WO2010065801A1 - Composés de pipérazine spécifiques des récepteurs de la mélanocortine substitués par un amine - Google Patents

Composés de pipérazine spécifiques des récepteurs de la mélanocortine substitués par un amine Download PDF

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Publication number
WO2010065801A1
WO2010065801A1 PCT/US2009/066671 US2009066671W WO2010065801A1 WO 2010065801 A1 WO2010065801 A1 WO 2010065801A1 US 2009066671 W US2009066671 W US 2009066671W WO 2010065801 A1 WO2010065801 A1 WO 2010065801A1
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amino
substituents
compound
alkoxy
compounds
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PCT/US2009/066671
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English (en)
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James Bullington
Axel Metzger
Xin Chen
John H. Dodd
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Palatin Technologies, Inc.
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Publication of WO2010065801A1 publication Critical patent/WO2010065801A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/30—Nitrogen atoms non-acylated

Definitions

  • This invention provides amine substituted piperazine compounds that are specific for one or more melanocortin receptors, and which may be used in the treatment of a wide variety of diseases, syndromes and conditions. Background:
  • MCR-1 Melanocortin-1 receptors
  • NK natural killer cells
  • MCR-2 receptors MCR-2 receptors
  • ACTH adrenocorticotropin
  • Melanocortin-3 and melanocortin-4 receptors are expressed primarily in cells in the hypothalamus, mid-brain and brainstem, but are reported to be expressed in other cells.
  • Melanocortin-5 receptors are expressed in a wide distribution of central nervous system and peripheral tissues.
  • diseases, conditions and syndromes have been identified for which compounds specific for one or more melanocortin receptors may have utility.
  • compounds that are specific for MCR-1 particularly agonists, may be useful as tanning agents by increasing melanin production.
  • Compounds specific for MCR-1 or MCR-3 may be useful in regulation of inflammatory processes, and thus applicable to treatment or prevention of a wide variety of diseases.
  • Compounds specific for MCR-3 or MCR-4 are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and treatment of other food intake and metabolism-related purposes.
  • Compounds specific for MCR-3 and MCR-4 can further be used as agents for treatment of sexual dysfunction, including male erectile dysfunction and female sexual dysfunction.
  • Compounds specific for MCR-4 can further be used as agents for treatment of alcohol abuse, anxiety and related conditions.
  • melanocortin receptors particularly MCR-1 or MCR-3
  • MCR-1 or MCR-3 have an effect on the activity of various cytokines
  • high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.
  • compounds specific for MCR-4 for treatment of conditions relating to sexual dysfunction, including female sexual dysfunction and male erectile dysfunction, and regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for treatment of obesity, and treatment of other food intake and metabolism-related purposes.
  • R 1 is not present if X is O or N forming a double bond with another ring atom, and otherwise R 1 is H, a C 1 to C 17 linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, optionally substituted with a terminal amide, amino, monosubstituted amino, disubstituted amino, or nitrile, a C 1 to C 7 acyl group, optionally substituted with a terminal amide, amino, monosubstituted amino, disubstituted amino, or nitrile, an amide, an amino, a monosubstituted amino, a disubstituted amino or nitrile; R 2a and R 2b are each independently
  • L 1 and L 2 are each independently a bond or a Ci to C 6 aliphatic chain, and if a Ci to C 6 aliphatic chain, optionally wherein one or more carbon atoms in the Ci to C 6 aliphatic chain are replaced by oxygen or nitrogen atoms, and further optionally wherein the Ci to C 6 aliphatic chain is substituted with one or more substituents, and when one or more substituents are present, such substituents are the same or different and independently alkyl,
  • R 3 is one or two cyclic radicals, and if two cyclic radicals, fused cyclic radicals or cyclic radicals joined by L 3 , the one or two cyclic radicals optionally substituted with one or more ring substituents, and when one or more substituents are present, such substituents are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, oxo, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy- carbonyl, or R 3 is a group of the structure
  • Q is a monocyclic or polycyclic aryl or heteroaryl group, optionally substituted with one or more ring substituents, and when one or more substituents are present, such substituents are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, oxo, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl;
  • R 5 is H or one or two cyclic radicals, and if two cyclic radicals, fused cyclic radicals or cyclic radicals joined by L 3 , the one or two cyclic radicals optionally substituted with one or more ring substituents, and when one or more substituents are present, such substituents are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, oxo, halo, nitro, acyl, cyano, aryl, al
  • the invention provides compounds of formula II:
  • R 4 is heteroaryl, phenyl or naphthyl, optionally substituted with one or more ring substituents, and when one or more substituents are present, such substituents are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, oxo, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy- carbonyl; and t is from O to 4.
