WO2008024692A1 - Sulfones de n-oxyde aryle et sulfoxydes - Google Patents

Sulfones de n-oxyde aryle et sulfoxydes Download PDF

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WO2008024692A1
WO2008024692A1 PCT/US2007/076266 US2007076266W WO2008024692A1 WO 2008024692 A1 WO2008024692 A1 WO 2008024692A1 US 2007076266 W US2007076266 W US 2007076266W WO 2008024692 A1 WO2008024692 A1 WO 2008024692A1
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compound
alkyl
hydrate
salt
independently chosen
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PCT/US2007/076266
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English (en)
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David C. Ihle
Guiying Li
David J. Wustrow
Kevin Hodgetts
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Neurogen Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • 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

Definitions

  • This invention relates generally to N-oxide aryl sulfones and sulfoxides, and to the use of such compounds to treat conditions responsive to bradyki ⁇ iii 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 5 , and as probes for the detection and localization of B].
  • 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 Bj and B 2 .
  • Bj and B 2 The B 2 receptor is expressed constitutively in a variety of tissues.
  • the Bj receptor is inducibly expressed in response to pathophysiological conditions such as inflammation, pain, trauma, bacteria! infection, burns and shock.
  • 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 normal tissues.
  • compounds that bind to Bi and/or modulate the activity of Bi also find use as research tools.
  • the present invention provides N-oxide aryl sulfones and sulfoxides that satisfy Formula I:
  • Formuia I or are a pharmaceutically acceptable salt, solvate (e.g., hydrate) or ester of such a compound.
  • Ar is phenyl or a 5- or 6-membered heteroaryl. each of which is optionally substituted, and each of which is preferably substituted with from 0 to 4 substituents independently chosen from R s ; R x and R ⁇ are: fi) independently chosen from: (a) hydrogen; and
  • W is CrQalkylene that is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from R 2 o;
  • Z is absent, divalent phenyl, NR G or CR E R F wherein:
  • R G is hydrogen, Cj-C 6 alkyl or taken together with R B or R D to form a 4- to 7-membered heterocycloalkyl that includes W and is optionally substituted; preferably such heterocycloalkyl is substituted with from 0 to 4 substituents independently chosen from R 20 ;
  • R E is hydrogen, Ci-Qalkyl or taken together with R 8 to form a 4- to 7-membered heterocycloalkyl that includes W and is optionally substituted; preferably such heterocycloalkyl is substituted with from 0 to 4 substituents independently chosen from R 20 ; and
  • R F is hydrogen, or taken together with R D to form a 4- to 7-membered heterocycloalkyl that includes V and is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from R 20 ;
  • V is absent or Cj-C 6 a!ky!ene that is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from (i) R 20 and (ii) groups that are taken together with R 0 to form a 4- to 7-membered heterocycle that is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from R 2 o;
  • is independently chosen from:
  • R B is: (i) hydrogen, C,-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyny!, C r C 6 haloalkyl, (C 3 -C 3 cycloalky])Co-
  • Rc is absent, C r C 6 alkyl or taken together with R D to from a 4- to 7-menibered heterocycle that is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from R 2 0;
  • R D is CpQalkyl or taken together with Rc, R F , R G or a substituent of V to form an optionally substituted 4- to 7-membered heterocycle; and
  • Each R 2O is independently selected from:
  • Ciocarbocycle Co-C 4 alkyl and (4- to 10-membered heterocycle)C 0 -C 4 alkyl.
  • N-oxide aryl sulfones and sulfoxides of Formula I, and other Formulas provided herein are B t modulators and exhibit a K 1 of no greater than 5 micromolar, 2 micrornolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in a Bi binding assay and/or have an EC S0 or IC 50 value of no greater than 5 micromolar, 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in an assay for determination of B ⁇ agonist or antagonist activity.
  • B 3 modulators provided herein are Bi antagonists; preferably such antagonists exhibit no detectable B] agonist activity,
  • N-oxide aryl sulfones and sulfoxides 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 N-oxide aryl sulfone or sulfoxide of Formula I in combination with a physiologically acceptable carrier or excipient.
  • Methods are further provided for inhibiting agonist-induced B 1 activity.
  • the inhibition takes place in vitro.
  • Such methods comprise contacting a B
  • the B 5 receptor is in a patient.
  • Such methods comprise contacting cells expressing a B] receptor in a patient with at least one Bi 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 B] receptor in vitro.
  • the present invention further provides methods for treating a condition responsive to Bj receptor modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one N-oxide aiyl sulfone or sulfoxide 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 N-oxide aryl sulfone or sulfoxide of Formula ⁇ .
  • 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 N-oxide aiyl sulfone or sulfoxide of Formula I under conditions that permit binding of the compound to B,; and (b) detecting a signal indicative of a level of the compound bound to Bi.
  • the present invention provides methods of preparing the compounds disclosed herein, including the intermediates.
  • the present invention provides N-oxide aryl suifones and sulfoxides, which may be used in vitro or in vivo in a variety of contexts, as described herein.
  • N-oxide aryl sulfone or sulfoxide encompasses all compounds that satisfy Formula I, including compounds in which the Ar moiety is heteroaryl and compounds in which the Ar moiety is aiyl. This term further includes pharmaceutically acceptable salts, solvates (e.g., hydrates) 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, bitartrate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochloride, diphosphate, edetate, estolate (ethylsuccinate), formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methyl bromide
  • pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethyl enediamine, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • 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
  • each compound provided herein may, but need not, be formulated as a solvate (e.g., a hydrate) or non-covalent complex.
  • the various crystal forms and polymorphs are within the scope of the present invention.
  • prodrugs of the compounds provided herein are also provided herein.
