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WO2008016811A2 - Aminopipéridines et composés apparentés - Google Patents

Aminopipéridines et composés apparentés Download PDF

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Publication number
WO2008016811A2
WO2008016811A2 PCT/US2007/074282 US2007074282W WO2008016811A2 WO 2008016811 A2 WO2008016811 A2 WO 2008016811A2 US 2007074282 W US2007074282 W US 2007074282W WO 2008016811 A2 WO2008016811 A2 WO 2008016811A2
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Prior art keywords
alkyl
compound
mono
hydrate
salt
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PCT/US2007/074282
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English (en)
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WO2008016811A3 (fr
Inventor
Manuka Ghosh
Christopher K. Seekamp
Xuechun Zhang
James G. Tarrant
Che-Wah Lee
Bernd Kaiser
Mary-Margaret Zablocki
Bertrand L. Chenard
Dario Doller
Yasuchika Yamaguchi
David J. Wustrow
Guiying Li
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Neurogen Corporation
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Publication of WO2008016811A2 publication Critical patent/WO2008016811A2/fr
Publication of WO2008016811A3 publication Critical patent/WO2008016811A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • This invention relates generally to aminopiperidines and related compounds.
  • the invention further relates to the use of such compounds for treating a variety of metabolic, eating and sexual disorders, and as probes for the detection and localization of melanin concentrating hormone receptors.
  • MCH Melanin concentrating hormone
  • Agents capable of modulating MCH receptor activity are highly desirable for the treatment of a variety of diseases and disorders, including obesity, metabolic syndrome, eating disorders (e.g., bulimia and anorexia), sexual disorders (e.g., anorgasmic or psychogenic impotence) and metabolic disorders, such as diabetes.
  • Small molecule, non-peptide antagonists of MCH receptors would be of particular value for such therapies.
  • the present invention fulfills this need, and provides further related advantages.
  • R A is 6- to IO-membered aryi, 5- to I O-membered heteroaryl, Q-Csalkyl, Cj-Cehaloaikyl, (C 3 - Cgcycloalkyl)Co-Gia]kyl or (5- to 7-membered heterocycloalkyl)Co-QalkyI, each of which is optionally substituted and each of which is preferably substituted with from 0 to 4 substituents independently chosen from R B ;
  • Each R B is independently:
  • U and T are independently N or CRy; P is N or CRi 5 ; Q is N or CR 9 ; Ri is cyano, nitro, halogen or a group of the formula -L-M, wherein:
  • M is hydrogen, Q-CgalkyL C 2 -C 8 alkenyl, C 2 -C 8 aikynyl, C 2 -C 8 alkyl ether, mono- or di-(Q-
  • R is taken together with R 9 to form a fused C 5 -C 3 cycloalkyi or 5- to 8-membered heterocycloalkyl; in certain embodiments, R 1 is not H;
  • R 2 represents from 0 to 4 substituents independently chosen from Q -C h alky], C r C 4 haloalkyl and oxo; or two R 2 groups are taken together to form a bridge (e.g., methylene, ethylene, propylene or -CH 2 -O-CH 2 -);
  • R 3 is hydrogen, C]-C 4 aikyi or Ci ⁇ hal ⁇ alkyl;
  • R 4 is:
  • Each R 7 , R 9 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, -COOH. aminocarbonyl. aminosulfonyi, CrQalkyl. C 2 -Qalkenyl, C 2 -C 6 alkynyl, C]-C 6 alkoxy, C r
  • R 9 is taken together with R ; to form a fused cycloalkyl or heterocycloalkyl; and R I G is hydrogen, Q-Cgalkyl, C ⁇ -Cealkenyl or C 2 -C6alkynyL
  • R I G is hydrogen, Q-Cgalkyl, C ⁇ -Cealkenyl or C 2 -C6alkynyL
  • Rs is hydrogen, Q-Cgalkyl, C 2 -Cgaikenyl, Cj-CgaJkynyl.
  • R 9 and R !5 are independently halogen, hydroxy, nitro, cyano, amino, -COOH, aminocarbonyl, aminosulfonyl, CrQalkyl, C 2 -Qalkenyl, C 2 -Qalkynyl. Cj-Qalkoxy, CpCealkanoyl, C ⁇ - C 6 alkanone, Ci-C 6 alkanoyloxy, C 2 -C 6 alky ⁇ ether, C]-C 6 alkoxycarbonyl, Ci-Csalkylthio. Q- Csalkylsulfonyl. mono- or di-(C ⁇ -C6alkyl)aminoC 0 -C 4 alkyl, mono- or di-(Ci-
  • R 2 represents from 1 to 4 substituents independently chosen from Q ⁇ alkyl, Cr
  • P is N, CH or CR 15 ;
  • Ri is a group of the formula -L-M, wherein: L is a single covalent bond, O, C(O) 8 OC(O), C(O)O, OC(O)O, S(0) w , N(R x ),
  • each R x is independently hydrogen, C,-C 6 alkyl, C 2 -C 6 aikenyl.
  • C 2 -C 6 alkynyl or C r C 6 haloalkyl and w is independently selected at each occurrence from O, 1 and 2;
  • M is hydrogen, Ci-C 3 alkyi, Ci-Cgalkenyl, C ⁇ -Cgalkynyl, Ca-Cgalkyl ether, mono- or di-(C r C 8 aiky])aminoC 0 -C 6 alkyl, (C 3 -C 7 cycloalkyi)Co-C 6 aikyI or (5- to 10-membered heterocycle)Co-C 6 aikyl, each of which is substituted with from O to 3 substituents independently chosen from halogen, amino, hydroxy, cyano, oxo, aminocarbo ⁇ yl, imino, aminosulfonyl, -COOH, cyanoimido, CrQalkyl, Ci-Cghaloalkyl, Ci-C f ialkoxy, C r
  • R] is taken together with R 9 to form a fused Cs-Cgcycloalkyl or 5- to 8-membered heterocyc loal ky i ; such that R] is not hydrogen;
  • 5 are independently halogen, hydroxy, nitro, cyano, amino, -COOH, aminocarbonyl, aminosulfonyl.
  • Cj-Cealkyi C 2 -C 6 alkenyl, C ⁇ -C ⁇ alkynyl, C]-C 6 alkanoyl, Cs-Qalkanone, C;- C 6 a ⁇ kanoy!oxy, C 2 -C 5 alkyi ether, C r C 6 alkoxycarbonyl, C]-C e alkylthio ; Cs-C ⁇ alkylsulfonyl, mono- or di-(Ci-C ⁇ alkyl)ammoCo-C 4 alkyl, mono- or di»(C r C ⁇ a!kyl)aminocarbonylCo-C 4 afkyl, mono- or di-fCrQalkylJaminosuifo ⁇ yiCo-Cjafkyl, CpCehaloalkyl, Ci-Cehaloalkoxy, Cp C ⁇ hydroxyalkyl, Ci-C 6 aminoalkyl, Ci-C 6 cyanoalkyl, or mono
  • Formula VII Formula VIII or are a pharmaceutically acceptable salt, solvate or esters of such a compound.
  • Variables within Formulas V, VI 3 VIl and VIII are generally as described for Formula I.
  • Formula IX are a pharmaceutically acceptable salt, solvate or esters of such a compound. Variables within
  • Formula TX are generally as described for Formula I.
  • aminopiperidines and related compounds provided herein are MCH receptor modulators and exhibit a K 1 of no greater than 1 micromolar, 500 nanomolar, 100 nanomolar, or 10 nanomolar in a MCH receptor binding assay and/or have an ECj 0 or IC 5 O value of no greater than 1 micromolar, 500 nanomolar, 100 nanomolar, or 10 nanomolar in an assay for determining MCH receptor agonist or antagonist activity.
  • aminopiperidines and related compounds provided herein are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).
  • a detectable marker e.g., radiolabeled or fluorescein conjugated.
  • the present invention further provides, within other aspects, pharmaceutical compositions comprising at least one aminopiperidine or related compound provided herein in combination with a physiologically acceptable carrier or excipient.
  • a pharmaceutical composition provided herein may further comprise one or more additional active agents (i.e., drugs).
  • compositions provided herein may be formulated, for example, as an injectable fluid, an aerosol, a cream, an oral liquid, a tablet, a gel, a pill, a capsule, a syrup or a transdermal patch.
  • Methods are further provided for modulating binding of ligand (e.g., MCH) to cellular MCH receptor, comprising contacting cells expressing MCH receptor with a MCH receptor modulator as described above, in an amount that would be sufficient to detectab ⁇ y modulate MCH binding to MCH receptor in vitro.
  • the cells may, but need not, be present in a human nor non-human animal. 5 Tn other aspects, methods are provided for modulating binding of ligand (e.g., MCH) to
  • MCH receptor in vitro comprising contacting MCH receptor with a MCH receptor modulator as described above, in an amount sufficient to detectably modulate MCH binding to MCH receptor.
  • the present invention provides methods for modulating the signal- transducing activity of MCH receptor in a cell, comprising contacting a cell expressing MCH I O receptor, either in vivo or in vitro, with a MCH receptor modulator as described above, under conditions and in an amount that is sufficient to detectably alter the electrophysiology of the cell.
  • the MCH receptor is a MCHlR.
  • the present invention further provides, within other aspects, methods for treating a disease or disorder associated with MCH receptor activation, comprising administering to a patient in need 5 of such treatment a therapeutically effective amount of a MCH receptor modulator as described above.
  • Such diseases and disorders include, for example, obesity, metabolic syndrome, eating disorders (e.g., bulimia nervosa), sexual disorders, diabetes, heart disease and stroke.
  • the MCH receptor modulator may be administered oralfy, or via another means such as intranasal Iy, intravenously or topically.
  • the patient is a human, companion animal0 (e.g., dog or cat) or livestock.
  • MCH receptor modulator and administering to the patient an effective amount of a MCH receptor5 modulator as described above.
  • Methods are provided, within other aspects, for determining the presence or absence of MCH receptor in a sample, comprising: (i) contacting a sample with a compound as described above under conditions that permit binding of the compound to MCH receptor; and (ii) detecting a level of the compound bound to MCH receptor.
  • the compound is radiolabeled,0 and the step of detection comprises: (i) separating unbound compound from bound compound; and (ii) determining an amount of bound compound in the sample. Detection may be achieved, for example, using autoradiography.
  • Representative samples include, for example, tissue sections.
  • Packaged pharmaceutical preparations comprising: (a) a pharmaceutical composition as described above in a container; and (b) instructions for using the composition to treat5 a patient suffering from or at risk for developing a disease or disorder associated with MCH receptor activation.
  • methods for preparing the compounds disclosed herein, including the intermediates are also provided herein.
  • the present invention provides aminopiperidines and related compounds of
  • MCH receptor modulators that may be used in vitro or in vivo, to inhibit MCH binding to MCH receptors, activate MCH receptors, or to otherwise modulate MCH receptor activity in a variety of contexts, as discussed in further detail below.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C and ]A C.
  • Certain compounds are described herein using a genera! formula that includes variables (e.g., X, V, R 3 ). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. In general, the variables may have any definition described herein that results in a stable compound.
  • aminopiperidines and related compounds refers to any compound that satisfies Formula I, or other Formula provided herein, or is a pharmaceutically acceptable salt, solvate (e.g., hydrate) or ester of such a compound. Certain aminopiperidines and related compounds further satisfy one or more additional formulas provided herein.
  • a "pharmaceutically acceptable salt' 1 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, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochloride, diphosphate, ditartrate, edetate, estolate (ethylsuccinate). formate, fumarate, gluceptate.
  • gluconate glutamate, glycolate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaieate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methylbroraide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phenylacetate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamate, sulfanilate, sulfate, sulfonates including besylate (benzenesuifonate).