  • the invention provides compounds of formula III:
  • the invention provides compounds of formula V:
  • R 1 may be:
  • R 2a may be:
  • R 13 may be
  • R 4 may be phenyl, optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl.
  • R 4 may be naphthyl, optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl.
  • R 4 may be heteroaryl which is pyridine, pyrimidine, thiophene, thiazole, oxazole or imidazole, optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl.
  • R 3 may alternatively be a group of the formula:
  • the invention further provides a pharmaceutical composition comprising a compound of any of formulas I, II, III, IV or V, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • This pharmaceutical composition may further comprise at least one additional active pharmaceutical agent.
  • the invention further provides a method of treating a patient with a disease, disorder, condition or syndrome responsive to modulation of a melanocortin receptor, comprising administration to the patient of a pharmaceutically effective amount of the pharmaceutical composition as provided.
  • the invention further comprises a method for stimulating sexual response in a mammal, comprising administering a pharmaceutically sufficient amount of a composition including a compound of this invention or pharmaceutically acceptable salt thereof.
  • the mammal may be a male or a female.
  • the composition may further comprise a pharmaceutically acceptable carrier.
  • administering may include administering by any method of administration, such as administration by injection, administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration, parenteral administration, pulmonary administration, ocular administration, sublingual administration and vaginal adminstration.
  • nasal administration it may be nasal administration of a metered amount of a formulation comprising an aqueous buffer.
  • the invention further comprises a method for inhibiting food uptake in a mammal, comprising administering a pharmaceutically sufficient amount of a composition comprising a compound of this invention or pharmaceutically acceptable salt thereof, and particularly an MCR-3 and/or MCR-4 selective agonist or partial agonist.
  • the composition may further comprise a pharmaceutically acceptable carrier.
  • administering may include administering by any method of administration, such as administration by injection, administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration, parenteral administration, pulmonary administration, ocular administration and sublingual administration.
  • nasal administration it may be nasal administration of a metered amount of a formulation comprising an aqueous buffer.
  • the invention further comprises a method for increasing weight gain in a mammal, comprising administering a pharmaceutically sufficient amount of a composition comprising a compound of this invention or pharmaceutically acceptable salt thereof, and particularly an MCR-3 and/or MCR-4 selective antagonist.
  • the composition may further comprise a pharmaceutically acceptable carrier.
  • administering may include administering by any method of administration, such as administration by injection, administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration, parenteral administration, pulmonary administration, ocular administration and sublingual administration.
  • nasal administration it may be nasal administration of a metered amount of a formulation comprising an aqueous buffer.
  • One object of this invention is a melanocortin receptor-specific pharmaceutical for use in treatment of sexual dysfunction.
  • Another object is to provide a melanocortin receptor-specific pharmaceutical for use in treatment of male sexual dysfunction, including erectile dysfunction.
  • Another object is to provide a melanocortin receptor-specific pharmaceutical for use in treatment of female sexual dysfunction.
  • Another object is to provide a melanocortin receptor-specific pharmaceutical for use in treatment of eating disorders. Another object is to provide a melanocortin receptor-specific pharmaceutical which is effective by oral administration.
  • Another object of this invention is to provide compounds which are specific for melanocortin receptors MCR-1 and/or MCR-3 and/or MCR-4 and/or MCR-5 and which are agonists, partial agoists, inverse agonists or antagonists.