  • prodrug is a compound that may not fully satisfy the structural requirements of a formula provided herein, but is modified in vivo, following administration to a patient, to produce a compound within the scope of such formula.
  • 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 that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, or suifhydryl 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 (C r C s alkyl), from 1 to 6 carbon atoms (C r C 6 aiky! and from 1 to 4 carbon atoms (Ci-C 4 alkyl) 3 such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, / ⁇ ?r/-butyi, pentyl, 2-pentyl, isopentyl, neopentyl, hexyi. 2-hexyl, 3-hexyl or 3-metliylpentyl.
  • C 0 -C 4 alkyr' refers to a single covalent bond (C 0 ) or an alkylene group having 1, 2, 3 or 4 carbon atoms;
  • C 0 -C 2 alky! refers to a single covalent bond or a methylene or ethylene group.
  • Alkenyl refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C 2 -Qalkenyl, C 2 -C 6 alkenyl and C 2 - C 4 alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, ailyl or isopropenyl.
  • AlkynyP 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 -Cgalkynyl, C 2 -C 6 aikynyl and C 2 -C 4 alkynyl 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 -Cscycloalkyl, in which the ring contains from 3 to 8 ring members, all of which are carbon.
  • a "(C 3 -C 3 cyc]oalkyI)C 0 -C 4 alkyr is a C 3 -Cgcycloalkyl group linked via a single covalent bond or a C r C 4 alkyIene group.
  • alkoxy is meant an alkyl group attached via an oxygen bridge (i.e., -O- alkyl).
  • Alkoxy groups include Cj-Qalkoxy and Cj-C 4 alkoxy groups, which have from 1 to 6 or from
  • 3-methyipentoxy are representative alkoxy groups.
  • alkylthio refers to an alkyl group as attached via a sulfur bridge (i.e., -S-alkyl).
  • Alkylthio groups include C r C 6 alkylthio and C r C 4 alky!thio groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • Alkylsulfinyl refers to groups of the formula -(SO)-alky!, in which the sulfur atom is the point of attachment.
  • Alkylsulfinyl groups include Cj-Cealkylsulfinyl and Ci-C 4 alkyisulfinyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • Alkylsulfonyl refers to groups of the formula -(SO 2 )-alkyl, in which the sulfur atom is the point of attachment. Alkylsuifonyl groups include Ci-C 6 alkylsulfonyl and C r C 4 alkylsulfonyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • C 4 alkyi refers to a Cj-C fi alkylsulfonyl that is linked via a single covalent bond or a C r C 4 aIkylene group (i.e., -(C 0 -C 4 alky I)-(S O 2 HC i-C 6 alky I)).
  • alkanoyl groups inciude C ⁇ -Cgalkanoyl, Co-Cgalkanoyl and C 2 -
  • C 4 alkanoyl groups which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • alkyl ether refers to a linear or branched ether substituent
  • Alkyl ether groups include C 2 -C 8 alkyl ether, Q-Qalkyl ether and C 2 -C 4 a!ky! ether groups, which have 2 to 8. 6 or 4 carbon atoms, respectively.
  • a C 2 alkyl ether is -CH 2 -O-CH 3 .
  • Alkoxycarbonyl groups include C]-Cg, Ci-C 6 and C r C 4 alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group, "Cj alkoxycarbonyl” refers to
  • Alkylamino refers to a secondary or tertiary amine that has the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloalkyl and (cycloaikyl)alkyl groups.
  • groups include, for example, mono- and di-(Ci-C 8 alkyl)amino groups, in which each Cj-Cgalkyi may be the same or different, as well as mono- and di-(C]-C(;alky1)ammo groups and mono- and di-(C r C 4 alkyl)amino groups.
  • Alkylaminoalkyl refers to an alkylamino group linked via an alkylene moiety (i.e., a group having the general structure -alkylene— NH-afky! or -aIkylene-N(aikyl)(alkyl)) in which each alkyf is selected independently from alkyl, cycloalkyl and (cycloalkyl)a ⁇ kyl groups.
  • Alkylaminoalkyl groups include, for example, mono- and di-(C]-C 3 a]kyl)aminoC,-C6alkyl, and mono- and di-(Q- C 6 alkyl)aminoCi-C 4 alkyl.
  • “Mono- or di-(Ci-Qalkyl)aminoC 0 -C 4 alkyi” refers to a mono- or di-(C,- C 6 aikyl)amino group linked via a single covalent bond or a C]-C 4 alkylene group.
  • alky as used in the terms “alkylamino” and “alkylaminoalkyl' 1 differs from the definition of "aikyl” used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups (e.g., (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl).
  • “Mono- or di-(C r C(;alkyl)aminocarbony]Co-C 4 alkyr refers to an aminocarbonyl group in which one or both hydrogens are replaced with an independently selected Ci-C 6 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 r C 6 alkyl)aminosulfonylCo-C 4 aikyl” refers to an aminosulfonyl group in which one or both hydrogens are replaced with an independently selected CpQalkyl group, and which is linked via a single covalent bond or a Ci-C 4 alkylene group.
  • 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., "Ci-Cghaloaikyl” groups have from 1 to 8 carbon atoms; "Q-Qhaloalkyl” groups have from 1 to 6 carbon atoms).
  • haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyi; mono-, di-, tri-, tetra- or penta-fiuoroethyl; mono-, di-, tri-, t ⁇ tra- or penta-chloro ⁇ thyl; and 1,2,2,2-tetrafluoro-l-trifluoromethyl-ethyI.
  • Typical haloalkyl groups are trifluoromethyl and difluoromethyl.
  • a dash (“-") that is not between two letters or numbers is used to indicate a point of attachment for a substituent.