  • carnsylate (camphorsulfonate), edisylate (ethane- 1 ,2- disulfonate), esylate (ethanesulfonate) 2-hydroxy ethyl sulfonate, mesylate (methanesulfonate), Inflate (trifluoromethanesulfonate) and tosylale (p-toluenesulfonate), tannate, tartrate, teoclate and trieth iodide.
  • pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediami ⁇ e, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile, is preferred.
  • nonaqueous media such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile
  • each compound of Formula I may, but need not, be formulated as a solvate (e.g., a hydrate) or a non-covalent complex.
  • the various crystal fo ⁇ ns and polymorphs are within the scope of the present invention.
  • prodrugs of the aminopiperidines and related compounds provided herein.
  • a "prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce an aminopiperidine or related compound.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, amine or sulfhydryi groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon. Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-Qalkyl), from 1 to
  • Ci-C 6 alkyl and from 1 to 4 carbon atoms (Cj-C 4 alkyl), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyi, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl and 3-methylpentyl.
  • C 0 -C n a3kyl refers to a single covalent bond (C 0 ) or an alky!
  • CVCealkyi refers to a single covalent bond or a Cj-Qalkyl group. In some instances, a substituenl of an alky! group is specifically indicated.
  • Ci-Cehydroxyalkyl refers to a CrCgalkyl group that has at least one hydroxy substituent
  • Ci-C 6 aminoalkyl refers to a C r C 6 alkyI group that has at least one amino substituent
  • Ci-C ⁇ Cyanoalkyi refers to a CpCsalkyl group that has at least one cyano (C ⁇ N) substituent.
  • Alkylene refers to a divalent alkyi group, as defined above.
  • Co-C 4 alkyle ⁇ e is a single covalent bond or an alkylene group having from 1 to 4 carbon atoms.
  • Alkenyl refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include, for example, C 2 -C 8 alkenyl and
  • alkenyi groups which have from 2 to 8 or from 2 to 6 carbon atoms, respectively ⁇ e.g., ethenyl, allyl or isopropenyl).
  • alkynyl refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond.
  • Aikynyl groups include, for example, Cj-Cgalkynyl and Ci-Cgalkynyl groups, which have from 2 to 8, or from 2 to 6 carbon atoms, respectively.
  • a “cycloalkyl” is a group that comprises one or more saturated and/or partially saturated rings in which ail ring members are carbon, such as cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl. decahydr ⁇ -naphthalenyl, octahydro-indenyl, and partially saturated variants of the foregoing, such as cyclohexenyl.
  • Certain cycloalkyl groups are Ci -C 7 cycloalkyl, in which the group contains from 3 to 7 ring members.
  • a "cycloalkyiCo-C n alkyi” is a cycloalkyl group linked via a single covalent bond or a C r C n alkylene group (e.g., (C 3 - C 7 cycloalkyl)C 0 -C,alkyl).
  • alkoxy is meant an alky I group as described above attached via an oxygen bridge.
  • Alkoxy groups include Cj-C ⁇ alkoxy and C
  • Methoxy, ethoxy. propoxy, isopropoxy, n-butoxy, sec- butoxy. ter/-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy. and 3-methyIpentoxy are representative alkoxy groups.
  • alkylthio refers to an alkyl group as described above attached via a sulfur bridge.
  • Alkylsulfonyl refers to groups of the formula - ⁇ S ⁇ 2 )-aikyL in which the sulfur atom is the point of attachment.
  • Alkylsulfonyl groups include Ci-C 6 alkylsulfonyl and Ci-C 4 alkylsuifonyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • Methylsulfonyl is one representative alkylsulfonyl group.
  • Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms.
  • - Alkanoyl groups include, for example, C ⁇ -Cealkanoyl, which have from 2 to 6 carbon atoms.
  • Alkyl ether refers to a linear or branched ether substituent (i.e., an alkyl group that is substituted with an alkoxy group). Such groups include C 2 -C 3 alkyi ether and C 2 -C 6 alkyl ether. A C 2 alkyl ether group has the structure -CH 2 -O-CH 3 .
  • Alkoxycarbonyl groups include, for example, Ci-Ce and C]-C 4 alkoxycarbonyl groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively, in the alkyl portion of the group (i.e., the carbon of the keto bridge is not included in the indicated number of carbon atoms).
  • Alkanoylamino groups include, for example, C 2 -C 6 alkanoylamino groups, which have from 2 to 6 carbon atoms.
  • Alkylamino refers to a secondary or tertiary amine having the general structure -NH- alkyl or -N ⁇ alkyl)(alkyl), wherein each "alkyl” is selected independently from alkyl, cycloalkyl and
  • (cycioaikyl)alkyl groups include, for example, mono- and di-(C]-CgalkyI)amino groups, as well as mono- and di-(C
  • Alkylaminoalkyl refers to an aikylamino group linked via an alkylene group (i.e., a group having the general structure -alkylene-NH-alkyl or -alkyIene-N(aIkyl)(alkyI), in which each alkyi is selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups).
  • Alkylaminoalkyl groups include, for example, mono- and di-(Ci-Cgalkyl)aminoCrCga!kyl, mono- and di-(Cj- C 6 atkyl)ammoCj-C 6 alkyl and mono- and dHCj-C ⁇ alkyOaminoCi-Qalkyl.
  • "Mono- or di-(C r C 6 alkyl)aminoC 0 -C 6 alkyl” refers to a mono- or di-(C r C 6 alky!)amino group linked via a single covalent bond or a Ci-Cealkylene group.
  • alkyl as used in the terms “alkylamino” and “alkylaminoalkyl” differs from the definition of "alkyl” used for all other alkyl-containing groups, in the inclusion of cyc ⁇ oalkyi and (cycloalkyl)a!kyl groups (e.g., tC 3 -C 7 cycloaikyl)C 0 -C 6 alkyl).
  • “Mono- or di-(C r Cgalkyl)aminocarbonyi” is an aminocarbonyl group in which one or both of the hydrogen atoms is replaced with Ci-Cgalkyi. If both hydrogen atoms are so replaced, the alkyl groups may be the same or different.
  • “Mono- or di-(CrC 6 a!kyl)aminocarbonylC 0 -C 4 alkyl is a mono- or di-(C r
  • Aminosulfonyi refers to groups of the formula "-(SOi)-NH 2 , in which the sulfur atom is the point of attachment.
  • the term “mono- or di-(C]-C ⁇ alkyl)aminosulfonyl” refers to groups that satisfy the formula - ⁇ SOi)--NR 2 , in which the sulfur atom is the point of attachment, and in which one R is C r C n alkyI and the other R is hydrogen or an independently chosen Cj-C ⁇ alkyl.
  • “Mono- or di-(Ci-C 6 alkyl)aminosulfonylCo-C 4 alkyl is a mono- or di-(C]-C 6 alkyl)aminosulfonyl group that is attached via a single covalent bond or a Q-C ⁇ alkyiene group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • a “haioalkyl” is an alkyl group that is substituted with 1 or more independently chosen halogens ⁇ e.g., "CrQhaloalkyl” groups have from 1 to 6 carbon atoms, each of which is optionally substituted with 1 or more halogens). Examples of haloalkyl groups include, but are not limited to.
  • Typical haioalkyl groups are trifluoromethy! and difluoromethyl.
  • haloalkoxy refers to a haloalkyi group as defined above attached via an oxygen bridge.
  • C r C 6 haIoalkoxy have 1 to 6 carbon atoms.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH 2 is attached through the carbon atom.
  • a “carbocycle” or “carbocyclic group” comprises at least one ring formed entirely by carbon-carbon bonds (referred to herein as a carbocyclic ring), and does not contain a heterocycle. Unless otherwise specified, each ring within a carbocycle may be independently saturated, partially saturated or aromatic, and is optionally substituted as indicated.
  • a carbocycle generally has from 1 to 3 fused, pendant or spiro rings; carbocycies within certain embodiments have one ring or two fused rings. Typically, each ring contains from 3 to 8 ring members ⁇ i.e., C 3 -C 5 ); C 5 -C 7 rings are recited in certain embodiments.
  • Carbocycies comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain carbocycies are C 4 -C] 0 (i.e., contain from 4 to 10 ring members and I or two rings). Certain representative carbocycies are cycloalkyl as described above. Other carbocycies are aiyl (i.e., contain at least one aromatic carbocyclic ring, with or without one or more additional aromatic and/or cycloalkyl rings).
  • Such aryl carbocycies include, for example, phenyl, naphthyl (e.g., 1-naphthyl and 2-naphthyl), biphenyl, fluorenyl, indanyl and 1 ,2,3,4- tetrahydro-naphthyl.
  • preferred carbocycles are carbocycles having a single ring, such as phenyl and 3- to 7-membered cycloalkyl groups (C 3 -C7cycloalkyl).
  • aryl indicates aromatic groups containing only carbon in the aromatic ring or rings. Such aromatic groups may be further substituted with carbon and/or non- carbon atoms or groups. Typical aryl groups contain 1 or 2 separate, fused, or pendant rings and from 6 to about 12 ring atoms, without heteroatoms as ring members. 6- to 10-membered aryl groups include phenyl, naphthyl and phenyl groups that are fused to a 5 to 7-membered saturated or partially saturated ring that optionally contains 1 or 2 heteroatoms independently chosen from N, O and S (e.g., 3,4-methyIenedioxy-phenyl).
  • arylalkyl refers to an aryl group linked via an alkylene bridge.
  • phenylCo-C ⁇ alkyl indicates a phenyl group that is attached via a single covalent bond ( ⁇ henylC o alkyi) or attached through an alkylene group having 1 or 2 carbon atoms.
  • an aryl group may be attached through other linker groups; such groups include, for example, arylCV C 6 alkanoylamino and arylalkoxy groups, in which the aryl is attached via the indicated linker group.
  • a “heterocycle” or “heterocyclic group” has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a heteroatom independently chosen from O, S and N, with the remaining ring atoms being carbon). Additional rings, if present, may be heterocyclic or carbocyclic. Typically, a heterocyclic ring comprises 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 sulfur 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.
  • a heterocycle may be a heterocycloalkyl group (i.e., each ring is saturated or partially saturated) or a heteroaryl group (i.e., at least one heterocyclic ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6- membered heteroaryl (e.g., pyridyl or pyrimidyl).
  • N-linked heterocyclic groups are linked via a component nitrogen atom.
  • 4-to 7-membered heterocycloalkyl groups include, for example, piperidinyl, piperazinyl.
  • aromatic heterocycles include azocinyl, pyridyl, pyrimidyl, imidazolyl and tetrazolyl.
  • preferred heterocycles are 5- to 7-membered heterocycles having a single saturated, partially unsaturated or aromatic heterocyclic ring with 5 to 7 ring members, 1 or 2 ring members independently chosen from N, O and S, with remaining ring members being carbon.
  • heterocycles are attached via an indicated linker group (e.g., (heterocycle)alkyl, (heterocycle)alkoxy and (heterocycle)alkylamino groups).
  • the heterocycle is covalently bound to the indicated linker group, each of which carries the definition set forth above.
  • a (4- to 10-membered heterocycle)Co-C 2 alkyl is a heterocyclic group, which may be saturated, partially saturated or aromatic, that contains from 4 to 10 ring members and that is linked via a single covalent bond or a methylene or ethylene linker.
  • heteroary indicates a monocyclic, bicyclic or tricyclic ring system that comprises at least one 5- or 6-membered heterocyclic aromatic ring that contains from 1 to 4 (preferably from 1 to 3) heteroatoms independently chosen from N, O and S, with remaining ring atoms being carbon. If the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is generally preferred that the total number of S and O atoms in the heteroaryl group is not more than 2; in certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyi, thienylpyrazolyl, thiophenyl, triazolyl, benzo[ ⁇ i]oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, be ⁇ zoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indoiyl, and isoxazolyl.