  • alkyl or "alkyl group” means a saturated unbranched or branched hydrocarbon chain.
  • (CrC 6 ) alkyl means an alkyl having from 1 to 6 carbon atoms.
  • Non-limiting examples of (CrC 6 ) alkyl groups include methyl, ethyl, propyl, isopropyl, 2-methyl-1 -propyl, 2-methyl-2-propyl, 2- methyl-1 -butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1- pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1 -butyl, butyl, isobutyl, t-butyl,
  • aliphatic means compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.
  • alkenyl or “alkenyl group” means an unbranched or branched hydrocarbon chain having one or more double bonds therein (i.e., comprising an alkene or olefin).
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to (C 2 -C 6 ) alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3- butene)-pentenyl.
  • An alkenyl group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • alkynyl or “alkynyl group” means an unbranched or branched hydrocarbon chain having one or more triple bonds therein.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to, (C 2 -C 6 ) alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methyl propynyl, 4-methyl-1 -butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.
  • An alkynyl group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • aralkyl means a radical -R a R b where R a is an alkylene (a bivalent alkyl) group and R b is an aryl group as defined above.
  • aralkyl groups include benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
  • aryl or “aryl group” means a monocyclic or polycyclic (e.g., bicyclic) aromatic ring system comprising carbon and hydrogen atoms.
  • aryl also includes polycyclic aromatic ring systems wherein at least one ring is aromatic and one or more rings are non-aromatic (including saturated or partially saturated rings).
  • Non-limited examples include phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, naphthyl, 1-naphthyl, 2-naphthyl, and biphenyl as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • An aryl group can be unsubstituted or optionally substituted with one or more suitable substituents as defined below.
  • An aryl group may be fused to a cycloalkyl group, fused to another aryl group, fused to a heteroaryl group, or fused to a heterocycloalkyl group.
  • Preferred aryl groups include, but are not limited to, monocyclic or bicyclic aromatic hydrocarbon radicals of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl.
  • heteroaryl or “heteroaryl group” means a monocyclic or polycyclic aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably 1 to 4 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include pyridyl, pyridazinyl, pyrazyl, indolyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1 ,2,3,)-triazolyl, (1 ,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, thiadiazolyl, furyl, phienyl, isoxazolyl, oxazolyl, pyrazolyl, tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, triazinyl, and pyrazinyl.
  • Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazolyl, indolyl, benzothiophenyl, benzofuryl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, benzotriazolyl, benzoxazolyl, isoquinolinyl, purinyl, furopyridinyl and thienopyridinyl.
  • a heteroaryl can be unsubstituted or optionally substituted with one or more suitable substituents as defined below.
  • a heteroaryl group optionally may be fused to another heteroaryl group, fused to an aryl group, fused to a cycloalkyl group, or fused to a heterocycloalkyl group.
  • cycloalkyl or cycloalkyl group means a monocyclic or polycyclic saturated ring comprising carbon and hydrogen atoms and having no carbon-carbon multiple bonds.
  • cycloalkyl groups include, but are not limited to, (C 3 -C 7 ) cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl group can be unsubstituted or optionally substituted with one or more suitable substituents as defined below.
  • a cycloalkyl group optionally may be fused to another cycloalkyl group, fused to an aryl group, fused to a heteroaryl group, or fused to a heterocycloalkyl group.
  • heterocycloalkyl or “heterocycloalkyl group” means a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
  • a heterocycloalkyl group may be fused to an aryl or heteroaryl group.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or optionally substituted with one or more suitable substituents as defined below.
  • a heterocycloalkyl group optionally may be fused to a cycloalkyl group, fused to an aryl group, fused to a heteroaryl group, or fused to another heterocycloalkyl group.
  • a heterocycloalkyl group can be fused to or substituted with an aryl group or heteroaryl group, for example, but not limited to, 1 ,2,3,4-tetrahydroisoquinolinyl and 1 ,2,3,4- tetrahydroquinolinyl, tetrahydronaphthyridinyl, phenylpiperidinyl, and piperidinylpyridinyl.