  • 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 -Cgcarbocycles); rings having from 4 or 5 to 7 ring members (i.e., C 4 -C 7 carbocycles or C 5 -C 7 carbocycles) 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 (i.e., at least one ring within the group is aromatic).
  • Representative aromatic carbocycles are phenyl, ⁇ aphthyi, tetrahydronaphthyl and bi phenyl.
  • preferred carbocycles have a single ring, such as phenyl and C 3 - Cscycloalkyl groups.
  • carbocycles recited herein are groups (i.e., groups in which a 3- to IO-membered carbocyclic group (which may be cycloalkyl or aryl) is linked via a single covalent bond or a C r C 4 aIkylene group).
  • Phenyl groups linked via a single covalent bond or C r C 2 alkylene group are designated phenyiC 0 -C 4 alkyl (e.g., benzyl, l-phenyl-ethyl, 1 -phenyl-propyl and 2-phenyl-ethyl).
  • phenyiC 0 -C 4 alkyl e.g., benzyl, l-phenyl-ethyl, 1 -phenyl-propyl and 2-phenyl-ethyl.
  • a "phenylC 0 -C4alkoxy” group is a phenyl ring that is linked via an oxygen atom (i.e., phenoxy) or via a Ci-C 4 alkoxy group (e.g., benzyloxy).
  • a “heterocycle” (also referred to herein as a “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 oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon).
  • a heterocyclic ring comprises 1 , 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring has 1 or 2 heteroatoms per ring.
  • Each heterocyclic ring generally contains from 3 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 suifur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO 2 .
  • Heterocycles may be optionally substituted with a variety of substituents, as indicated.
  • Certain heterocycles are 4- to 10-membered and comprise one or two rings; in certain embodiments, such heterocycles are monocyclic (e.g., 4- to 8-rnembered, 5- to 8-membered, 4- to 7-membered, or 5- or 6-membered).
  • heterocycles are heteroaiyl groups (i.e., at least one heterocyclic ring within the group is aromatic), such as a 5- to 10-membered heteroaiyl (which may be monocyclic or bicyclic) or a 5- or 6-membered heteroaryl (e.g., thienyl, imidazolyl, pyridy ⁇ or pyrimidyl).
  • Other heterocycles are heterocycloalky] groups (i.e., do not comprise an aromatic heterocyclic ring).
  • heterocycles may be linked by a single covalent bond or via an alkylene group, as indicated, for example, by the term “(4- to 8-membered heterocycloalkyl)Co-C 4 alkyl.”
  • a "substituent,” as used herein, refers to 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, haioalkyl group or other group discussed herein that 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, by 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 substituents.
  • 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).
  • 1 1 Bi refers to the human Bj bradykinin receptor reported by Menke et al.
  • Bi agonist refers to a compound that binds Bi and induces signal transduction mediated by B ⁇ .
  • Bi agonists include, for example, bradykinin and kallidin (lysyl-bradykinin), as well as peptide portions or variants of bradykinin or kallidin that bind Bj and retain activity.
  • Representative Bj agonists include, but are not limited to, desArg 9 bradykinin and desArg'°kallidin.
  • a "Bi antagonist” is a compound that detectably inhibits signal transduction mediated by B 1 . Such inhibition may be determined using the representative calcium mobilization assay provided in Example 7.
  • Preferred Bi antagonists have an IC 50 Of 5 ⁇ M or less in this assay, more preferably 2 ⁇ M or less, and still more preferably 1 ⁇ M or less, 500 nM or less, 100 nM or less or IO nM or less.
  • the B] antagonist is specific for B 1 (i.e., the IC 50 value in a similar assay performed using the B 2 receptor is greater than 2 ⁇ M and/or the IC 50 ratio (B 2 /Bi) is at least 10, preferably 100, and more preferably at least 1000).
  • B] 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 5O of the peptide agonist desArg'°kallidin, and more preferably have no detectable agonist activity within the assay described in Example 7).
  • B 1 antagonists for use as described herein are generally non-toxic.
  • Bi antagonists include neutral antagonists and inverse agonists.
  • a "neutral antagonist" of Bj is a compound that inhibits the activity of B 1 agonist (e.g., desArg'°kallidin) 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).
  • B 1 agonist e.g., desArg'°kallidin
  • 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 activity level in the absence of activating concentrations of agonist. Inverse agonists may also inhibit the activity of agonist at Bi, and/or may inhibit binding of B, agonist to B]. 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 relief 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. synovial fluid, lymph, cellular interstitial fluid, tears or urine) that is sufficient to result in detectable alteration in Br 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 administrations.
  • a “patient” is any individual treated with an N-oxide aryl sulfone or sulfoxide 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 N-oxide aryl sulfones and sulfoxides of Formula I that may be used in a variety of contexts, including in the treatment of conditions responsive to B] modulation, as described herein.
  • Such compounds may also be used within in vitro assays (e.g., assays for B 1 activity), as probes for detection and localization of Bi and within assays to identify other Bi antagonists.
  • Ar is phenyl, naphthyl, pyridyl or pyrimidinyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, C r C 6 alkyL C r C 6 haloalkyl, CpQalkoxy and mono- or
  • Ar is phenyl that is substituted with from 0 to 4 substituents independently chosen from Rj (e.g., substituted with 1, 2 or 3 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, C r Q
  • each substituent (e.g., I 5 2 or 3 substituents) represented by Ri is independently chosen from halogen, hydroxy, cyano, amino, nitro, Ci-Cealkyl, CVQ,haloalkyl, C r C 6 alkoxy, C]-C 6 haloalkoxy and mono- or di-(C r C 6 alkyl)aminoC 0 -C 4 alkyl.