  • heterocycloalkyl is a heterocycle as described above, which is fully or partially saturated.
  • preferred heterocycloalkyl groups are 5- to 7-membered heterocycloalkyi groups having a single saturated ring with 5 to 7 ring members. I or 2 ring members independently chosen from N, O and S, and remaining ring members being carbon. Certain such heterocycloalkyl groups are 5- or 6-membered.
  • a "heterocyc]oalkyICo-C n aIkyl” is a heterocycloalkyi group linked via a single covalent bond or group, such as a C 1 - Cjaikylene group.
  • (3- to 10-membered cycle) refers to any carbocycie or heterocycle that has from
  • C ⁇ alkoxy groups include "(3- to 10-membered cycle)-O-" moieties, such as phenoxy and
  • cycloalkyloxy groups e.g., cyclopentyloxy
  • 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, haloalkyl group or other group discussed herein that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member.
  • Substituents of aromatic groups are generally covalently bonded to a ring carbon atom.
  • substitution refers to replacing a hydrogen atom in a molecular structure with a substituent, 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 I 5 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).
  • MCH receptor refers to any naturally-occurring mammalian (e.g., human, monkey, or canine) MCH type 1 or type 2 receptor, as well as chimeric receptors in which one or more domains of a naturally-occurring MCHlR or MCH2R are replaced with a corresponding domain of a different G protein-coupled receptor, such that the ability of the chimeric receptor to bind MCH and mediate a dose-dependent release of intracellular calcium is not diminished.
  • MCH receptors for use within the various assays and other methods described herein include, for example, recombinantly expressed human MCHlR (e.g., SEQ ⁇ D NO:6 of US Patent No.
  • a “MCH receptor modulator,” also referred to herein as a “modulator,” is a compound that alters (increases or decreases) MCH receptor activation and/or MCH receptor-mediated signal transduction.
  • MCH receptor modulators specifically provided herein are aminopiperidines and related compounds.
  • a modulator may exhibit an EC 50 or IC 5 0 at MCH receptor that is less than 1 micromolar, 500 11M, 200 nM, 100 nM, 50 nM, 25 nM or 10 nM in a standard calcium mobilization assay (as described in Example 10, herein) and/or an agonist- stimulated GTP gamma 35 S binding assay (as described in Example 8, herein).
  • a modulator may be a MCH receptor agonist or antagonist, although antagonists are preferred for certain purposes described herein.
  • a MCH receptor modulator binds with "high affinity” if the Kj at a MCH receptor is less than 1 micromolar, preferably less than 500 nanomolar, 100 nanomolar or 10 nanomolar.
  • a modulator binds "specifically" to MCH receptor if it binds to a MCH receptor (total binding minus nonspecific binding) with a K; that is 10-fold, preferably 100-fold, and more preferably 1000-fold, less than the Kj measured for modulator binding to other G protein-coupled receptors.
  • a modulator may have a K 1 of 500 nanomolar or less in an MCH receptor ligand binding assay and a
  • K of at least 1 micromolar in a dopamine receptor ligand binding assay, such as the assay described in Example 8 (pages 111-1 12) of PCT International Publication Number WO 02/094799, which is hereby incorporated by reference.
  • Representative assays for determining K, at MCH receptor are provided in Examples 6 and 8-10, herein.
  • a modulator is considered an "antagonist" if it detectably inhibits MCH binding to MCH receptor and/or MCH-mediated signal transduction (using, for example, the representative assay provided in Example 6 or Example 9); in general, such an antagonist has a IC 50 value of less than 1 micromoiar, preferably less than 100 nanomolar, and more preferably less than 10 nanomolar within the assay provided in Example 6 and/or the assay provided in Example 9.
  • MCH receptor antagonists include neutral antagonists and inverse agonists.
  • An "inverse agonist” is a compound that reduces the activity of MCH receptor below its basal activity level in the absence of added ligand. Inverse agonists may also inhibit the activity of MCH at MCH receptor, and/or may also inhibit binding of MCH to MCH receptor.
  • the ability of a compound to inhibit the binding of MCH to MCH receptor may be measured by a binding assay, such as the binding assays given in Example 6 or Example 9.
  • the basal activity of MCH receptor, as well as the reduction in MCH receptor activity due to the presence of antagonist may be determined from a calcium mobilization assay, such as the assay of Example 10, or an agonist- stimulated GTP gamma 33 S binding assay, such as the assay described in Example 8.
  • a "neutral antagonist" of MCH receptor is a compound that inhibits the activity of MCH at
  • MCH receptor but does not significantly change the basal activity of the receptor (e.g., within an assay as described in Example 8 or Example 10 performed in the absence of ligand, MCH receptor 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 also inhibit ligand binding to MCH receptor.
  • MCH receptor agonist is a compound that elevates the activity of the receptor above the basal activity level of the receptor (i.e., enhances MCH receptor activation and/or MCH receptor-mediated signal transduction).
  • MCH receptor agonist activity may be identified using the representative assays provided in Examples 8 and 10. In general, such an agonist has an EC 50 value of less than 1 micromoiar, preferably less than 100 nanomolar, and more preferably less than 10 nanomolar within one or both of the assays provided in Examples 8 and 10.
  • a “therapeutically effective amount” is an amount that, upon administration, is sufficient to provide a discernible patient benefit.
  • a therapeutically effective amount may reduce symptom severity or frequency, and/or may result in detectable weight loss.
  • a therapeutically effective amount may improve patient status or outcome and/or prevent or delay disease or symptom onset.
  • 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
  • a “disease or disorder associated with MCH receptor activation,” as used herein is any condition that is characterized by inappropriate stimulation of MCH receptor, regardless of the amount of MCH present locally, and/or that is responsive to modulation of MCH receptor activity (i.e., the condition or a symptom thereof is alleviated by such modulation).
  • Such conditions include, for example, metabolic disorders (such as diabetes), heart disease, stroke, eating disorders (such as obesity and bulimia nervosa) and sexual disorders such as anorgasmic and psychogenic impotence, as well as other diseases and disorders recited herein.
  • a “patient” is any individual treated with an aminopiperidine or related compound 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 MCH receptor modulation, or may be free of such symptom(s) (i.e., treatment may be prophylactic).
  • MCH receptor modulators may be specific for a particular MCH receptor (e.g., type 1 or type 2) or may inhibit or enhance ligand binding to multiple MCH receptors.
  • MCH receptor modulators may be used to modulate MCH receptor activity in vivo, especially in the treatment of metabolic, feeding and sexual disorders in humans, domesticated companion animals and livestock animals. Modulators may also be used within a variety of in vitro assays, such as assays for receptor activity, as probes for detection and localization of MCH receptors and as standards in assays of MCH binding and MCH-mediated signal transduction.
  • the MCH receptor modulators provided herein detectably modulate
  • MCH receptor activity at submicromoiar concentrations, preferably at subnanomolar concentrations.
  • Certain aminopiperidines and related compounds further satisfy Formula II, III, IV, V, VI,
  • Formula I lie Formula HId
  • variables are generally as described above, f ⁇ certain embodiments of the Formulas provided herein, one or more of the variables are as follows.
  • R] groups satisfy the formula -L-M, in which L and M are as noted above. It will be apparent that the "L” moiety in such groups is divalent and is directly finked both to M and to the aromatic ring that comprises U and T. If L is a single covalent bond, then the "M” moiety is linked via a single covalent bond to the aromatic ring.
  • Ri is a group of the Formula Rs-O-, in which linkage is via the oxygen atom and Rg is as defined for Formula IL
  • R 8 is hydrogen, Cj-Qalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, mono- or di-(Ci-C 3 alkyl)aminoCi-C 6 alkyi or (5- to 7-membered heterocycle)C 0 -C 6 alkyl.
  • R, groups are Ci-C 6 alkoxy, such as methoxy; other R
  • Q is substituted carbon.
  • P is CR 55 , and at least one of P and Q is substituted carbon.
  • R 9 and R i5 are independently hydrogen, C r C 2 alkyl, C r C 2 alkoxy or CV Cihaloalkyl; within further embodiments, R 9 and R S 5 are independently C r C 2 aikyl, C]-C 2 alkoxy or Cj-Cihaloalkyi. Rg and Rj 5 are both methyl within other embodiments.
  • the variables U and T. within certain compounds provided herein, are both CR 7 .
  • each R 7 is hydrogen, C]-C 2 alkyL C r C 2 aIkoxy or Ci-C 2 haloalkyl; in further embodiments, each R 7 is hydrogen.
  • R9 and Rj 5 are independently chosen from Ci-C 4 alkyl and each R 7 is independently hydrogen, C r C 2 alkyl, C r C 2 alkoxy or Q- Cjhaloalkyl.
  • R 3 is hydrogen. Within other such compounds, R 3 is not H (e.g., R 3 is methyl or ethyl). Within certain such compounds, the group
  • n is 0, 1 or 2.
  • Representative combinations for n and m include, for example, (a) n is 0 and m is 1, 2 or 3; (b) n is 1 and m is 2 or 3; (c) n is 2 and m is 0, 1 or 2; and (d) n is 3 and m is 0 or 1 .
  • Certain n and m combinations are illustrated in the following table, in which the n and m values are given along with the resulting core ring:
  • Such core rings may, but need not, be substituted as provided herein (e.g., by the formation of a bridge).
  • R 2 represents zero substituents.
  • R? represents from 0 to 4 substituents independently chosen from Cj-dalkyl and
  • two R 2 groups are taken together to form a bridge.
  • variable q is 0 in certain embodiments and 1 in other embodiments.
  • Representative R 10 moieties include, for example, methyl, ethyl, propyl and butyl.
  • X is C(O).
  • R n and R !2 are independently H, Ci-Cgalkyl, CrQalkoxy, C 2 -C ⁇ ;alky1 ether, or taken together with a R B or R 6 moiety to form a Cs-Cycycioalkyl or heterocycloalkyl. It will be apparent that, if R A is a cyclic moiety, such a cycloalkyl or heterocycloalkyl will be a ring that is fused to R A . If X is C(O)NR n , R n is preferably H, C,-C 6 alkyl or C 2 -C 6 alkyl ether.
  • R A within certain aminopiperidines and related compounds of the Formulas provided herein, is (e.g., methyl, ethyl, propyl, butyl or pentyl); (e.g., trifluoroethyl); (e.g., cyclopropyl, cyc ⁇ obutyl, cyclopentyl.
  • R A is (Cj- C 7 cycloalkyi)Co-C 2 alkyl within certain such compounds. Representative such compounds of
  • Formula IIj Formula ITk wherein f is 0, 1 , 2 or 3.
  • Representative compounds of Formula Hm further satisfy one of Formulas Hk-I to IIk-3:
  • each R B is independently (i) halogen, hydroxy, nitro or cyano; or (ii) C,-C 6 alkyl, C 2 -Qalkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkanoyl, C]-C 6 alkyltliio, C]-C 6 alkanoyloxy, Ci-Qalkoxycarbonyl, C
  • R A is 6- to 10-membered aryl ⁇ e.g., phenyl) or 5- to 10-membered heteroaiyl (e.g., a 5- or 6-membered heteroaryl such as pyridyl, pyrimidyl, thiazolyl, thiophenyl, imidazolyl, triazolyL tetrazolyl or furanyl; or a 9- or 10-membered heteroaiyl such as indolyl, IH-indolyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl.