  • a heterocycloalkyl group may be a monocyclic or bicyclic ring, such as a monocyclic ring comprising from 3 to 6 carbon atoms and from 1 to 3 heteroatoms, referred to herein as (C 3 -C 6 ) heterocycloalkyl.
  • a heterocycloalkyl group may also be fused to or substituted with an aryl group or a heteroaryl group.
  • heterocyclic radical or “heterocyclic ring” mean a heterocycloalkyl group or a heteroaryl group.
  • cyclic radical means an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group or a combination of two or more thereof.
  • alkoxy means an -O-alkyl group, wherein alkyl is as defined above.
  • An alkoxy group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • the alkyl chain of an alkyloxy group is from 1 to 6 carbon atoms in length, referred to herein as "(Ci-C 6 ) alkoxy”.
  • aryloxy means an -O-aryl group, wherein aryl is as defined above.
  • An aryloxy group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryloxy”.
  • alkoxycarbonyl means a monovalent group of the formula
  • the hydrocarbon chain of an alkoxycarbonyl group is from 1 to 8 carbon atoms in length, referred to herein as a "lower alkoxycarbonyl" group.
  • R is an organic group, including but not limited to a Ci to C 7 alkyl.
  • an “amine” means compounds that contain an amino group (-NH 2 ), monosubstituted amino group (-NHR) or disubstituted amino group (-NRR), where each R is independently a suitable substituent.
  • an "alkylamine” means a saturated, monovalent, unbranched or branched hydrocarbon chain with a terminal amine.
  • alkylamine groups include, but are not limited to, (C 1 -C 6 ) alkyl-amino groups, such as methylamine, ethylamine, propylamine, butylamine, pentylamine and hexylamine, branched groups such as isopropylamine, sec-butylamine and so on, (C 1 -C 6 ) alkyl- monosubstituted amino groups, such as dimethylamine, and (C 1 -C 6 ) alkyl-disubstituted amino groups, such as trimethylamine.
  • An alkylamine group can be unsubstituted or optionally substituted with one or two suitable substituents.
  • a "nitrile" means compounds that are carboxylic acid derivatives and contain a
  • halogen means fluorine, chlorine, bromine, or iodine.
  • halo and “Hal” encompass fluoro, chloro, bromo, and iodo.
  • R any organic group, including but not limited to alkyl, and where sulfonamide is a suitable substituent, where R is a portion of the substituted group.
  • nitrogen protecting group means a group that replaces an amino hydrogen for the purpose of protecting against side reactions and degradation during a reaction sequence.
  • Nitrogen protecting groups useful in the invention include nitrogen protecting groups well known in the synthetic arts, including, but not limited to, boc, Fmoc, 2-chlorobenzyloxycarbonyl, alloc, benzyloxycarbonyl (Z), 2-(4-biphenylyl)propyl-2-oxycarbonyl (Bpoc), 1-adamantyloxycarbonyl, triphenylmethyl (trityl), and toluene sulphonyl.
  • suitable substituent means a group that does not nullify the synthetic, therapeutic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them.
  • suitable substituents include, but are not limited to: alkyl; haloalkyl; cycloalkyl; alkoxy; alkythio; halo; nitro; acyl; cyano; aryl; alkylaryl; aryloxy; amino; monosubstituted amino; disubstituted amino; carbamoyl, urea; sulfonamide; sulfonyl; oxo, hydroxyl; carboxy; alkoxy- carbonyl; alkenyl; alkynyl; heteroaryl; heterocycloalkyl; O-alkenyl; O-alkynyl; oxo; CF 3 ; NO 2 ; NH 2 ;
  • the above arrow when drawn from an atom in a chemical group indicates the point of attachment of that chemical group to another chemical group, without specifying the other chemical group.
  • the point of attachment of the depicted piperidine to another chemical group such as for example the following:
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of this invention encompass any composition made by admixing a compound of this invention and a pharmaceutically acceptable carrier.
  • EC 50 is intended to include the molar concentration of an agonist which produced 50% of the maximum possible response for that agonist.