  • Ar is a group of the formula:
  • R 4 , R 5 and R 6 are independently chosen from hydrogen, halogen, hydroxy, C r C 6 alkyl, Ci- Qhaloalkyl, C r C 6 alkoxy and CrQhaloalkoxy.
  • at least one of R 4 , R 5 and R 5 is not hydrogen; within further such compounds, at least two of R 4 , R 5 and R 6 are not hydrogen; within still further such compounds, R 4 , R 5 and R 6 are independently chosen from halogen, hydroxy, C r C 6 alkyl, Ci-C 6 haloalkyl.
  • C r Q,aIkoxy and C r C 6 haioa!koxy e.g., R 5 is methyl or methoxy and R 4 and R 6 are each methyl).
  • Y the sum of r and p ranges from 1 to 6 for certain N-oxide aryl sulfones and sulfoxides. Within certain such compounds, p is not zero.
  • Certain Y groups satisfy the formula (C H 2 X-O-(CH 2 ) p , which is substituted with from O to 4 substituents independently chosen from amino, hydroxy, cyano, C r C 6 alkyl, C 2 -C 6 alkenyi, C 2 -C 6 aikynyl, d-Qhaloalkyl and substituents of the same carbon atom or adjacent carbon atoms that are taken together to form C 3 -C 6 cycloalkyl. Representative such Y groups include, for example.
  • Y is a group of the formula (CH 2 ) r -(CH 2 ) p that is substituted with from O to 4 substituents independently chosen from amino, hydroxy, cyano, C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-Cghaloaikyl and substituents of the same carbon atom or adjacent carbon atoms that are taken together to form C3-C ⁇ ;cycloalkyl.
  • Representative such Y groups include, for example, -CH 2 -, -CH 2 -CH 2 -, and -CH 2 -CH 2 -CH 2 -, each of which is optionally substituted as indicated above.
  • the variables Rx and Ry of Formula I are, within certain embodiments, independently chosen from hydrogen and C r C 6 aikyl. Within other embodiments, R x and R ⁇ are taken together to form an aromatic group. Representative such aromatic groups include, for example, naphthyl, quinolinyl, phenyl and pyridyl, each of which is optionally substituted as described above. Within further embodiments, R x and Ry are taken together to form an optionally substituted partially or fully saturated ring. Representative such rings include, for example, piperazine, morpholine, thiomorpholine, piperidine and pyrrolidine.
  • R x and Ry are taken together to form an optionally substituted 4- to 8-membered heterocycloalkyl.
  • X is CH 2 , NR 3 , O, S, SO or SO 2 ; m and q are independently 0, 1 or 2: R 2 represents from 0 to 4 substituents independently chosen from oxo, hydroxy and C
  • N-oxide aryl sulfones and sulfoxides of Formula III further satisfy Formula IV or Formula V:
  • X is CH 2 in certain compounds; for other compounds X is O.
  • R 2 represents from 0 to 4 substituents independently chosen from C
  • the variable R c is absent in certain embodiments. It will be apparent that R c may only be absent if R D forms a heteroaryl with R F or a substituent of V (and any heteroaryl so formed comprises V and the tetravalent nitrogen atom as ring members).
  • variable "Z" is NR 0 or CR E Rp within certain embodiments of Formulas I-V, It will be apparent that R E , R F and RG are intended to be substituents of the base carbon or nitrogen atom (i.e.,
  • R E or R 0 is taken together with R B to form a 4- to 7-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from: (i) hydroxy, oxo, cyano and amino; and (ii) C,-C 6 alkyl, C r C 6 alkoxy, mono- or di-(C r C 6 aIkyl)aminoCo-C 4 alkyl, (Cj-Ci ⁇ carbocycle)C 0 -C ⁇ alky] and (4- to 10-membered heteiOcycle)Co-C 4 alkyl; each of which is substituted with from 0 to 2 substituents independently chosen from hydroxy, halogen, oxo, cyano, C r C 6 alkyl, C]-C 6 alkoxy, (C 3 -C i
  • s is O, 1 or 2; R D is Ci-Qalkyl; V is absent or Ci- C 4 alkylene; and the remaining variables are as described above.
  • s is O, 1 or 2; R D is C r C 6 aIkyl; V is C]-C 4 alkylene; and the remaining variables are as described above.
  • R x and R ⁇ are independently hydrogen or Ci-Cealkyl.
  • Other compounds of Formula VI or Formula VlI further satisfy Formula VIII or Formula IX, respectively:
  • Formula V ⁇ II Formula IX in which m and q are independently O, 1 or 2, such that the sum of m and q is 1, 2 or 3; X is NR 3 , O, S, SO or SO 2 ; R 2 represents from O to 4 substituents independently chosen from oxo, hydroxy and Q- Qalkyl; and the remaining variables are as described for Formula VI. Still further N-oxide aryl sulfones and sulfoxides provided herein satisfy Formula X or
  • Formula X Formula Xl in which each s is independently O, 1 or 2.
  • R x and R Y are independently hydrogen or Ci-C ⁇ alkyl.
  • Other compounds of Formula X or Formula XI further satisfy Formula XII or Formula XIII, respectively: Formula XII Formula XIII in which m and q are independently O, 1 or 2, such that the sum of m and q is 1, 2 or 3;
  • X is NR 3 , O, S, SO or SO 2 ;
  • R- 2 represents from O to 4 substituents independently chosen from oxo. hydroxy and Ci- C 6 alkyl; and the remaining variables are as described above.