  • aryl e.g., phenyl
  • 5- to 10-membered heteroaiyl e.g., a 5- or 6-membered heteroaryl such as pyridyl, pyrimidyl, thiazolyl, thiophenyl, imidazolyl, triazolyL tetrazolyl or furanyl
  • benzisoxazolyl benzothiadiazolyl, benzoxadiazolyl. benzotliiophenyi, benzodioxolyl, dihydrobenzodioxinyl, quinolinyl, quinazolinyl, and the like), each of which is
  • R A is H E ⁇ ⁇ D ' ; wherein A and E are independently M or CR 5 ; B, J and D are independently N or CR 6 ; each R 5 is independently: (i) hydrogen, halogen, nitro, cyano or -COOH; (ii) Cj-C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, Ci-C 6 alkanoyl, C 3 -C 6 a!kanone, C 2 -C 6 alkyl ether, C r C 6 alkoxycarbonyl, C 1 - C 6 alkylsulfonyl or Ci-C 6 haloalkyl; each of which is substituted with from 0 to 3 substituents independently chosen from hydroxy, amino, cyano, Ci-C 6 alkoxy and mono- or di-(C r C 6 alkyl)amino; or (iii) taken together with a
  • each R 5 is independently: (i) hydrogen, halogen, nitro, cyano or -COOH; or (ii) CpC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C ⁇ ;aikynyl, CpQalkanoyl, Cs-C ⁇ alkanone,
  • C 2 -C 6 alkyl ether CpCealkoxycarbony ⁇ , CpC 6 aIkylsulfony! or CpQhaloalkyl; each of which is substituted with from O to 3 substituents independently chosen from hydroxy, amino, cyano, Cp
  • each R 6 is independently: (i) hydrogen, halogen, hydroxy, nitro, cyano or-COOH; or (ii) CpQalkyl, C 2 -Qalkenyl, C 2 -Qalkynyl, CpCgalkoxy, C]- C f ialkanoyl, Cj-C ⁇ alkylthio, CpC 6 aIkanoyIoxy, Ci-C 6 alkoxycai'bonyl, CpC 6 alkyIsulfonyl, C]-
  • C 2 alkyl each of which is substituted with from O to 4 substituents independently chosen from hydroxy, cyano, halogen, amino, oxo, CpC 4 aIkyl, C r C 4 alkoxy, CpQhaloalkyl, C r C 4 haloalkoxy, mono- or di-(C r C 6 alkyl)ammo and 5- or 6-membered heterocycloalkyi; or two adjacent R 6 groups are taken together to form a fused, 5- or 6-membered ring.
  • substituents independently chosen from hydroxy, cyano, halogen, amino, oxo, CpC 4 aIkyl, C r C 4 alkoxy, CpQhaloalkyl, C r C 4 haloalkoxy, mono- or di-(C r C 6 alkyl)ammo and 5- or 6-membered heterocycloalkyi; or two adjacent R 6 groups are taken together to form a fused, 5- or 6-
  • Still further compounds of Foi ⁇ nuia ⁇ lm further satisfy one of Formulas 1Im-I to l ⁇ m-3:
  • At least one of B, J and D is substituted carbon.
  • J is substituted carbon
  • B is substituted carbon
  • both J and B are substituted carbon.
  • at least two, or exactly two, of B, J and D are carbon that is substituted (e.g., with a substituent independently chosen from methyl, ethyl, halogen, C]-C 2 HaIOaIkVl and C]-C 2 alkoxy).
  • A, J and E are optionally substituted carbon and D is N; in certain such compounds A and E are each CH.
  • R A is E-G ; E-A or D-E ; wherein A, B, E and D are independently N or CR 6 ; G is NR 6 , S or O; and R 6 is as described above.
  • Representative such R A groups include, for
  • R 5 and R 6 are generally as indicated above.
  • each R 6 is independently: (i) hydrogen, halogen, hydroxy, nitro or cyano; or (ii) d-Qalkyl, C 2 - Qalkenyl, C 2 -C 6 alkynyl, C r C 6 alkoxy, C r C 6 alkanoyl, C r C 6 alkylthio, C r QalkanoyIoxy, C 1 - C 6 alkoxycarbony], C]-C 6 alky]sulfonyl, C,-C 6 haloaikyl, (C 3 -C 7 cycioalkyl)Co-C 2 aikyl, (4- to 7- membered heteiOcycle)C,-C 2 alkyl or phenyiCo-C 2 alkyl; each of which is substituted with from O to 4 substituents independently chosen from hydroxy, cyano, halogen,
  • R 3 or R 6 is taken together with R n or R ]2 to form a cycloalkyl or heterocycloalkyl ring. It will be apparent that, if R A is a cyclic moiety, the cycloalkyi or heterocycloalkyl ring so formed will result in fused rings (e.g., benzodioxolyl). In further embodiments, two substituents represented by R 6 are taken together to fo ⁇ n a carbocycle or heterocycle.
  • R A is 6- to 10-membered aryl or 5- to 10- membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from R B .
  • Representative R A groups include D . wherein A and E are independently
  • N or CR 5 B, J and D are independently N or CR ⁇ ; and each R 5 and R 5 is independently: (i) hydrogen, halogen, hydroxy, nitro, cyano, amino, -COOH, aminocarbonyl or aminosulfonyl; (ii) C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 aikynyl, C,-C 6 alkoxy, C r C 6 alkanoyl, C r C 6 alkylthio, C 1 - C f ialkanoyloxy, C r C 6 alkoxycarbonyl ; CpC 6 alkylsulfonyl, CpC ⁇ haloalkyl, mono- or di-(C r C 6 alkyl)aminoC 0 -C 4 alkyl, mono- or di-(CpC 6 alkyl)aminocarbonylCo-C 4 alkyl, mono- or di-(C
  • R 5 groups include (i) hydrogen, halogen, nitro, cyano or -COOH; and (ii) C,-C 6 alkyi, C r C 6 alkenyl, C 2 -C 6 alkynyl, CpQalkanoyL C 3 -C 6 aikanone, C 2 - C 6 alkyl ether, CpC 6 alkoxycarbonyl, CpCealkylsulfonyl or CpCshaloalkyl; each of which is substituted with from O to 3 substituents independently chosen from hydroxy, amino, cyano, Cj- Qaikoxy and mono- or di-(CrC 6 alky!)amino; and representative R/, groups include: (i) hydrogen, halogen, hydroxy, nitro, cyano or-COOH; and (ii) CpQalkyl, Q-Qalkenyl, Ci-C ⁇ alkynyl, C r C 6 alkoxy, C r C
  • R A groups are 5-membered heteroaryl groups that are substituted with from 0 to 3 substituents independently chosen from: (i) halogen, hydroxy, nitro, cyano, amino, -COOH, aminocarbonyl or aminosulfonyl; (ii) Ci-C 6 a ⁇ kyl, CrQaSkenyl, C 2 -C 6 alkynyl, Cj-C ⁇ alkoxy, C,- Cealkanoyl, CrCgalkylthio, Cj-C ⁇ salkanoyloxy, C]-C 6 alkoxycarbonyi, Ci-Cgalkylsulfo ⁇ yl, Q- C f ehaioalkyl, mono- or di-(CrC 6 aIkyl)ammoC 0 -C 4 aIkyl, mono- or di-(Ci-C6aIky!)aminocarbonylCo- C 4 alkyl, mono- or di-(C l -C
  • at least one of R 9 and R 15 is not H
  • -C 2 alkyl, C]- C 2 aikoxy or C)-C 2 haloalkyl; R 9 and R, 5 are each methyl; or R 9 and R
  • the variable R ⁇ in certain compounds of Formula VII, VIII or IX, is not H.
  • R 8 is hydrogen, C r C 6 alky1, C 2 -C ( ,alkenyl, C 2 -C 6 alkyny], mono- or di-(C r C 8 alkyl)aminoC]-C 6 alkyl or (5- to 7-membered heterocycle)Co-C ⁇ jalkyl, each of which is substituted with from O to 3 substituents independently chosen from halogen, amino, hydroxy, cyano, oxo, aminocarbonyl, imino, aminosuifonyl, C 1 - C 4 alkyi, and mono- and di-(C ! -C 8 alkyl)aminoCo-C 6 a]kyl.
  • Ri is methoxy.
  • aminopiperidines and related compounds provided herein include, but are not limited to, those specifically described in Examples 1-4, herein. It will be apparent that the compounds recited therein are representative only, and are not intended to limit the scope of the present invention. Further, as noted above, all compounds may be present as a free base, a pharmaceutically acceptable salt (such as an acid addition salt) or other form, such as a solvate (e.g., hydrate).
  • a pharmaceutically acceptable salt such as an acid addition salt
  • solvate e.g., hydrate
  • aminopiperidines and related compounds provided herein detectably alter (modulate) MCH binding to MCHlR and/or MCH2R, as determined using a standard in vitro MCH receptor ligand binding assay and/or functional assay. References herein to a
  • MCH receptor ligand binding assay refer to either of the assays provided in Examples 6 and 9.
  • the receptor is incubated with labeled MCH (or other suitable ligand) and a test compound.
  • a test compound that detectably modulates binding of ligand to MCH receptor will result in a decrease or increase in the amount of label bound to the MCH receptor preparation, relative to the amount of label bound in the absence of the compound.
  • such a compound will exhibit a K 1 at an MCH receptor that is less than 1 micromolar, more preferably less than 500 nM, 100 nM, 20 nM or 10 nM, within an assay performed as described in Example 6 and/or within an assay performed as described in Example 9.
  • Certain preferred compounds are MCH receptor antagonists, and exhibit IC 50 values of about 4 micromolar or less, more preferably 1 micromolar or less, still more preferably about 100 nanomolar or less, or 10 nanomolar or less within a standard in vitro MCH receptor mediated calcium mobilization assay, as provided in Example 10 and/or an agonist-stimulated GTP gamma 35 S binding assay, as described in Example 8.
  • aminopiperidines and related 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 oral 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), 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 vitro half-life that is equal to an in vivo half-life allowing for Q.
  • oral bioavailability preferred compounds are orally bioavailable to an extent allowing for oral 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
  • LD. dosing preferably T.I.D. dosing, more preferably B. I. D. dosing, and most preferably once-a- day dosing).
  • differential penetration of the blood brain barrier may be desirable for compounds used to treat CNS disorders, while low brain levels of compounds used to treat peripheral disorders are preferred.
  • Routine assays that are well known in the art may be used to assess these properties and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco ⁇ 2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously).
  • Serum protein binding may be predicted from albumin binding assays.
  • Compound half-life is inversely proportional to the frequency of dosage of a compound.
  • In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described in Example 12.
  • nontoxic 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 when administered in minimum therapeutically effective amounts, or when contacted with cells at a concentration that is sufficient to inhibit the binding of Iigand to MCH receptor in vitro: (1) does not substantially inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial liver enlargement and (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 1 1. In other words, cells treated as described in Example 1 1 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.
  • concentration of compound used in such assays is generally at least 10-fold, 100-fold or 1000-fold greater than the EC 50 or IC 50 for the modulator in the assay of Example 8 or Example 10.
  • 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 ECjo 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 is meant 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. If non-rodent mammals (e.g., dogs) are used, such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls. Preferred doses within such assays include 0.01, 0.05. 0.1 , 0.5, 1, 5, 10.
  • 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 J O or IC 50 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 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 5 Q 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, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC50 or IC50 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 ovaiy cells) at such concentrations.
  • aminopiperi dines and related compounds provided herein may be isotopically-iabeled or radiolabeled.
  • compounds of Formula I 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, ⁇ , 1 1 C, ' J C, 1 4 C. 15 N, ' 8 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • substitution with heavy isotopes such as deuterium (i.e., " H) can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Aminopiperidines and related compounds can be administered as the neat chemical, but are preferably administered as a pharmaceutical composition comprising such a compound, together with at least one physiologically acceptable carrier or excipient.
  • Representative carriers include, for example, water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanof, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol and proteins.