  • a compound which, at a concentration of 72 nM, produces 50% of the maximum possible response for that compound as determined in a cAMP assay has an EC 50 of 72 nM.
  • the molar concentration associated with an EC 50 determination is in nanomoles (nM).
  • Ki is intended to include the equilibrium receptor binding affinity representing the molar concentration of a competing compound that binds to half the binding sites of a receptor at equilibrium in the absence of a competitor.
  • the Ki is inversely correlated to the affinity of the compound for the receptor, such that if the Ki is low, the affinity is high. Ki may be determined using the equation of Cheng and Prusoff (Cheng Y., Prusoff W. H., Biochem. Pharmacol. 22: 3099-3108, 1973):
  • ligand is the concentration of ligand, which may be a radioligand
  • K d is an inverse measure of receptor affinity which produces 50% receptor occupancy.
  • the molar concentration associated with a Ki determination is nM.
  • IC 50 is the concentration of ligand at which 50% of receptor-bound radioligand or other ligand is displaced from the receptor sites in a competitive receptor binding displacement assay.
  • treat contemplate an action that occurs while a patient is suffering from the specified disease or disorder, which reduces the severity of the disease or disorder.
  • pharmaceutically effective amount means the amount of a compound of the invention that will elicit a biological or medical response in the mammal that is being treated by a medical doctor or other clinician.
  • prophylactically effective or “preventive” means the amount of a compound of the invention that will prevent or inhibit affliction or mitigate affliction of a mammal with a medical condition that a medical doctor or other clinician is trying to prevent, inhibit, or mitigate before a patient begins to suffer from the specified disease or disorder.
  • pharmaceutically acceptable salt(s) includes salts prepared from pharmaceutically acceptable non-toxic inorganic or organic bases or acids, thereby constituting pharmaceutically acceptable acid and base addition salts (see Handbook of Pharmaceutical Salts:
  • Acid addition salts are formed from inorganic or organic acids.
  • suitable non-toxic acid addition salts are acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pa
  • Base- addition salts are formed from inorganic or organic bases.
  • suitable non-toxic base-addition salts are salts derived from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl
  • the compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., cis-trans isomers or geometric isomers), enantiomers (optical isomers), or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., cis-trans isomers or geometric isomers), enantiomers (optical isomers), or diastereomers.
  • the chemical structures depicted herein, and therefore the compounds of the invention encompass the racemic form of compounds as well as all enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • a compound is considered optically active or enantiomerically pure (i.e., substantially the R-form or substantially the S-form) with respect to a chiral center when the compound is about 90% ee
  • enantiomeric excess or greater, preferably, equal to or greater than 95% ee with respect to a particular chiral center.
  • a compound of the invention is considered to be in enantiomerically enriched form when the compound has an enantiomeric excess of greater than about 80% ee, preferably greater than about 85% ee.
  • a racemic mixture means about 50% of one enantiomer and about 50% of its corresponding enantiomer relative to all chiral centers in the molecule.
  • the invention encompasses all enantiomerically pure, enantiomerically enriched, and racemic mixtures of compounds of the invention.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the compounds of the invention also include, where possible, all tautomeric isomers thereof, such as prototropic tautomerism (e.g. hydroxypyridine - pyridone, ketone - enol, amide - imidic acid, amine - imine), annular tautomerism, ring-chain tautomerism and valence tautomerism.
  • prototropic tautomerism e.g. hydroxypyridine - pyridone, ketone - enol, amide - imidic acid, amine - imine
  • annular tautomerism e.g. hydroxypyridine - pyridone, ketone - enol, amide - imidic acid, amine - imine
  • annular tautomerism e.g. hydroxypyridine - pyridone, ketone - enol, amide - imidic acid, amine - imine
  • Prodrugs are further intended to include prodrugs of the compounds of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological compounds.
  • prodrugs will be functional derivatives of compounds of the invention, which are readily convertible in vivo into a compound of formula (I).