  • variable "Z" is CR E R F , and R F is taken together with R D to form a 4- to 7-membered heterocycloalkyl that is substituted with from 0 to 4 substituents independently chosen from: (i) hydroxy, oxo, cyano and amino; and (ii) CVCgalkyl, C.- Qafkoxy, mono- or di- ⁇ C,-C 6 alkyl)aminoCo-C 4 alkyi, (C 3 -Ci 0 carbocycle)C 0 -C 4 a]ky!
  • R x and R ⁇ are independently hydrogen or CrQalkyl.
  • Other compounds of Formula XIV further satisfy Formula XV:
  • Formula XV in which m and q are independently 0. 1 or 2, such that the sum of m and q is 1, 2 or 3; X is NR 3 . O, S, SO or SO 2 ; R 2 represents from 0 to 4 substituents independently chosen from oxo, hydroxy and Ci- Cgalkyi; and the remaining variables are as described above.
  • variable "Z" is NR 0 and RQ is hydrogen or CrC 6 alkyl.
  • N-oxide aryl sulfones and sulfoxides 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, hydrate or ester.
  • compounds provided herein are Bi modulators.
  • certain compounds provided herein are specific for B 1 .
  • Bj 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 B] may be confi ⁇ ned using the representative assay described in Example 6, herein, or using an assay described by Fox et al.
  • Preferred B] modulators exhibit a K 1 within such an assay of 5 micromolar or less, more preferably 2 micromolar or less, 1 micromolar or less, 500 nanomolar or less, 100 nanomolar or less or 10 nanomolar or less.
  • Bi modulators In vivo activity of Bi 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 et al. (2003) J. Med. Chem. 46: 1803-06 - carrageenan-mduced mechanical pressure hyperalgesia; Cottley et al. (2005) Eur. J. Pharmacol, 527:44-51 - thermal antinociception and carrageenan-induced mechanical pressure hypersensitivity;
  • 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 half-life allowing for Q. ⁇ .D.
  • dosing preferably T.I.D. dosing, more preferably B. LD. 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-iives of compounds may be predicted from assays of microsomal half-life as described herein.
  • 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 States 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 States Food and Drug Administration
  • a highly preferred nontoxic compound generally satisfies one or more of the following criteria: (1) 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 cells.
  • such cells exhibit
  • ATP levels that are at least 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, minipigs or dogs upon administration of a dose that yields a serum concentration equal to the EC 50 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 p ⁇ 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 equal to the EC 50 or IC 50 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 that yields a serum concentration equal to the EC 50 or IC 5 O 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.
  • 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 50 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 ten-fold the EC 50 or IC 50 for the compound.
  • 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, CYP2EI activity or CYP3A4 activity at a concentration equal to the EC 50 or IC 50 for the compound.
  • microsomal cytochrome P450 enzyme activities such as CYP 1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2EI activity or CYP3A4 activity at a concentration equal to the EC 50 or IC 50 for the compound.
  • Certain preferred compounds are not clastogenic (e.g., as determined using a mouse erythrocyte precursor cell micronucieus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) at a concentration equal the EC 50 or IC 50 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-Iabeled 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, 13 C. 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • substitution with heavy isotopes such as deuterium 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 stereo isomeric forms.
  • Such forms can be, for example, racemates or optically active forms.
  • All stereoisomers are 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., 3 ⁇ 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 trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas using che 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 N- oxide ary! sulfones and sulfoxides 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., neutral buffered saline or phosphate buffered saline), ethanoi, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), rnannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
  • other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.
  • compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral (including, but not limited to, sublingual), nasa ⁇ , rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spina!, 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.
  • compositions of the present invention 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).
  • inert diluents e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents e.g., corn starch or
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • 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 excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents (e.g., sodium carboxymethylcellulose, methylceliulose, 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 hexitoi such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitoi anhydrides such as polyethylene sorbitan
  • 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 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 anti-oxidant 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, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • 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., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitoi), anhydrides (e.g., sorbitan monoleate) and condensation products of partial esters derived from fatty acids and hexitoi with ethylene oxide (e.g., polyoxyethylene 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, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile): and hydrocarbon-based materials such as m ⁇ crosponges and polymer matrices.
  • organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin
  • glycols e.g., butylene, iso
  • 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 hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemuisions, nanoparticles or nanocapsules.
  • a topical formulation may be prepared in a variety of physical forms including, for example, sofids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions.
  • 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. Controlled release vehicles can also be used.
  • a pharmaceutical composition may be prepared as a sterile injectible aqueous or oleaginous suspension.
  • the compound(s) provided herein can either be suspended or dissolved in the vehicle.
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, 1,3-butanedioi, Ringer's solution and isotonic sodium chloride solution.
  • 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.
  • Compounds may also be formulated as suppositories (e g., for rectal administration). Such 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 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) foliowing 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 control led-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 8 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 througii 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 ingredient(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 are 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 fo ⁇ n.
  • a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ingredient(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., po!y(acrylic acid), poiy(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate, methacrylic acid alkamide copolymer, poly(methyl methacrylate), polyacrylamide, ammonio methacrylate copolymers, aminoalkyi methacrylate copolymer, ⁇ oly(methacrylic acid anhydride) and glycidyl methacrylate copolymers) and mixtures of the foregoing.
  • AQUACOAT® FMC Corp., Philadelphia, PA
  • SURELEASE® Colorcon, Inc., West Point
  • 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.
  • Suitable plasticizers for alkyl celluloses include, for example, dibutyi sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin.
  • Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as triethyl citrate and tributyl citrate, dibutyi phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oii 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 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., hydroxypropylmethylcellulose), 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 tran sdermal 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; 4,587,1 17; 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.