  • Additional optional components include adjuvants, diluents, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
  • Preferred pharmaceutical compositions are formulated for oral delivery to humans or other animals (e.g., companion animals such as dogs or cats).
  • other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.
  • Pharmaceutical compositions may also optionally comprise an activity enhancer, chosen from a wide variety of molecules that function in different ways to enhance MCH receptor modulator effect. Particular classes of activity enhancers include skin penetration enhancers and absorption enhancers, Pharmaceutical carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits.
  • the amount of carrier employed in conjunction with the compound is sufficient Io provide a practical quantity of material for administration per unit dose of the compound.
  • Representative pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, giucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth; malt; gelatin: talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; polyols such as propylene glycol, glycerine, sorbitol, mannitol and polyethylene glycol; alginic acid; phosphate buffer solutions; emuisifiers, such as the TWEENS; we
  • a pharmaceutical composition effective concentrations of one or more aminopiperidines or related compounds provided herein are mixed with one or more suitable pharmaceutical earners or excipients.
  • methods for solubilizing compounds may be used. Such methods are known to those of skill in this art and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using a surfactant, such as TWEEN, or dissolution in aqueous sodium bicarbonate.
  • DMSO dimethylsulfoxide
  • TWEEN a surfactant
  • dissolution in aqueous sodium bicarbonate dissolution in aqueous sodium bicarbonate.
  • the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the chosen carrier.
  • compositions may be formulated for administration by any suitable route, including orally, topically, parenterally, by inhalation (e.g., nasal or oral) or spray, sublingually, transdermally, via buccal administration, rectal Iy, as an ophthalmic solution or by other means, and may be prepared in dosage unit formulations and/or formulated as a lyophilizate.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.
  • Dosage formulations suitable for oral use include, for example, tablets, troches, lozenges, liquid solutions, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, tinctures, syrups or elixirs.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Such formulations may also contain a demulcent.
  • formulations containing these compounds can be presented as a dry product (optionally as an admixture with a dispersing or wetting agent, suspending agent and one or more preservatives) for constitution with water or other suitable vehicle before use.
  • Aqueous suspensions comprise the active materials ) in admixture with one or more suitable excipients, such as suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropyjmethylcellulose, AVICEL RC-591, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., polysorbate 80, naturaily- occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate. or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monoo
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil), a mineral oil (such as liquid paraffin) or a mixture of such oils.
  • the oily suspensions may further contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • compositions provided herein may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, mineral oil, or mixture thereof as described above.
  • Suitable emulsifying agents include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean phosphatide, lecithin and esters or partial esters derived from fatty acids and hexitol), and anhydrides (e.g., sorbitan monoleate and condensation products of the above partial esters with ethylene oxide, such as polyoxyethylene sorbitan monoleate).
  • naturally-occurring gums e.g., gum acacia or gum tragacanth
  • naturally-occurring phosphatides e.g., soy bean phosphatide, lecithin and esters or partial esters derived from fatty acids and hexitol
  • anhydrides e
  • Excipients suitable for the manufacture of tablets and capsules include, for example, inert diluents to increase the bulk weight of the material to be tableted (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents that modify the disintegration rate in the environment of use (e.g., corn starch, starch derivatives, alginic acid and salts of carboxymethylcellulose), binding agents that impart cohesive qualities to the powdered material(s) (e.g., starch, gelatin, acacia and sugars such as sucrose, glucose, dextrose and lactose) and lubricating agents (e.g., magnesium stearate, calcium stearate, stearic acid or talc).
  • inert diluents to increase the bulk weight of the material to be tableted e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • GIidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture.
  • Tablets may be formed using standard techniques, including dry granulation, direct compression and wet granulation. Tablets may be uncoated or may be coated by known techniques.
  • Capsules include, for example, hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), as well 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
  • Compositions intended for oral use may further contain one or more optional agents, such as sweetening agents (e.g., glycerol, propylene glycol, sorbitol, sucrose, aspartame, saccharin, menthol, peppermint or fruit flavor); suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel and hydrogenated edible fats); emulsifying agents (e.g., lecithin, sorbitan monsoleate or acacia); nonaqueous vehicles such as edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol); preservatives (e.g., methyl or propyl p-hydroxybenzoate, sodium benzoate, methyl paraben, ascorbic acid and/or sorbic acid); flavoring agents; and/
  • a pharmaceutical composition may be prepared as a sterile injectable aqueous or oleaginous suspension.
  • the active ingredient(s), depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • Such a composition may be formulated according to the known art using suitable dispersing, wetting agents and/or suspending agents such as those mentioned above.
  • suitable dispersing, wetting agents and/or suspending agents such as those mentioned above.
  • suitable dispersing, wetting agents and/or suspending agents such as those mentioned above.
  • suitable dispersing, wetting agents 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 injectable compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
  • compositions may also be prepared in the form of 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 body temperature and will therefore melt in the body to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propel! ant (e.g., dichlorodifiuoromethane or trichiorofluoromethane).
  • a conventional propel! ant e.g., dichlorodifiuoromethane or trichiorofluoromethane.
  • compositions may be formulated for local or topical application, such as for topical application to the skin or mucous membranes.
  • Topical compositions may be in any suitable form including, for example, solutions, creams, ointments, gels, lotions, milks, cleansers, moisturizers, sprays, skin patches and the like. Such solutions may, for example, be formulated as 0.01 %- 10% isotonic solutions, pH about 5-7, with appropriate salts.
  • Pharmaceutical compositions may also be formulated for transdermal administration as a transdermal patch. Pharmaceutical compositions may be formulated for release at a pre-determined rate.
  • Instantaneous release may be achieved, for example, via sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract).
  • Controlled release formulations i.e., formulations such as a capsule, tablet or coated tablet that slows and/or delays release of active ingredient(s) following administration
  • a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and thereby provides a delayed action or a sustained action over a longer period.
  • One type of controlled-release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate.
  • the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least 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 active ingredient contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controiled-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 form.
  • 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
  • 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.
  • multiple coatings may be employed (e.g., to allow release of a portion of the dose in the stomach and a portion further along the gastrointestinal tract).
  • a portion of active ingredient(s) may be coated over an enteric coating, and thereby released in the stomach, while the remainder of active ingredient(s) in the matrix core is protected by the enteric coating and released further down the GI tract.
  • 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 alkyi celluloses (e.g., ethylcellulose or carboxymethylcellulose), cellulose ethers, cellulose esters, acrylic polymers (e.g., poly( acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy ethyl meth aery 1 ate s, cyanoethyl methacrylate.
  • alkyi celluloses e.g., ethylcellulose or carboxymethylcellulose
  • cellulose ethers e.g., cellulose ethers, cellulose esters
  • acrylic polymers e.g., poly( acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy
  • aqueous dispersions of ethylceliulose include, for example,
  • AQUACOAT® FMC Corp., Philadelphia, PA
  • SURELEASE® Colorcon, Inc., West Point
  • PA both of which can be applied to the substrate according to the manufacturer's instructions.
  • Acrylic polymers include, for example, the various EUDRAGIT® (Rohm America,
  • Piscataway, NJ Polymers, which may be used singly or in combination depending on the desired release profile, according to the manufacturer's instructions.
  • Suitable plasticizers for alkyi celluloses include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin.
  • Suitable piasticizers for acrylic polymers include, for example, citric acid esters such as triethyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
  • Controiled-release coatings are generally applied using conventional techniques, such as by spraying in the form of an aqueous dispersion, if desired, the coating may comprise pores or channels or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic material that is dissolved, extracted or leached from the coating in the environment of use.
  • 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. Controiled- release may also be achieved through the use of transdermal patches, using conventional technology (see, e.g., US Patent No. 4,668,232).
  • controlled release formulations and components thereof, may be found, for example, in US Patent Nos. 4,572,833; 4,587,117; 4,606,909; 4,610,870; 4,684,516; 4,777,049;
  • an aminopiperidine or related compound may be conveniently added to food or drinking water, for administration to humans or 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.
  • Aminopiperidines and related compounds are generally present within a pharmaceutical composition at levels providing a therapeutically effective amount upon administration, as described above.
  • Dosage forms providing dosage levels ranging from about 0.1 mg to about 140 mg per kilogram of body weight per day are preferred (about 0.5 mg to about 7 g per human patient per day), with dosages ranging from 0.1 mg to 50 mg, 30 mg or 10 mg particularly preferred.
  • the amount of active ingredient that may be combined with the carrier to produce a single dosage form will vary depending upon the patient to be treated and the particular mode of administration.
  • Dosage unit forms generally contain from about 1 mg to about 500 mg of an active ingredient.
  • Dosage units generally contain from about 10 ⁇ g to about 500 mg of each active ingredient. Optimal dosages may be established using routine testing and procedures that are well known in the art.
  • compositions provided herein may also contain additional active agents, which can be chosen from a wide variety of molecules and can function in different ways to enhance the therapeutic effects of a MCH receptor modulator, or to provide a separate therapeutic effect that does not substantially interfere with the activity of the MCH receptor modulator.
  • additional active agents when present, are typically employed in the compositions described herein at a level ranging from about 0.01% to about 50% by weight of the composition, preferably 0.1% to 25%, 0.2% to 15, 0.5% to 10% or 0.5% to 5% by weight of the composition.
  • compositions intended for the treatment of obesity and/or eating disorders may further comprise leptin, a leptin receptor agonist, a melanocortin receptor 4 (MC4) agonist, sibutramine, dexfenfluramine, a growth hormone secretagogue, a beta-3 agonist, a 5HT-2 agonist, an orexin antagonist, a neuropeptide Yi or Y 5 antagonist, a galanin antagonist, a CCK agonist, a GLP-I agonist, a cannabinoid receptor antagonist ⁇ e.g., a CB 3 antagonist) and/or a corticotropin-releasing hormone agonist.
  • leptin a leptin receptor agonist
  • a melanocortin receptor 4 (MC4) agonist sibutramine
  • dexfenfluramine a growth hormone secretagogue
  • beta-3 agonist a beta-3 agonist
  • 5HT-2 agonist an orexin antagonist
  • a neuropeptide Yi or Y 5 antagonist
  • an additional active agent is a CBl antagonist.
  • Representative CBl antagonists include, for example, certain pyrimidines ⁇ e.g., PCT International Application Publication No. WO 04/029,204), pyrazines ⁇ e.g., PCT International Application Publication Nos. WO 01 /1 1 1 ,038; WO 04/1 1 1,034 and WO 04/11 1 ,033). azetidine derivatives ⁇ e.g., US Patent Nos.
  • WO 03/063781 and WO 03/040107 substituted furo[2,3-b]pyridine derivatives ⁇ e.g., PCT International Application Publication No. WO 04/012671); substituted aryl amides ⁇ e.g., PCT International Application Publication Nos. WO 03/087037 and WO 03/077847); substituted bicyclic or spirocyclic amides ⁇ e.g., PCT International Application Publication Nos. WO 03/086288 and WO 03/082190); and substituted 2,3-diphenyl pyridines ⁇ e.g , PCT International Application Publication No. WO 03/08219 ] ).
  • CBl antagonists are cannabidiol and its derivatives.
  • Preferred CB l antagonists include, for example, aryl substituted pyrazole carboxamides such as SR-141716A (N- ⁇ iperidin-1- yl)-5-(4-chIoropheny1)-l-(2,4-dichloro ⁇ henyl)-4-methyi- 1 -H-pyrazole-3-carboxamide) as well analogues thereof such as AM251 (N-piperidin-l-yl)-5-(4-iodophenyl)-l-(2,4-dichlorophenyl)-4- methyl- 1 -H-pyrazole-3-carboxamide) and AM281 (N-(morphoIin-4-yl)-] -(2,4-dichioiOphenyl)-5-(4- iodophenyl)-4-methyl-l -H-pyrazole-3-carboxamide); various
  • compositions may be packaged for treating or preventing a disease or disorder that is associated with MC ⁇ receptor activation (e.g., treatment of metabolic disorders such as diabetes, heart disease, stroke, metabolic syndrome, obesity and eating disorders such as bulimia, skin disorders such as vitiligo, or sexual disorders such as anorgasmic or psychogenic impotence), or for promoting weight loss.
