINATION OF ANTAGONIST ACTIVITY Various concentrations of test compounds are added to the cell plate prepared as described above in 100 μL KRH + 2% DMSO, such that the final volume in each well is 200 microliters and the final DMSO concentration is 1%. The EC50 concentration of desArg'0Kailidin is then added to each well of plates containing test compound to determine the extent to which each test compound inhibits an agonist-induced B] response. The maximum fluorescent response is plotted as a function of test compound concentration in order to determine the IC50 (concentration required to inhibit 50% of the effect of agonist) for each compound at B|. Antagonists of B1 decrease this response by at least about 20%, preferably by at least about 50%, and most preferably by at least 80%, as compared to matched control (i.e., cells treated with dcsArg'°Kal]idin at the EC50 concentration in the absence of test compound), at a concentration of 10 micrornolar or less, preferably 1 micromolar or less. Alternatively, the data is analyzed as follows. First, the average maximum relative fluorescent unit (RFU) response from negative control wells (no agonist) is subtracted from the maximum response detected for each of the other experimental wells. Second, average maximum RFU response is calculated for the positive control wells (agonist wells). Then, percent inhibition for each compound tested is calculated using the equation:
D Percen +t τ In Uhi-Ubi-+ti-on = i 1n0n0 — i 1 n0n0 x P - — Pe ; —ak : — Sig —npa —l in Test . W , ,,e ,lls ,r "] I
L Peak signal m Agonist Wells J The % inhibition data is plotted as a function of test compound concentration and test compound IC50 is determined using a linear regression in which x is ln(concβntration of test compound) and y is ln(percent inhibition/(100 - percent inhibition). Data with a percent inhibition that is greater than 90% or less than 15% are rejected and are not used in the regression. The IC50 is
(-intercepi/slope)
EXAMPLE 8. MDCK CYTOTOXICITY ASSAY
This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) ceil cytotoxicity assay.
1 μL of test compound is added to each well of a clear bottom 96-weIJ plate (Packard, Meriden, CT) to give final concentration of compound in the assay of 10 μM, 100 μM or 200 μM. Solvent without test compound is added to control wells.
MDCK cells, ATCC no. CCL-34 (American Type Culture Collection, Manassas, VA), are maintained in sterile conditions following the instructions in the ATCC production information sheet. Confluent MDCK cells are trypsinized, harvested, and diluted to a concentration of 0.1 x I O6 cells/mL with warm (37°C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30-
2003). 100 μL of diluted cells is added to each well, except for five standard curve control wells that contain 100 μL of warm medium without cells. The plate is then incubated at 37°C under 95% O2-
5% CO2 for 2 hours with constant shaking. After incubation, 50 μL of mammalian cell lysis solution (from the Packard (Meriden, CT) ATP-LITE-M Luminescent ATP detection kit) is added per well, the wells are covered with PACKARD TOPSEAL stickers, and plates are shaken at approximately
700 rpm on a suitable shaker for 2 min.
Compounds causing toxicity will decrease ATP production, relative to untreated cells. The
ATP-LlTE-M Luminescent ATP detection kit is generally used according to the manufacturer's instructions to measure ATP production in treated and untreated MDCK cells. PACKARD ATP
LITE-M reagents are allowed to equilibrate to room temperature. Once equilibrated, the lyophilized substrate solution is reconstituted in 5.5 mL of substrate buffer solution (from kit). Lyophilized ATP standard solution is reconstituted in deionized water to give a 10 mM stock. For the five control wells, 10 μL of serially diluted PACKARD standard is added to each of the standard curve control wells to yield a final concentration in each subsequent well of 200 nM, 100 πM, 50 nM, 25 11M, and
12.5 nM. PACICARD substrate solution (50 μL) is added to all wells, which are then covered, and the plates are shaken at approximately 700 rpm on a suitable shaker for 2 min. A white PACKARD sticker is attached to the bottom of each plate and samples are dark adapted by wrapping plates in foil and placing in the dark for 10 miiκ Luminescence is then measured at 22°C using a luminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or
TECAN SPECTRAFLUOR PLUS), and ATP levels calculated from the standard curve. ATP levels in cells treated with test compound(s) are compared to the levels determined for untreated cells. Ceils treated with 10 μM of a preferred test compound exhibit ATP levels that are at least 80%, preferably at least 90%, of the untreated cells. When a 100 μM concentration of the test compound is used, cells treated with preferred test compounds exhibit ATP levels that are at least 50%, preferably at least
80%. of the ATP levels detected in untreated cells.