  • Prodrugs are any covalently bonded compounds, which release the active parent compound drug of formula (I) in vivo. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985 and Rautio, J., et al., "Prodrugs: design and clinical applications," Nat. Rev. Drug Disc. 7:255-270 (2008). Typical examples of prodrugs have biologically labile protecting groups on a functional moiety, such as for example by esterification of hydroxyl, carboxyl or amino functions.
  • prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, de hydroxy lated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated or dephosphorylated to produce an active parent drug of formula (I) in vivo.
  • Isotopically-Substituted Compounds The subject invention also includes compounds which are identical to those recited in formula (I), but for the fact that one or more atoms depicted in formula (I) are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O or 19 F.
  • Compounds of this invention and pharmaceutically acceptable salts or solvates of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of this invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, may have use in a variety of assays, such as drug and/or substrate tissue distribution assays.
  • lsotopically labeled compounds of formula (I) can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Compounds of the invention can be used for both medical applications and animal husbandry or veterinary applications.
  • the compound, or a pharmaceutical composition including the compound is used in humans, but may also be used in other mammals.
  • the term "patient” is intended to denote a mammalian individual, and is so used throughout the specification and in the claims.
  • the primary applications of this invention involve human patients, but this invention may be applied to laboratory, farm, zoo, wildlife, pet, sport or other animals.
  • the compounds disclosed herein, or made by methods disclosed herein may be used for the treatment of any condition, syndrome or disease, and in particular for any condition, syndrome or disease for which a melanocortin receptor-specific molecule has some efficacy.
  • the compounds disclosed herein, or made by methods disclosed herein can have one or more advantages relative to melanocortin receptor-specific peptides, including but not limited to advantages such as increased resistance to enzymatic degradation, increased circulation half life, increased bioavailability, increased efficacy, increased specificity, prolonged duration of effect and combinations of the foregoing.
  • the compounds of this invention may be in the form of any pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts may be salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • acid addition salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p- toluenesulfonic acid, trifluoroacetic acid, and the like.
  • Acid addition salts of the compound of this invention are prepared in a suitable solvent from the compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid.
  • an acid such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid.
  • suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
  • Pharmaceutical Compositions Another embodiment of this invention provides a pharmaceutical composition that includes a compound of this invention and a pharmaceutically acceptable carrier.
  • the carrier may be a liquid formulation, and is preferably a buffered, isotonic, aqueous solution.
  • Pharmaceutically acceptable carriers also include excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as hereafter described.
  • compositions that include at least one compound of this invention together with one or more pharmaceutically acceptable carriers, including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
  • excipients such as diluents, carriers and the like
  • additives such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
  • Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, manniton, sodium chloride and sodium citrate.
  • water containing at least one or more buffering constituents is preferred, and stabilizing agents, preservatives and solubilizing agents may also be employed.
  • any of a variety of thickening, filler, bulking and carrier additives may be employed, such as starches, sugars, amino acids, fatty acids and the like.
  • For topical administration formulations any of a variety of creams, ointments, gels, lotions and the like may be employed.
  • non-active ingredients will constitute the greater part, by weight or volume, of the preparation.
  • any of a variety of measured- release, slow-release or time-release formulations and additives may be employed, so that the dosage may be formulated so as to effect delivery of a compound of this invention over a period of time.
  • the actual quantity of compounds administered to a patient will vary between fairly wide ranges depending on the mode of administration, the formulation used, and the response desired.
  • the compounds can be combined as the active ingredient in an admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, for example, oral, parenteral (including intravenous), urethral, vaginal, nasal, dermal, transdermal, pulmonary, deep lung, inhalation, buccal, sublingual, or the like.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets. Because of their ease of administration, tablets and capsules represent an advantageous oral dosage unit form.
  • compositions including a compound of this invention may be coated by standard aqueous or nonaqueous techniques.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • sublingual pharmaceutical compositions may be employed, such as sheets, wafers, tablets or the like.
  • the active compound can also be administered intranasally as, for example, by liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds may also be administered parenterally. Solutions or suspensions of active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. These preparations may optionally contain a preservative to prevent the growth of microorganisms. Lyophilized single unit formulations may also be employed, such as are reconstituted with saline prior to administration, and thus do not require a preservative.