  • Packaged pharmaceutical preparations comprise a container holding a therapeutically effective amount of MC ⁇ receptor modulator as described herein and instructions (e.g., labeling) indicating that the contained composition is to be used for promoting weight loss or for treating or preventing a disease or disorder that is associated with MC ⁇ receptor activation in the patient.
  • Prescribing information may be provided separately to a patient or health care provider, or may be provided as a label or package insert. Prescribing information may include, for example, efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation. Certain packaged pharmaceutical preparations further include a second therapeutic agent, as discussed above.
  • the present invention provides methods for treating, preventing, or inhibiting the development or progression of a disease or disorder responsive to MCH receptor modulation.
  • therapeutic methods provided herein may be used to treat a patient already afflicted with such a disease or disorder, or may be used to prevent or delay the onset of such a disease or disorder in a patient who is free of detectable disease or disorder that is associated with MCH receptor activation.
  • a disease or disorder is "associated with MCH receptor activation " ' if it is characterized by inappropriate stimulation of MCH receptor, regardless of the amount of MCH present locally, and/or is responsive to modulation of MCH receptor activity.
  • Such conditions include, for example, metabolic disorders (such as diabetes), metabolic syndrome, heart disease, stroke, eating disorders (such as obesity and bulimia nervosa), disorders of the skin such as vitiligo, and sexual disorders such as anorgasmic or psychogenic impotence. These conditions may be diagnosed and monitored using criteria that have been established in the art.
  • MCH antagonists provided herein may be used to promote weight loss in patients
  • MCH agonists provided herein may be used to promote weight gain in patients.
  • Patients may include humans, domesticated companion animals (pets, such as dogs and cats) and livestock animals, with dosages and treatment regimes as described above.
  • MCH receptor activation includes cognitive impairment and memory disorders, such as Alzheimer's disease, Parkinson's disease. mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety and psychosis (including schizophrenia and hallucinatory disorders);
  • MCI mild cognitive impairment
  • ARCD age-related cognitive decline
  • stroke traumatic brain injury
  • AIDS associated dementia dementia associated with depression
  • anxiety and psychosis including schizophrenia and hallucinatory disorders
  • Anxiety, depression and other mood disorders including general anxiety disorder (GAD), agoraphobia, panic disorder with and without agoraphobia, social phobia, specific phobia, post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders and cyclothymia; Reward system disorders such as addiction (e.g., opioid, nicotine or alcohol); Pain such as migraine, peripheral inflammatory pain, neuropathic pain and sympathetic nervous system associated pain; and
  • Peripheral indications such as respiratory disorders (e.g., asthma), urinary disorders (e.g., urinary incontinence), gastrointestinal disorders, reproductive function disorders and cardiovascular disorders (e.g., arteriosclerosis and hypertension).
  • respiratory disorders e.g., asthma
  • urinary disorders e.g., urinary incontinence
  • gastrointestinal disorders e.g., reproductive function disorders
  • cardiovascular disorders e.g., arteriosclerosis and hypertension
  • Frequency of dosage may vary depending on the compound used and the particular disease to be treated or prevented. In general, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of eating disorders and obesity, a dosage regimen of 1 or
  • methods for treating a patient comprising diagnosing the patient as having a disease or disorder associated with MCH receptor activation, correlating the diagnosis of the disease or disorder with the need for MCH modulator administration, and administering an a effective amount of an aminopiperidine or related compound provided herein.
  • a method for treating a patient comprising administering an effective amount of an aminopiperidine or related compound to a patient having a disease or disorder associated with MCH receptor activation is also provided herein.
  • the disease or disorder associated with MCH receptor activation is obesity, metabolic syndrome, an eating disorder, a sexual disorder, diabetes, heart disease or stroke.
  • aminopiperidine or related compound is administered orally, intranasally, intravenously or topically.
  • MCH receptor modulators provided herein may be used within combination therapy for the treatment of conditions associated with MCH receptor modulation.
  • a MCH receptor modulator is administered to a patient along with a second therapeutic agent that is not primarily a MCH receptor modulator, but that is appropriate for treatment of the condition(s) of interest.
  • the MCH receptor modulator and second therapeutic agent(s) may be present in the same pharmaceutical composition, or may be administered separately in either order. Suitable second therapeutic agents include those listed above.
  • Suitable dosages for MCH receptor modulator(s) within such combination therapy are generally as described herein. Dosages and methods of administration of other therapeutic agents can be found, for example, in the manufacturer's instructions in the Physician's Desk Reference.
  • the combination administration results in a reduction of the dosage of the second therapeutic agent required to produce a therapeutic effect ⁇ i.e., a decrease in the minimum therapeutically effective amount).
  • the dosage of second therapeutic 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 second therapeutic agent without combination administration of a MCH receptor modulator.
  • this dosage is less than 3 Zi, even more preferably less than 14, and highly preferably, less than VA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the second therapeutic agent(s) when administered without combination administration of a MCH receptor modulator. It will be apparent that the dosage amount of MCH receptor modulator component of the combination needed to achieve the desired effect may similarly be affected by the dosage amount and potency of the second therapeutic agent component of the combination.
  • the combination administration of a MCH receptor modulator with a second therapeutic agent is accomplished by packaging one or more MCH receptor modulators and one or more second therapeutic agents in the same package, either in separate containers within the package or in the same container as a mixture of one or more MCH receptor modulators and one or more second therapeutic agents.
  • Preferred mixtures are formulated for oral administration ⁇ e.g., as pills, capsules, tablets or the like).
  • the package comprises a label or package insert indicating that the one or more MCH receptor modulators and one or more second therapeutic agents are to be taken together for the treatment of a condition that is associated with MCH receptor activation, such as obesity.
  • one or more MCH receptor modulators provided herein are used along with one or more CBl antagonists within a combination therapy. Such combinations are of particular use for weight management, to reduce appetite and/or food intake or to prevent or treat obesity (e.g., promote weight loss).
  • Patients may include humans, domesticated companion animals and livestock animals, with dosages and treatment regimes as described above.
  • the MCH receptor modulator(s) may be administered to the patient at the same time as the CBl antagonist(s) (e.g., as a single dosage unit), or may be administered separately (before or after CBl antagonist).
  • the MCH receptor modulators) and CBl antagonist s) are ultimately simultaneously present at effective concentrations in a body fluid (e.g., blood) of the patient.
  • An effective concentration of MCH receptor modulator or CBl antagonist is a concentration that is sufficient to reduce one or more of food consumption, appetite and/or body mass index in the patient when repeatedly coadministered as described herein.
  • the present invention provides a variety of in vitro uses for the compounds provided herein.
  • such compounds may be used as probes for the detection and localization of MCH receptors, in samples such as tissue sections, as positive controls in assays for receptor activity, as standards and reagents for determining the ability of a candidate agent to bind to MCH receptor, 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
  • Such assays can be used to characterize MCH receptors in living subjects.
  • Compounds provided herein are also useful as standards and reagents in determining the ability of a test compound to bind to MCH receptor.
  • a sample may be incubated with a compound as provided herein under conditions that permit binding of the compound to MCH receptor.
  • the amount of compound bound to MCH receptor in the sample is then detected.
  • a compound may be labeled using any of a variety of well-known techniques (e.g., radiolabeled with a radionucleide such as tritium, as described herein), and incubated with the sample (which may be. for example, a preparation of cultured cells, a tissue preparation or a fraction thereof).
  • a suitable incubation time may generally be determined by assaying the level of binding that occurs over a period of time.
  • unbound compound is removed, and bound compound detected using any method 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 matched sample may be simultaneously contacted with radiolabeled compound and a greater amount of unlabeled compound. Unbound labeled and unlabeled compound is then removed in the same fashion, and bound label is detected. A greater amount of detectable label in the test sample than in the control indicates the presence of MCH receptor in the sample.
  • Detection assays including receptor autoradiography (receptor mapping) of MCH receptors 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.
  • Compounds provided herein may also be used within a variety of well-known cell culture and cell separation methods.
  • compounds may be linked to the interior surface of a tissue culture plate or other cell culture support, for use in immobilizing MCH receptor-expressing cells for screens, assays and growth in culture.
  • Compounds may also be used to facilitate ceil identification and sorting in vitro, permitting the selection of cells expressing a MCH receptor.
  • the compound(s) for use in such methods are labeled as described herein.
  • a compound linked to a fluorescent marker such as fluorescein
  • FACS fluorescence activated cell sorting
  • methods for modulating binding of MCH to an MCH receptor in vitro or in vivo, comprising contacting a MCH receptor with a sufficient amount of a modulator provided herein, under conditions suitable for binding of MCH to the receptor.
  • MCH binding to receptor is inhibited by the modulator.
  • the MCH receptor may be present in solution, in a cultured or isolated cell preparation or within a patient.
  • the MCH receptor is a MCHlR receptor present in the hypothalamus.
  • the amount of compound contacted with the receptor should be sufficient to modulate MCH binding to MCH receptor in vitro within, for example, a binding assay as described in Example 6 and/or Example 9.
  • MCH receptor preparations used to determine in vitro binding may be obtained from a variety of sources, such as from HEK 293 cells or Chinese Hamster Ovary (CHO) cells transfected with a MCH receptor expression vector, as described herein.
  • the MCH receptor may be present in solution, in a cultured or isolated cell preparation or within a patient.
  • the amount of modulator contacted with the receptor should be sufficient to modulate MCH receptor signal transducing activity in vitro within, for example, a calcium mobilization assay as described in Example 30 and/or an agonist-stimulated GTP gamma 35 S binding assay as described in Example 8.
  • An effect on signal-transducing activity may be assessed as an alteration in the electrophy ⁇ iology of the cells, using standard techniques, such as intracellular patch clamp recording or patch clamp recording. If the receptor is present in an animal, an alteration in the electrophysiology of the cell may be detected as a change in the animal's feeding behavior.
  • Aminopiperidines and related analogues provided herein may generally be prepared using standard synthetic methods. Starting materials are generally readily available from commercial sources, such as Sigma-Aldrich Corp. (St. Louis, MO). For example, a synthetic route similar to that shown in any one of the following Schemes may be used. It will be apparent that the finai product and any intermediate(s) shown in the following schemes may be extracted, dried, filtered and/or concentrated, and may be further purified (e.g., by chromatography). Each variable (e.g , "R”) in the following Schemes, refers to any group consistent with the description of the compounds provided herein.
  • compounds provided herein may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • ail stereoisomers are encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (Le., 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.
  • R3 is methyl
  • Each isotope is preferably carbon (e.g., 14 C), hydrogen (e.g., 3 H or
  • Tritium labeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or exchange with tritium gas under heterogeneous catalysis using the compound as substrate.
  • certain precursors may be subjected to tritium- halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
  • Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • HPLC and MS conditions are as follows. Unless otherwise specified, mass spectroscopy data in the following Examples is obtained via HPLC MS Method 1. Where a different method is used, the method is indicated. Method 1
  • Sample volume of 1 microliter is injected onto a 50x4.6mm Chromolith SpeedROD RP-I Se column (Merck KGaA, Darmstadt, Germany), and eluted using a 2- ⁇ hase 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, hold at ⁇ 00%B to 1.2 min, return to 10%B at 1.2 ] min. Inject to inject cycle is 2.15 min.