Claims

What is claimed is:
1. A compound of the formula:
Figure imgf000104_0001
or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is 0 or 1 ; if n is 0, then m is 1 and q is 0 or 1 ; if n is 1, then either (i) ra is 1 and q is 1 or 2 or (i) q is 1 and m is 1 or 2;
X is NR3, O, S, SO or SO2;
Y is -0-CH2-, -N(R1O)-CH2-, -CH2-CH2-, -CH=CH-, -CH2-O-CH2-, -CH2-CH2-CH2- or -0-CH2-CH2-;
Rι represents from O to 5 substituents independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbony], aminosulfonyl and -COOH; (ii) Ci-C6afky], C2-C6alkenyl, C2-C6alkyny!, (C3-C8cycloalky])Co-C4alkyi, C[-C6alkoxy5 Cr Cf,alkylthio, Ci-Cήaikylsulfinyl, Ci-C≤alkoxycarbonyi., Ci -Qalky isulfonylCo-Oalkyl, mono- or
Figure imgf000104_0002
mono- or di-(C|-C6a]kyl)aminosuifonyICo-C4alkyI, mono- or di-(Ci-C5alky])aminocarbonyICo-C4alkyl, and (4- to 8-membered heterocydoalkylJQ^alkyl; each of which is substituted with from O to 6 substituents independently chosen from halogen, hydroxy, cyano and amino; and
(iii) groups that are taken together to form a fused carbocyclic ring that is substituted with from O to 4 substituεnts independently chosen from halogen, hydroxy, cyano, amino, nitro, Q-QaJkyl, Ci-Cβhaloalkyl, C|-C6alkoxy, and mono- or di-(C|-C6alkyf)aminoCfl-C4alkyl; R2 represents from O to 4 substituents independently chosen from oxo, hydroxy and Ci-Cgalkyl; R3 is hydrogen, C:-Csalkyl or CpCgalkanoyl; Rio is hydrogen or CrC4alkyi; RA is hydrogen. C]-C6alkyl, QrQaJkeny], CyCβalkynyl, (Cj-Cscycloalkyl)C0-C4aikyl, C2-C6aikyl ether, or mono- or di-(Ci-C6alkyl)aminoCrC4afkyl; and
RB is C|-C6alkyl, C2-C6alkenyl, C?-C6alkynyl, (C3-C8cycloalkyl)C0-C4aIkyI, C2-Cea!kyl ether, mono- or di-(Ci-C<saIkyl)aminoCi-C4aikyl, or (4- to 7-membered heterocycloalkyl)Co-C4alkyI? each of which is substituted with from O to 6 substituents independently chosen from: (i) amino, halogen, hydroxy, cyano and oxo; and
(ii) CrQalkyl, (C3-C3cycloa]kyI)C0-C4alkyl, CrQa!koxy, phenyIC0-C4alkyl and (5- or 6- membered heterocycle)C0-C4alkyl, each of which is substituted with from O to 4 substituents independently chosen from amino, cyano, halogen, hydroxy, C|-C6alkyl, (C3-C8cycloalky I)C0- Qalkyl, CpCβhaloalkyl, C1-CCaIkOXy, Ci-Cβalkoxycarbonyi, mono- or di-(Ci-C6alkyl)amino, phenyIC0-C4aIkyl and phenyIC0-C4alkoxy; or RΛ and RB are taken together to form a 4- to 7-membered heterocycfoalkyl that is substituted with from 0 to 4 substituents independently chosen from:
(i) hydroxy, oxo, cyano and amino; and
(H) Ci-Cβalkyl. CrC6alkoxy, mono- or di-(CrC,salkyl)aininoC(rC4a-kyI, (C3-C, 0carbocycle)C0~ C4alkyl and (4- to 10-membered heterocycle)Co-C4alkyl; each of which is substituted with, from 0 to 2 substituents independently chosen from hydroxy, halogen, oxo, cyano, CrC6alkyl, Cr Qalkoxy. (C3-CiocarbocycIe)C0-C4alkyl and (4- to 10-membered heterocyc]e)C0-C4aJkyl.