  • N-oxide aryl sulfones and sulfoxides 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 vaiy 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 mg 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 cyciooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, leflunomide, cyclosporine A, IM gold, minocycline, azathioprine, tumor necrosis factor (TNF) receptor antagonists, soluble TNF alpha receptor
  • IL-I interleukin- 1 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., alefacept
  • LFA-I antagonists anti-VLA4 monoantibody ⁇ e.g., natalizumab
  • anti-CDl la monoclonal antibody anti-CD20 monoclonal antibody ⁇ e.g., rituximab
  • anti-IL-12 monoclonal antibody anti-IL-15 monoclonal antibody
  • CDP 484, CDP 870 chemokine receptor antagonists, selective iNOS inhibitors, p38 kinase inhibitors, integrin antagonists, angiogenesis inhibitors, and TMI-! dual inhibitors.
  • Further anti-inflammatory agents include meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valciecoxib 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, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.
  • One class of NSAIDs consists of compounds that inhibit eye 1 ⁇ oxygenase (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, methylprednisolone, 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, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.
  • analgesics for use in combination with B] modulators 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.
  • narcotic analgesics include, within preferred embodiments, alfentanil, a ⁇ phaprodine, anileridine, bezitramide, buprenorphine, butorphanol, codeine, diacetyidihydromorphine, 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, racemeth
  • narcotic analgesic agents include acetorphine, acetyldihydrocodeine, acetylmethadol, allylprodine, alphracetylmethadol, alphameprodine, alphamethadol, benzethidine, benzyimo ⁇ hine, betacetylmethadol, betameprodine, betamethadol, betaprodine, clonitazene, codeine methylbromide, codeine-N-oxide, cypreno ⁇ hine, desomorphine, dextromoramide, diampromide, diethylthiambutene, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiamubutene, dioxaphetyl buryrate.
  • naloxone naltyhexone, nicocodeine, ⁇ icomo ⁇ hine, noracymethadol, norlevo ⁇ hanol, normethadone, normo ⁇ hine, no ⁇ ipanone, pentazocaine, phenadoxone, phenampromide, phenomo ⁇ han, phenoperidine, piritramide, pholcodine, proheptazoine, properidine, prop Iran, racemoramide, thebacon, trimeperidine and the pharmaceutically acceptable salts and hydrates thereof.
  • analgesic agents include, for example acetaminophen
  • NR2B antagonists capsaicin receptor antagonists
  • anti-migraine agents such as oxcarbazepine and carbamazepine
  • antidepressants such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.
  • spinal blocks pentazocine/naloxone; meperidine; levorphanol; buprenorphine; hydromorphone; fentanyl; sufentanyi; oxycodone; oxycodone/acetaminophen, nalbuphine and oxymorphone.
  • analgesic agents include CB2-receptor agonists, such as AM 1241, capsaicin receptor antagonists and compounds that bind to the ⁇ 2 ⁇ subunit of voltage-gated calcium channels, such as gabapentin and pregabalin.
  • compositions may be packaged for treating conditions responsive to B] 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 B s modulation in a patient (e.g., pain or other disorder as indicated herein).
  • a packaged pharmaceutical preparation comprises one or more N-oxide aryl sulfone or sulfoxide 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 formulated 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 B] 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 B 1 modulation' 1 if the condition or symptom(s) thereof are alleviated, attenuated, delayed or otherwise improved by modulation of B s activity.
  • such methods comprise administering to the patient a therapeutically effective amount of at least one N-oxide aiyl suifone or sulfoxide as provided herein.
  • Conditions responsive to B 1 modulation include, for example pain; inflammation including neuroinflammation (such as atherosclerosis), inflammation associated with airway diseases (e.g., asthma, including allergic asthma, exercise-induced bronchoconstriction, occupational asthma, and other non-allergic asthmas), and inflammatory skin disorders (e.g., psoriasis and eczema)); respiratory disorders including bronchoconstriction, 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.
  • neuroinflammation such as atherosclerosis
  • airway diseases e.g., asthma, including allergic asthma, exercise-induced bronchoconstriction, occupational asthma, and other non-allergic asthmas
  • inflammatory skin disorders e.g.
  • diabetes e.g., type II or non insulin dependent, as well as diabetic vasculopathy, 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, crania!
  • Bj modulators may also be used as smooth muscle relaxants for treating spasms of the gastrointestinal tract of uterus.
  • the condition responsive to B] modulation is pain or inflammation.
  • Pain that may be treated using the Bi modulators provided herein may be chronic or acute and includes, but is not limited to, peripheral nerve-mediated pain (especially neuropathic pain, such as pain due to diabetes, postherpetic neuralgia, nerve injury, vulvodynia, root avulsions, painful traumatic neuropathy and painful polyneuropathy).
  • peripheral nerve-mediated pain especially neuropathic pain, such as pain due to diabetes, postherpetic neuralgia, nerve injury, vulvodynia, root avulsions, painful traumatic neuropathy and painful polyneuropathy).
  • visceral pain e.g., pancreatitis, interstitial cystitis and renal colic
  • persistent hyperalgesia inflammatory pain, repetitive motion pain, carpel tunnel syndrome, perioperative pain, algesia, oral neuropathic pain, toothache (dental pain), denture pain, ocular pain, postherpetic neuralgia, diabetic neuropathy, chemotherapy- induced neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, bone and joint pain (e.g., pain associated with osteoarthritis), rheumatoid arthritis, myofascial pain (e.g., muscular injury and fibromyalgia), Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome and/or 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 nerve disorders e.g., nerve entrapment and
  • Additional neuropathic pain conditions include causalgia (reflex sympathetic dystrophy - RSD, secondary to injury of a peripheral nerve), neuritis (including, for example, sciatic neuritis, peripheral neuritis, polyneuritis, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis and Gombault's neuritis), neuronitis, neuralgias (e.g., those mentioned above, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migranous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Binder's neuralgia, splenopalatine neuralgi
  • 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.