  • Method 3 The conditions and procedure are the same as for Method 1, except that the following gradient is used: 0-0.5 min 5-300%B, hold at 100%B to 1.2 min, return to 5%B at 1.21 min. Inject to inject cycle is 2.15 min. Method 3
  • Sample volume of 1-10 microliter is injected onto a 30x4.6mm XBridge Cl 8 5 micron column or equivalent, and eluted using a 2-phase linear gradient at a flow rate of 4 ml/min. Sample is detected using total absorbance count over the 220-254 UV range.
  • the elution conditions are: Mobile Phase A - 95% water, 5% MeOH with 0.1% ammonium hydroxide; Mobile Phase B - 5% water, 95% MeOH with 0.025% formic acid. The following gradient is used: 0.01-2.00 min 0- 100% B, hold at 100%B to 3.50 min, return to 0%B at 3.51 min.
  • This Example illustrates the preparation of certain representative aminopiperidines and related compounds.
  • Step 1 8-[4-(2-Methoxy-ethoxy)-2,3-dimethy i-benzyl]-8-aza-bicycIo[3.2.1 ]octan-23-one oxime
  • Nortropinone prepared essentially as described by Berdini et a!. (2002) Tetrahedron 58:5669; 1.50 g, 12.0 mmol
  • 2,3-dimethyI-4-ethoxy(2-methoxy)benzaIdehyde (2.71 g, 13.0 mmol) are dissolved in dry CH 2 Cl? (100 mL).
  • Sodium triacetoxyborohydride (3.56 g, 17,0 mmol) is added and the mixture is stirred overnight. The reaction is quenched by the addition of 1 N NaOH solution (50 mL) and the resulting layers are separated.
  • the aqueous iayer is extracted with CH 2 Cl 2 (2 x 50 mL), and the combined organic layers are dried over Na 2 SC ⁇ and evaporated to yield crude intermediate.
  • the crude intermediate is dissolved in pyridine (20 mL), and water (10 mL) and hydroxylamine hydrochloride (0.92 g, 13.3 mmol) are added. The solution is stirred for 6 h. The volatiles are evaporated and the product is partitioned between 1 N NaOH (50 mL) and EtOAc (50 mL), The layers are separated, and the aqueous layer is extracted with EtOAc (2 x 25 mL). The combined organic layers are washed with brine, dried over Na 2 SO 4 and evaporated.
  • Step 2 8-[4-(2-Methoxy-ethoxy)-2,3-dimethy l-benzyl]-8-aza-bicycIo[3.2.1]oct-3-ylamine
  • This compound is prepared a described for Compound 1, with readily apparent modification of starting materials.
  • N-(8- ⁇ 4-[(R)-2-(fer/-butyl-dimethyl-silanyloxy)-propoxy]-2,3-dimethyl-benzyl ⁇ -8-aza- bicyclo[3.2.1]oct-3-yl)-3-chloro-4-fluoro-benzamide (0.06 g, 0.15 mmoi) is dissolved in dry THF (10 ml), cooled to 0 0 C, and TBAF (IM in THF, 0.15 mL, 0.15 mmoi) is added. The solution is allowed to warm to rt, stirred for a further 3 h, and the volatiles are evaporated.
  • Step 1 l -(4-methoxy-2,3-dimethyiphenyl)ethanone
  • the light pink solid is collected via filtration and washed with water.
  • the solid is redissolved in EtOAc (500 mL), washed with water and brine, and dried over Na 2 SO 4 . Removal of the solvent under reduced pressure affords the title compound as a light pink solid.
  • the organic layer from the filtration of the solid is separated, and the aqueous phase is extracted with CH 2 Cl 2 (2 x 100 mL). Organic layers are combined, washed with water (2 x 250 mL), brine (250 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue is triturated with CH 2 CWEt 2 O (1 : 1, 50 mL) to afford additional title compound as a light pink solid.
  • the reaction is quenched by addition of aq. NaOH (IN, 75 mL), and stirred at rt for 0.5 h.
  • Insoluble materials are removed by filtration through CeI ite ® , and the filter cake is washed with EtOAc.
  • the filtrate and wash are combined and concentrated under reduced pressure.
  • the residue is partitioned between water and EtOAc, The organic layer is washed with water and brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to afford a yellow oil.
  • the residue is purified by column chromatography on silica gel (4: 1 Hexane: EtOAc).
  • N-tl-l l- ⁇ -fallyloxy ⁇ -dimethylphenyljethylJpiperidin ⁇ -yl ⁇ -chloronicotinamide (100 mg, 0.234 mmol) is dissolved in xylenes, treated with r ⁇ -propylamine (40 ⁇ L, 0.468 mmol, 2.0 eq.) and heated in a sealed tube in a 180 0 C oil bath for 72 h. The solution is concentrated in vacuo and the residue purified by PTLC (2 mm silica gei plate) eluting with 4% MeOH (2M NH 3 )/DCM to provide the title compound as a tan oil.
  • LCMS: T R 2.10 min, m/z 451.17 (M+l).
  • Step 1 1 -[ 1 -(4-methoxy-2,3-dimethylphenyI)ethyl]piperidin-4-amine
  • the reaction is quenched by addition of aq. NaOH (IN, 75 mL), and stirred at rt for 0.5 h.
  • Insoluble materials are removed by filtration through Celite ® , and the filter cake is washed with EtOAc.
  • the filtrate and wash are combined and concentrated under reduced pressure.
  • the residue is partitioned between water and EtOAc.
  • the organic layer is washed with water and brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to afford a yellow oil.
  • the oil is dissolved in EtOAc (20 mL), and treated with 4M HCI in dioxane (15 mL) at rt overnight. The white solid is collected via filtration, and washed with EtOAc.
  • 2,5-Dichloronicotinoyl chloride is prepared from 2,5-dichloronicotinoyl acid (1.77 g, 9.22 mmol) by treatment with thionyl chloride (3.35 mL, 46.1 mmol, 5 eq.) at reflux for 18 h.
  • the material is concentrated in vacuo, and used as is to acylate l-[l-(4-methoxy-2,3- dimethylphenyl)ethyl]piperidin-4-amine (900 mg, 3.43 mmol) under Schotten-Baumann conditions (ziO-propyl acetate, aqueous Na 2 CO 3 ).
  • 2,5-DichIoro-N- ⁇ l-[l-(4-methoxy-2,3-dimethylphenyl)ethyl]piperidin-4-yl ⁇ nicotinamide (100 mg, 0.229 mmol) is dissolved in 5 mL xylenes, treated with w ⁇ -propylamine (50 ⁇ L, 0.458 mmol, 2.0 eq.) and heated in a sealed tube in a 195 0 C oil bath for 20 h. The solution is concentrated in vacuo and the residue purified by PTLC (2 mm silica gel plate) eluting with 4% MeOH (2M ⁇ H 3 )/DCM to provide the titie compound as a tan foam.
  • 3-Chloroisonicotinoyl chloride is prepared from 3-chloroisonicotinoyI acid (1.93 g, 12.25 mmol) by treatment with thionyl chloride (4.45 mL, 61.24 mmol, 5 eq.) at reflux for 18 h.
  • the material is concentrated in vacuo, and used as is to acylate I-[l-(4-methoxy-2,3- dimethylpheny!)ethyl] ⁇ i ⁇ eridin-4-amine (280 mg, 1.07 mmol) under Schotten-Baumarm conditions (/s ⁇ -propyl acetate, aqueous Na 2 CO 3 ).
  • Step 1 ] -[4-(2-methoxy-ethoxy)-2,3-dimethyI-phenyl]-ethanone
  • reaction mixture After stirring for 60 min at 0 0 C, the reaction mixture is poured onto 300g of ice cubes, and vigorously stirred as cone. HCI (5 mL) is added slowly. After 1 h stirring, the organic layer is isolated, washed with brine, and dried over NaiSCV Removal of the solvent under reduced pressure affords the title compound as an off white oil which becomes white crystalline after storage in a refrigerator overnight.
  • Step 2 ((R)-I - ⁇ l-[4-(2-Methoxy-ethoxy)-2,3-dimethyl-phenyl]-ethyI ⁇ -pyrrolidin-2- ylmethyl)carbamicacid tert-butyl ester
  • aqueous phase is made basic (pH>10) with 10 N NaOH and extracted with CH 2 CI 2 (6 x 25 ml). The combined organic layers are washed with brine, dried and concentrated to give crude product, which is used in the next step without further purification.
  • LCMS: T R 1.98 min, m/z 307.09 (M+l).
  • Step 4 N-((R)-l- ⁇ l-[4-(2-Methoxy-ethoxy)-2,3-dimethyl-phenyl]-ethyI ⁇ - ⁇ yrroIidin-2-ylmethyl)-6- trifluoromelhyl-nicotinamide
  • the mixture is cooled to 0 0 C and 10 ml 6% NaOH is added to quench the reaction. After stirring at 0 0 C for another 30 min, the solid is removed by filtering through Celite ® . The solvent is removed under vacuum, and the residue is diluted with 50 ml H 2 O and made acidic with 6N HCI. The mixture is then extracted with ether (3 x 40 ml) to remove impurities. The aqueous phase is made basic with I O N NaOH and extracted with CH 2 CI 2 (4 x 50 ml). The combined organic layers are washed with water (30 m!), dried and concentrated to give the title compound.
  • Step 7 N-((S)-l- ⁇ l-[4 ⁇ 2-Metlioxy-ethoxy)-2.3-dimethyl- ⁇ henyl]-ethyl ⁇ -pyrrolidin-2-yimethyl)-6- trifluoromethyl-nicotinamide
  • Step 1 ⁇ (R)-l-[4-(2-Methoxy-ethoxy)-2,3-dimethyl-benzyl]-pyrrolidin-2-ylmethyl ⁇ -carbamic acid fert-buty ⁇ ester
  • N-[l-(4-Methoxy-2,3-dimethyl-benzyl)-piperidin-2-ylmethyI]-3,4-dimethyI-benzamide (570 mg, 1.45 mrnol) in CH 2 Cl 2 (20 ml) is cooled to -78 0 C and BBr 3 (I M in CH 2 Cl 2 ; 7.9 m ⁇ j is added dropwise. The resulting mixture is stirred under a nitrogen atmosphere at -78 0 C to rt overnight.
  • Step 5 rac-N- ⁇ l-[4-(4-Chloro-butoxy)-2,3-dimethyi-benzyl]- ⁇ i ⁇ eridin-2-ylmethyl ⁇ -3,4-dimethyl- benzamide and N- ⁇ 1 -[4-(4-Iodo-butoxy)-2,3-dimethyI-benzyl]-piperidin-2-ylmethyl ⁇ -3,4-dimethyl- benzamide
  • a 25 nil sealed tube is charged with a mixture of rac-N- ⁇ l -[4-(4-chloro-butoxy)-2,3- dimetliyl-benzyi]-piperidin-2-ylmethyl ⁇ -3,4-dimethyl-benzamide and N- ⁇ l-[4-(4-iodo-butoxy)-2,3- dimethyl-benzyl]-piperidin-2-ylmethyl ⁇ -3,4-dimethyl-benzamide (0.37 mmol), CH 3 CN (6 ml), KI (10 mg), Cs 2 CO 3 (300 mg) and neat NMe 2 (2 ml). The resulting mixture is heated to 90 0 C for 18 h, and is then allowed to cool to rt.
  • Step 1 -(l -(4-inethoxy-2.3-dimethy]pheny])ethyl)piperidin-4-amine
  • reaction mixture is diluted with CH 2 Cl 2 , washed with IN NaOH and brine, dried over Na 2 SO 4 , and concentrated under reduced pressure, and the residue is purified by flash chromatography (EtOAc) to afford the title compound as an off white solid.
  • reaction mixture is cooled to 0 0C, and quenched with MeOH.
  • the solvent is removed under reduced pressure.