2. A compound, salt or hydrate according to claim 1, wherein the compound satisfies the formula:
Figure imgf000105_0001
3. A compound, salt or hydrate according to claim 1 or claim 2, wherein n is O.
4. A compound, salt or hydrate according to claim 1 or claim 2, wherein n is 1.
5. A compound, salt or hydrate according to any one of claims 1-4, wherein Rj represents from 1 to 3 substituents independently chosen from halogen, hydroxy, Ci-Cβalkyl, CrCishaloaikyl, C1- Cβalkoxy and Q-CβhaEoalkoxy.
6. A compound, salt or hydrate according to any one of claims 1-5, wherein R2 represents from 0 to 4 substituents independently chosen from Ci-Cjalkyl.
7. A compound, salt or hydrate according to claim 6, wherein R^ represents gem- dimethyl,
S. A compound, salt or hydrate according to any one of claims 1-7, wherein Y is -O-
CHr-.
9. A compound, salt or hydrate according to any one of claims 1-8, wherein the compound satisfies the formula:
wherein
Figure imgf000106_0001
represents a 4- to 7-membered, N-iinked heterocycloalkyl that is substituted with from
0 to 4 substituents independently chosen from:
(i) hydroxy, oxo, cyano and amino; and
(ii) Ci-Qalkyl, C]-C6alkoxy, mono- or di-(CrC6alkyl)aminoCo-C4aIkyl, (C3-Ciocarbocycle)C0- Qalkyl and (4- to 10-membered heterocycie)C0-Qalkyl; each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, oxo, cyano, Ci-Cgalkyl, Ci- Qalkoxy, (C3-C]0carbocyc]e)Co-C4aIkyl and (4- to 10-membered heterocycle)C0-C4a!kyK
10. A compound, salt or hydrate according to claim 9, wherein the compound satisfies the formula:
Figure imgf000106_0002
wherein: p is 0, 1 , 2 or 3; Z is CR7R8 or NR9;
R7 and Rg are independently chosen from: (i) hydrogen, hydroxy and cyano; and
(ii) C|-C6alkyl, C2-Qalkenyl, C2-C<5alkynyl, CrCfiaIkoxy, mono- or di-(C1-Cfialkyl)aminoC0- C4alkyl, (C3-C8cycIoaIkyl)Co-C4aIkyl and (4- to S-membered heterocycloaIkyl)C0-C4aIkyls each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, oxo and Ci-Cβalkyl; and
R9 is Ci-Cealkyl, C2-C6alkeny]:> C2-C3alkynyl, mono- or dKCrCealkyOaminoCrCjalkyl, (C3- Ciocarbocycle)Co-C4aIkyi or (4- to 10-membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, oxo and Ci-Cfialkyl. I I. A compound, salt or hydrate according to claim 10, wherein the compound satisfies the formula:
Figure imgf000107_0001
12. A compound, salt or hydrate according to claim 10, wherein the compound satisfies the formula:
Figure imgf000107_0002
13. A compound, salt or hydrate according to claim 10, wherein the compound satisfies the formula:
Figure imgf000107_0003
14. A compound, salt or hydrate according to claim 10, wherein the compound satisfies the formula:
Figure imgf000107_0004
wherein R^5. R3 and Rg are independently chosen from halogen, hydroxy, Cι-C6alkyl, Ci-Cghaloalkyl, Ci-C6aikoxy and C|-Cδhaloalkoxy.