  • Charcot's pains intestinal gas pains, ear pain, heart pain, muscle pain, eye pain, orofacial pain (e.g., odontalgia), abdominal pain, gynaec ⁇ logical pain (e.g., menstrual pain, dysmenorrhoea, pain associated with cystitis, labor pain, chronic pelvic pain, chronic prostitis and endometriosis), acute and chronic back pain (e.g., lower back pain), gout, scar pain, hemorrhoidal pain, dyspeptic pains, pain associated with angina, nerve root pain, "non-painful" neuropathies, complex regional pain syndrome, nomotopic pain and heterotopic pain — including pain associated with carcinoma, often referred to as cancer 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-
  • pain treated with B] 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.
  • 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 anti-inflammatory agent.
  • the B; modulator and additional analgesic and/or anti- inflammatory agent may be present in the same pha ⁇ naceutical 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 administration, or intravenous, intramuscular, subcutaneous, intrathecal, epidural, intracerebroventricular 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 genera!, 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 Bi 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 the
  • this dose is less than 3 ⁇ , even more preferably less than Vi, and highly preferably less than ! ⁇ 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.
  • 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-pharmaceuticai 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 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 i, or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
  • PET positron emission 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). 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 detect luminescent groups and fluorescent groups).
  • a radionuclide such as tritium, as described herein
  • a matched sample containing labeled compound and a greater (e.g., 10-foid 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 Bj in the sample.
  • Detection assays including receptor autoradiography (receptor mapping) of Bi 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.
  • Mass spectroscopy data in the following Examples is Electrospray MS, obtained in positive ion mode using a Micromass Time-of-Flight LCT (Micromass, Beverly MA), equipped with a Waters 600 pump (Waters Corp.; Milford, MA), Waters 996 photodiode array detector, and a Gilson 215 autosampler (Gilson, Inc.; Middleton, WI). 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 absorbance 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 10-100%B 3 hold at ] 00%B to ] .2 min, return to I0%B at 1.21 min. inject to inject cycle is 2.15 min.
  • Step 4 4-Methoxy-2,6,N-trimethyl-N- ⁇ 2-[2-(9-methyl-3,9-diaza-spiro[5.5]undec-3-yl)'2-oxo- ethoxy] ethyl ⁇ benzenesulfonamide
  • a 1.0 M solution of TEA in toluene (0.15 mL) is added to a solution of ⁇ 2-[(4-methoxy-2,6- dimethylbenzenesulfonyl)methylamino]ethoxy ⁇ acetic acid (24 mg, 72 ⁇ mol), 3-methyl-3,9-diaza- spiro[5.5]undecane (10 mg, 60 ⁇ mol), and DMA (0.3 mL) under N 2 .
  • a 0.2 M solution of 2-chloro- 1,3-dimethylimidazolidinium chloride in acetonitrile (0.6 mL) is added. The reaction vessel is sealed and the mixture is warmed to 50 0 C for 2.5 h.
  • Step I (3S)-Methyl 4-benzyl-6-(iodomethyl)-6-methy!morphofine-3-carboxylate
  • step 1 The mixture of diastereomers obtained in step 1 is combined with tributyltin hydride (73 mL, 272 mmol) in 400 mL refhixing toluene.
  • AIBN (1 g, 6 mmol) dissolved in 40 mL toluene is added dropwise. After 2 h reflux, the reaction mixture is cooled to it.
  • Saturated aqueous KF solution (800 mL) is added and the resulting heterogeneous mixture is filtered through Celite and the so ⁇ d 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 applied to a 10 g silica SPE cartridge and eluted with ⁇ O mL of EtOAc to remove non-polar impurities, followed by 10 mL of 10/1/1 EtOAc/MeOH/TEA to elute the title compound.
  • the solvent is removed in vacuo to afford the title compound.
  • the IC 50 (determined as described in Example 7) is I micromolar or less.
  • RNA is isolated as described by Chomzynski et al. (1987) Anal. Biochem. 762: 156-159.
  • a cDNA encoding Bj is cloned from the total RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) with the following oligonucleotides:
  • Primer 1 GGCGCTAGCCACCATGGCATCCTGGCCCCCTC (SEQIDNO:!)
  • Primer 2 AGCCGTCCCAGATCTGAAC (SEQIDNO:2)
  • Primer 3 GATCTGGGACGGCTTGGATG (SEQIDNO:3)
  • Primer 4 CGGAGCTCTTAATTCCGCCAGAAAAGTTGGA (SEQ ⁇ DNO: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 Bj 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) ceils using Lipofectamine (Invitrogen), resulting in cynomolgus macaque B r 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 Bi receptors. These cells are used in radioligand binding assays (Example 6).
  • 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. expression (Menke, et ai, (1994) J. Biol Chem. 269:21583-86).
  • CHO cells stably expressing rat B 5 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 10 KalIidin to define non-specific binding. All wells then receive 0.3 nM (final concentration) [3H]-desArg 10 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 min 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 SigmaPlot (Systat Software, Point Richmond, CA) to determine each compound's IC 50 and K 1 (e.g., as described by Szallasi. et al. (1993) J. Pharmacol Exp. Ther. 25(5:678-83).
  • Sf9 cells infected with a baculovirus carrying the coding sequence for cynomolgus macaque Bi are harvested by centrifugation and frozen at -SO 0 C. Pellets are subsequently resuspended on ice in Tris buffered saline (TBS; 50 mM Tris (pH 7.4), 120 mM NaCl), and cells are 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.