  • the residue is partitioned between EtOAc and 14 saturated NaHC ⁇ 3, and the aqueous layer is extracted with EtOAc. Organic layers are combined, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to afford the title compound as a yellow solid.
  • the reaction mixture is diluted with CH 2 Cl 2- washed with Vz saturated NaHCO 3 and brine, dried over Na 2 SOjJ, and concentrated under reduced pressure.
  • the residue is purified by PTLC (hexane/EtOAc/TEA: 50/50/1) to afford a yellow oil.
  • PTLC hexane/EtOAc/TEA: 50/50/1
  • Zn(CN) 2 29.4 mg, 0.25 mmol
  • Pd 2 (dba) 3 2.8 mg, 0.005 mmol
  • DPPF 4.5 mg, 0.005 mmoi
  • 2,3-Dimethylisonicotinic acid ethyl ester (4.0 g, 22.3 mmol) is dissolved in anhydrous THF (100 mL) at 0 0 C and treated with 1.5 equivalents of lithium aluminum hydride (33.5 mmol, IM solution in THF) for 1 h.
  • the flask is placed in an ice-water bath and the reaction is quenched by sequential addition of water (1.3 mL), 15% NaOH in water (1.3 mL), water (1.3 mL) and 13 g of MgSO 4 .
  • the resulting suspension is stirred at rt for 30 min, and filtered through Celite ® , and the filter cake is washed with 5% MeOH in DCM.
  • Step 1 /e/7-Butyl (l- ⁇ l-[4-(allyloxy)-2,3-dimethylphe ⁇ yi]ethyl ⁇ yrrolidin-3-yl)carbamate
  • tert-Butyl (l- ⁇ l-[4-(allyloxy)-2,3-diniethyIphenyI]ethyl ⁇ pyi ⁇ olidin-3-yl)carbamate (7.46 g, 19.9 mmol) is dissolved in EtOAc (30 mL) and treated with 4 M HCi in d ⁇ oxane (30 mL) at it overnight. The reaction mixture is then triturated with hexane, and resulting yellow solid is collected via filtration and washed with Et 2 O to afford the title compound.
  • N- ⁇ l-[l-(4-hydiOxy-2,3-dimethyl ⁇ henyI)ethyl]pynOlidi ⁇ -3-yl ⁇ -3,5-dimethoxybenzamide is alkylated with any variety of agents to generate compounds of the formula:
  • This compound is prepared from l-(4-melhoxy-2,3-dimethylphenyi)ethanone (5.02 g, 28.2 mmol) and (3R)-(+)-3-(/er/-butoxycarbonylamino)pyrrolidine (5 g, 26.85 mmol) via the synthetic sequence described above for l- ⁇ l-[4-(al!yloxy)-2,3-dimethylphenyl]ethyl ⁇ pyrrolidin-3-amine.
  • the resulting HCl salt is partitioned between EtOAc and IN NaOH. The organic phase is washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to afford the title compound as a brown oil. !
  • This compound is prepared from 3-hydroxy-5-methoxy-N- ⁇ l-[l-(4-methoxy-2,3- dimethylphenyl)ethyl]pyrrolidin-3-yl ⁇ benzamide as described above for Compound 31.
  • This compound is prepared from 3-hydroxy-5 ⁇ methoxy-N- ⁇ l-[l-(4-rnethoxy-2,3- dimethylphenyl)ethyl]pyrrolidin-3-yI ⁇ benzamide as described above for Compound 31.
  • Step 2A Preparation of(R)-l-(2,3-Dimethyl-phenoxy)-propan-2-ol
  • Step 2B Preparation of4-((R)-2-Hydroxy-propoxy)-2,3-dimethyl-benzaldehyde
  • Step 2C Preparation of 2-methy ⁇ -propane-2-s ⁇ dfmic acid l-[4-((R)-2-hydroxy-propoxy)-2,3- dimethyl-phenyl]-meth-(E)-ylideneamide To a mixture of 4-((R)-2-hydroxy-propoxy)-2,3-dimethyl-benzaldehyde (7.9 g. 38 mmol) in
  • Step 2D Preparation of 2-methy ⁇ -propane-2-sulfinic acid ⁇ (S)-l-[4-((R)-2-hydroxy-propoxy)-2,3- dimethyl-phenyl]-ethyl ⁇ -amide
  • Step 2E Preparation of (R)-I -[4- ((S)-I -amino-ethyl)-2, 3-dimethyI-phenoxy]-propan-2-ol
  • Crude 2-methyl-propane-2-sulf ⁇ nic acid ⁇ (S)-l-[4-((R)-2-hydroxy-p]Opoxy)-2,3-dimethyl- phenyl]-ethyl ⁇ -amide (35g) is dissolved in 400 ml MeOH, and 100 ml 4N HCl/dioxane is added and the mixture is stirred at rt for 2 h.
  • Step 4 fe?-/-butyl ⁇ (3R)-l-[(l S)-l-(4- ⁇ [(2R)-2-hydroxy ⁇ ropyI]oxy ⁇ -2,3-dimethylpheny])ethyl]-2- oxo ⁇ yrrolidin-3-yl ⁇ carbamate
  • 2,3-dimethyl ⁇ henyl)ethyl]amino ⁇ butanoate (0.72 g, 1.64 mmol) is treated with aq. IN NaOH (8.2 mL) and EtOH (8.2 mL) at it overnight EtOH is removed under reduced pressure. The residue is diluted with water (5 mL), and pH is adjusted to 5-6. The white precipitates are collected, washed with water, and dried by evaporation with toluene under reduced pressure. The white solid is dissolved in DMA (20 mL), CH 2 Cl, (10 mL) and TEA (2 mL). BOP (0.82 g, 1.85 mmol) is added.
  • This intermediate (21.2 g, 0.1 17 mol, 1 eq.) is dissolved in CH 2 Cl 2 (150 mL) and is slowiy added to a stirring solution of 1.0M TiCl 4 (234 mL, 0.234 mol, 2 eq.) and Cl 2 CHOCH 3 (1 1.5 mL, 0.128 mol, 1.1 eq.) cooled to - 78°C.
  • the reaction is allowed to slowly warm to rt and stirred overnight.
  • the reaction is poured into ice (75 g) and cone. HCl (30 mL).
  • the organic layer is separated, washed with water (100 mL) and brine (100 mL), dried over Na 2 SO.;, filtered and concentrated under reduced pressure.
  • This compound is prepared using the method described for Compound 31 , by reaction of I - (4-(2-methoxyelhoxy)-2,3-dimethylbenzyl)piperidin-4-amine with 2-chloroisonicotinic acid, m/z 446.1 1 (M+l).
  • the reaction is cooled to rt, quenched with NaOH (IN, 10 mL) and extracted with 10 mL EtOAc. The organic layer is separated, washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue is purified by PTLC to afford the desired intermediate as an oil, which is dissolved in anhydrous CH 3 CN (1 mL) with K 2 CO 3 (0.027 g, 0.199 mmol, 2.5 eq.). Morpholine (0.008 g, 0.096 mmol, 1.2 eq.) is added and the reaction is heated at 80 0 C overnight.
  • the reaction is allowed to cool to rt and is diluted with EtOAc (5 mL) and washed with NaOH (IN, 2 x 5 mL). The organic layer is separated, washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue is purified by PTLC to afford the title compound.
  • Step 1 l-(l-(4-methoxy-2,3-dimethylphenyl)ethyl)azetidin-3-arnine
  • the resulting slurry is filtered through Celite ® , and the filter cake is washed with EtOAc. The filtrate and wash are combined and concentrated under reduced pressure.
  • the residue is partitioned between water and EtOAc, and the organic layer is washed with water and brine, dried over Na 2 SO.*, and concentrated under reduced pressure.
  • the residue is purified by PTLC (hexane/EtOAc: 3/2) to afford a yellow oil.
  • the oil is dissolved in CH 2 CI 2 (3 mL), and treated with TFA (0.5 mL) at rt overnight. Solvent is removed under reduced pressure.
  • the residue is partitioned between EtOAc and IN NaOH.
  • the title compound is prepared from l-(l-(4-methoxy-2,3-dimethy]phenyI)ethyI)azetidin-3- ami ⁇ e and 3-chloro-4-fluoro-benzoic acid essentially as described for Compound 51.
  • the title compound is prepared from l-(l-(4-methoxy-2,3-dimethylphenyl)ethyl)azetidin-3- amine and 3-(2-fIuorophenyl)-arcylic acid essentially as described for Compound 51.
  • the mixture is stirred at 0 0 C for 1 h and then at rt overnight.
  • the reaction is poured into a flask containing 70 mL Na 2 CO 3 (minimal THF to transfer).
  • the reaction is stirred at rt for 1 h, after which time 80 mL of diethyl ether is added.
  • the biphasic solution is allowed to stir vigorously at it for 30 min.
  • the organic layer is decanted off the white precipitate.
  • the white solid is washed an additional two times with 80 mL diethyl ether in the same manner.
  • Step 3 4- ⁇ l-[4-(3-Chloro-4-fIuoro-benzoylamino)-piperidin-l-yl]-ethyl ⁇ -3-methyl-benzoic acid isopropyl ester
  • Step 5 4-(l - ⁇ 4-[(3-chloro-4-fluorobenzoyl)ammo]piperidin-] -yl ⁇ ethyl)-N-(2-methoxyethyl)-N,3- dimethylbenzamide
  • n 0 or L
  • n 1 and R 20 is piperidine
  • This intermediate is prepared using N-(2-aminoethyl)piperidinc via the procedure described above for intermediate I ⁇ l .
  • ⁇ is 1 and R 2 o is pyrrolidine
  • This intermediate is prepared using 4-(2-aminoethyI)morpholine via the procedure described above for intermediate 1-1.
  • n 1-5.
  • R 20 is N(CH 3 ),
  • This intermediate is prepared using N,N-dimelhy (ethylene diamine via the procedure described above for intermediate I- 1. 1-6. n is 1 and R 20 is CH 2 N(CHa) 2
  • This intermediate is prepared using N,N-dimethyl-l,3-propane diamine via the procedure described above for intermediate 1-1.
  • n 1 and R 20 is CH 2 OCH 3
  • This intermediate is prepared using 3 -methoxypropy famine via the procedure described above for intermediate 1-1.
  • N-alkylated intermediates 1-1 to 1-7 are acylated with any variety of agents to generate acylated intermediates of the Formula:
  • n 0 or 1.
  • n 1 and R 2 O is piperidine
  • ⁇ is 1 and R 20 is CH 2 N(CH 3 ) 2
  • n 0 or 1.
  • n 1-18.
  • R 2 o is morpholine
  • n 1-20.
  • R 20 is CH 2 N(CH 3 ),
  • This intermediate is prepared from 1-6, via the procedure described above for 1-15, LCMS: m/z 350.10 (M+l).
  • ⁇ is 1 and R 20 is CH 2 OCH 3

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Fodder In General (AREA)

Abstract

L'invention concerne des aminopipéridines et des composés apparentés représentés par les formules dans lesquelles des variables sont décrites dans les présentes. De tels composés peuvent être utilisés pour moduler l'activité du récepteur MCH in vivo ou in vitro, et sont particulièrement utiles dans le traitement d'une diversité de troubles métaboliques, de l'alimentation et sexuels chez les êtres humains, les animaux de compagnie domestiqués et les animaux de bétail. L'invention concerne des compositions pharmaceutiques et des procédés pour traiter de tels troubles, ainsi que des procédés pour utiliser de tels ligands pour détecter les récepteurs MCH (par exemple, études de l'emplacement des récepteurs).
PCT/US2007/074282 2006-07-31 2007-07-25 Aminopipéridines et composés apparentés WO2008016811A2 (fr)

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