15. A compound, salt or hydrate according to claim 14, wherein the compound has the formula:
Figure imgf000108_0001
(i) R5 is methyl or methoxy. and R4 and R6 are each methyl: or
(ii) R4 and Rβ each represent a halogen, and R5 is a halogen, methoxy, trifluoromethyl or methyl.
16. A compound, salt or hydrate according to claim 14, wherein the compound has the formula:
Figure imgf000108_0002
R4 is a halogen; and
R5 is a halogen, methoxy, trifluoromethyl or methyl.
17. A compound, salt or hydrate according to claim 10, wherein the compound satisfies the formula:
Figure imgf000108_0003
18. A compound, salt or hydrate according to cϊaim 10, wherein the compound satisfies the formula:
Figure imgf000108_0004
19. A compound, salt or hydrate according to claim 10, wherein the compound satisfies the formula:
Figure imgf000109_0001
20. A compound, salt or hydrate according to claim 11 , wherein the compound satisfies the formula:
Figure imgf000109_0002
wherein:
Z is CR7R8 or NR9;
R7 is hydrogen, hydroxy, cyano or C|-C6alkyl; and
Rg is C2-C6alkyl ether, mono- or di-(Cj-QaIkyl)aminoCo-C4alkyl, phenylCo-C4alkyl or (4- to 8- membered heterocycIoalkyI)Co-C4alkyl, each of which is substituted with from 0 to 2 substitυenls independently chosen from hydroxy, halogen, oxo, cyano, Q^alkyl and Ci-C4alkoxy; and
R9 is d-Cβalkyl. C2-C6alkenyl, C2-C6a]kyny3, mono- or di-(Ci-C6aIkyl)aminoC)-Qatkyl, (C3- Cιocarbocycle)Co-C4alkyl or (4- to 10-membered heterocycle)C0-C4alky3, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, oxo and Ci -Chalky I.
21. A compound, salt or hydrate according to any one of claims 10-20, wherein Z is CR7Rs.
22. A compound, salt or hydrate according to claim 21, wherein: R7 is hydrogen, hydroxy, cyano or Ci-Qalkyl; and
R8 is mono- or di-(C|-C6aIkyi)aminoC0-C4alkyl or (4- to 8-membered heterocycloalky I)C0-C4Bl kyl that is optionally substituted with C(-C2alkyl.
23. A compound, salt or hydrate according to claim 21 , wherein:
Figure imgf000109_0003
24. A compound, salt or hydrate according to any one of claims 10-20, wherein Z is NR9.
25. A compound, salt or hydrate according to claim 24, wherein R9 is CrQjalkyl, mono- or di-(Ci-C6alkyl)aminoCi-Qalkyl or (5- to 7-membered heterocycle)Co-C4alkyl, each of which is substituted with from 0 to 2 substituents independently chosen from halogen, hydroxy, cyano, oxo and C-Cβalkyl.
26. A compound, salt or hydrate according to claim 10, wherein the compound satisfies the formula:
Figure imgf000110_0001
27. A compound, salt or hydrate according to claim 1, wherein: RA is hydrogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyϊ, (C3-CsCycIoalkyl)C0-C4alkyi> C2-C5alkyl ether, or mono- or di-(Ci-C6alkyl)aminoC|-C4alkyl; and RB is Ci-Ceaikyl,
Figure imgf000110_0002
ether, mono- or di-(C|-C6a3kyl)aminoC]-C4alky], or (5- or 6-membered heteiOcycloalky{)CD-C4a[kyl, each of which is substituted with from 0 to 6 substituents independently chosen from:
(i) amino, halogen, hydroxy, cyano and oxo; and
(ii) C,-C6alkyl, (C3-Cscycloalkyl)Co-C4alkyl, C,-C6alkoxy, phenylC0-C4alkyl and (5- or 6- membered heterocycle)C0-C4alkyL each of which is substituted with from 0 to 4 subslituents independently chosen from amino, cyano, halogen, hydroxy, C]-C6alkyl, (C3-CgcycIoalkyi)Co- Gjalkyl, Ci-C6haloalkyl,
Figure imgf000110_0004
Ci-Cealkoxycarbonyl, mono- or
Figure imgf000110_0003
phenylCo-Qalkyl and phenylCo-C4alkoxy,
28. A compound, salt or hydrate according to claim 27, wherein the compound satisfies the formula:
Figure imgf000110_0005
29. A compound, salt or hydrate according to claim 28, wherein the compound satisfies the formula:
Figure imgf000111_0001
30. A compound, salt or hydrate according to claim 27, wherein the compound satisfies the foπxiula:
Figure imgf000111_0002
31. A compound, salt or hydrate according to claim 27, wherein the compound satisfies the formula:
Figure imgf000111_0003
wherein Rj, Rs and R5 are independently chosen from halogen, hydroxy, CVCβalkyl, Cj-Cβhaloalkyl, Ci-Cβalkoxy and Ci-Cehaloalkoxy.