  • TBS 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 10 ⁇ M desArg 10 Kallidin 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. After filtration, filters are dried and then counted in a Beta plate 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 5 0 and K 1 (e.g., as described by Szallasi, et al. (1993) J. Pharmacol. Exp. Th ⁇ r. 266:678-83).
  • EXAMPLE 7 CALCIUM MOBILIZATION ASSAY This Example illustrates representative calcium mobilization assays for use in evaluating test compounds for agonist and antagonist activity.
  • Cynomolgus macaque B r 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 mM KCl 3 0.96 mM NaH 2 PO 4 , 1 mM MgSO 4 , 2 mM CaCl 2 , 5 mM glucose, 1 rnM probenecid, pH 7.4) supplemented with the calcium- sensitive fluorescent dye Fluo4-AM (5 ⁇ g/ml; Teflabs, Austin, TX). The cells are then incubated at 37 0 C in an environment containing 5% CO 2 . 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.
  • KRH Krebs-Ringer HEP
  • y is the maximum fluorescence signal
  • x is the concentration of the B
  • agonist is the E max
  • b corresponds to the EC 50 value
  • c is the Hill coefficient.
  • this assay is also used to assess Bi agonist activity of the test compound. DETERMINATION OF ANTAGONIST ACTIVITY
  • 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 10 Kaliidin is then added to each well of plates containing test compound to determine the extent to which each test compound inhibits an agonist-induced Bi 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 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 desArg ! °Kallidin at the EC 50 concentration in the absence of test compound), at a concentration of I O micromoiar or less, preferably 1 micromolar or less.
  • 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 5O is determined using a linear regression in which x is ln(concentration of test compound) and y is ln( ⁇ ercent 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 IC 50 is
  • This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) cell cytotoxicity assay. 1 ⁇ L of test compound is added to each well of a clear bottom 96-wel! plate (Packard,
  • 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 10 6 cells/mL with warm (37°C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30-
  • ATP-LITE-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.
  • 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 nM, 50 nM, 25 nM, and 12.5 nM.
  • PACKARD 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 piates in foil and placing in the dark for 10 min.
  • 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.
  • a luminescence counter e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or TECAN SPECTRAFLUOR PLUS
  • Cells 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.
  • ATP levels that are at least 80%, preferably at least 90%, of the untreated cells.
  • cells treated with preferred test compounds exhibit ATP levels mat are at least 50%, preferably at least 80%, of the ATP levels detected in untreated cells.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des sulfones de N-oxyde aryle et des sulfoxydes selon la formule (I) : dans laquelle les variables sont telles que décrites ici. De tels composés peuvent être utilisés pour moduler l'activité du récepteur de la bradykinine in vivo ou in vitro, et ils sont particulièrement utiles dans le traitement des affections sensibles à une modulation Bi, y compris l'inflammation et la douleur, chez l'humain, les animaux de compagnie domestiques et le bétail. L'invention concerne également des compositions pharmaceutiques et des procédés destinés à utiliser celles-ci dans le traitement de tels troubles, mais elle concerne également des procédés destinés à utiliser de tels ligands à des fins d'études de localisation du récepteur et de diverses analyses in vitro.
PCT/US2007/076266 2006-08-23 2007-08-20 Sulfones de n-oxyde aryle et sulfoxydes WO2008024692A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008002849A2 (fr) * 2006-06-26 2008-01-03 Neurogen Corporation Aryl sulfones
WO2009124734A2 (fr) * 2008-04-08 2009-10-15 Grünenthal GmbH Dérivés de sulfonamide substitués
US20100317644A1 (en) * 2006-09-29 2010-12-16 Gruenenthal Gmbh Substituted Sulfonamide Compounds
JP2012517457A (ja) * 2009-02-13 2012-08-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新しい調製方法
US8318769B2 (en) 2008-04-08 2012-11-27 Gruenethal Gmbh Substituted sulfonamide compounds
WO2014029193A1 (fr) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006113140A2 (fr) * 2005-04-15 2006-10-26 Elan Pharmaceuticals, Inc. Nouveaux composes s'utilisant dans l'antagonisme du recepteur de bradykinine b1

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2006113140A2 (fr) * 2005-04-15 2006-10-26 Elan Pharmaceuticals, Inc. Nouveaux composes s'utilisant dans l'antagonisme du recepteur de bradykinine b1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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DATABASE CAPLUS [online] Database accession no. (2006:1124909) *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008002849A2 (fr) * 2006-06-26 2008-01-03 Neurogen Corporation Aryl sulfones
WO2008002849A3 (fr) * 2006-06-26 2008-12-04 Neurogen Corp Aryl sulfones
US20100317644A1 (en) * 2006-09-29 2010-12-16 Gruenenthal Gmbh Substituted Sulfonamide Compounds
US8435978B2 (en) * 2006-09-29 2013-05-07 Gruenenthal Gmbh Substituted sulfonamide compounds
WO2009124734A2 (fr) * 2008-04-08 2009-10-15 Grünenthal GmbH Dérivés de sulfonamide substitués
WO2009124734A3 (fr) * 2008-04-08 2010-04-01 Grünenthal GmbH Dérivés de sulfonamide substitués
JP2011516514A (ja) * 2008-04-08 2011-05-26 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 置換スルホンアミド誘導体
US8124624B2 (en) 2008-04-08 2012-02-28 Gruenenthal Gmbh Substituted sulfonamide compounds
US8318769B2 (en) 2008-04-08 2012-11-27 Gruenethal Gmbh Substituted sulfonamide compounds
JP2012517457A (ja) * 2009-02-13 2012-08-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新しい調製方法
WO2014029193A1 (fr) 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques

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