32. A compound, salt or hydrate according to any one of claims 1-31, wherein the compound exhibits no detectable agonist activity an in vitro assay of B] agonism.
33. A compound, salt or hydrate according to any one of claims 1-32, wherein the compound has an IC50 value of 1 micromo'ar or less in an in vitro assay of Bi antagonism.
34. A pharmaceutical composition, comprising at least one compound, salt or hydrate according to any one of claims 1 -33, in combination with a physiologically acceptable carrier or excipient.
35. A pharmaceutical composition according to claim 34, wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
36. A method for inhibiting induction of agonist-Induced B] activity in vitro, the method comprising contacting Bi receptor with at least one compound, salt or hydrate according to any one of claims 1-33, under conditions and in an amount sufficient to detectably inhibit agonist-induced B] activity.
37. A method for inhibiting induction of agonist-induced Bi activity in a patient, comprising contacting cells expressing Bi receptor with at least one compound, salt or hydrate according to any one of claims 1-332, in an amount sufficient to detectably inhibit agonist-induced Bj activity in cells expressing a cloned Bi receptor in vitro, and thereby inhibiting agonist-induced Bi activity in the patient.
3S, A method according to claim 37, wherein the patient is a human.
39. A method for treating a condition responsive to Bi receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound, salt or hydrate according to any one of claims 1-33, and thereby alleviating the condition in the patient.
40. A method according to claim 39, wherein the condition is inflammation or pain.
41. A method according to claim 39, wherein the condition is cough, asthma, vascular edema, or epilepsy.
42. A method for treating pain in a patient, comprising administering to a patient suffering from pain a therapeutically effective amount of at least one compound, salt or hydrate according to any one of claims 1 -33, and thereby alleviating pain in the patient.
43. A method according to claim 42, wherein the patient is suffering from inflammatory pain, acute pain, dental pain, back pain, surgical pain, headache, neuropathic pain or pain from osteoarthritis or trauma.
44. A method according to claim 42, wherein the patient is a human.
45. A compound, salt or hydrate according to claim 1, wherein the compound, salt or hydrate is radiolabeled.
I l l
46. A method for determining the presence or absence of B1 receptor in a sample, comprising the steps of:
(a) contacting a sample with a compound, salt or hydrate according to any one of claims 1-33, under conditions that permit binding of the compound to B] receptor; and
(b) detecting a signal indicative of a level of the compound bound to Bi receptor, and therefrom determining the presence or absence of B] receptor in the sample.
47. A method according to claim 46. wherein the compound is a radiolabeled compound according to claim 43^ and wherein the step of detection comprises the steps of:
(i) separating unbound compound from bound compound; and
(ii) detecting the presence or absence of bound radϊolabel in the sample.
48. A packaged pharmaceutical preparation, comprising:
(a) a pharmaceutical composition according to ciairn 34 in a container; and
(b) instructions for using the composition to treat pain.
49. The use of a compound, salt or hydrate according to any one of claims 1-33 for the manufacture of a medicament for the treatment of a condition responsive to B| receptor modulation.
50. A use according to claim 49, wherein the condition is an inflammatory condition or pain.
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