  • a surfactant such as hydroxy-propylcellulose
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. These preparations may optionally contain a preservative to prevent the growth of microorganisms. Lyophilized single unit formulations may also be employed, such as are reconstituted with saline prior to administration, and thus do not require a preservative.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders, such as lyophilized formulations, for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that it may be administered by syringe.
  • the form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol, for example glycerol, propylene glycol or liquid polyethylene glycol, suitable mixtures thereof, and vegetable oils.
  • nasal administration is meant any form of intranasal administration of any of the compounds of this invention.
  • the compounds may be in an aqueous solution, such as a solution including saline, citrate or other common excipients or preservatives.
  • the compounds may also be in a dry or powder formulation.
  • compounds may be administered directly into the lung, lntrapulmonary administration may be performed by means of a metered dose inhaler, a device allowing self-administration of a metered bolus of a compound of this invention when actuated by a patient during inspiration. Both dry powder inhalation and nebulized aerosols may be employed.
  • compounds of this invention may be formulated with any of a variety of agents that increase effective nasal absorption of drugs, including peptide drugs. These agents should increase nasal absorption without unacceptable damage to the mucosal membrane.
  • certain compounds of this invention may be appropriately buffered by means of saline, acetate, phosphate, citrate, acetate or other buffering agents, which may be at any physiologically acceptable pH, generally from about pH 4 to about pH 7.
  • a combination of buffering agents may also be employed, such as phosphate buffered saline, a saline and acetate buffer, and the like.
  • a 0.9% saline solution may be employed.
  • a 50 mM solution may be employed.
  • a suitable preservative may be employed, to prevent or limit bacteria and other microbial growth.
  • the compound may be in a dried and particulate form.
  • the particles are between about 0.5 and 6.0 ⁇ m, such that the particles have sufficient mass to settle on the lung surface, and not be exhaled, but are small enough that they are not deposited on surfaces of the air passages prior to reaching the lung.
  • Any of a variety of different techniques may be used to make dry powder microparticles, including but not limited to micro-milling, spray drying and a quick freeze aerosol followed by lyophilization. With micro-particles, the compounds may be deposited to the deep lung, thereby providing quick and efficient absorption into the bloodstream.
  • inhalers Any of a variety of inhalers can be employed, including propel lant-based aerosols, nebulizers, single dose dry powder inhalers and multidose dry powder inhalers.
  • Common devices in current use include metered dose inhalers, which are used to deliver medications for the treatment of asthma, chronic obstructive pulmonary disease and the like.
  • Preferred devices include dry powder inhalers, designed to form a cloud or aerosol of fine powder with a particle size that is always less than about 6.0 ⁇ m.
  • Microparticle size may be controlled by means of the method of making.
  • the size of the milling head, speed of the rotor, time of processing and the like control the microparticle size.
  • the nozzle size, flow rate, dryer heat and the like control the microparticle size.
  • the nozzle size, flow rate, concentration of aerosoled solution and the like control the microparticle size. These parameters and others may be employed to control the microparticle size.
  • the compounds of this invention may be therapeutically administered by means of an injection, typically a deep intramuscular injection, such as in the gluteal or deltoid muscle, of a time release injectable formulation.
  • a compound of this invention is formulated with a PEG, such as poly( ethylene glycol) 3350, and optionally one or more additional excipients and preservatives, including but not limited to excipients such as salts, polysorbate 80, sodium hydroxide or hydrochloric acid to adjust pH, and the like.
  • a compound of this invention is formulated with a poly(ortho ester), which may be an auto-catalyzed poly(ortho ester) with any of a variable percentage of lactic acid in the polymeric backbone, and optionally one or more additional excipients.
  • poly (D,L-lactide-co-glycolide) polymer (PLGA polymer) is employed, preferably a PLGA polymer with a hydrophilic end group, such as PLGA RG502H from Boehringer Ingelheim, Inc.
  • Such formulations may be made, for example, by combining a compound of this invention in a suitable solvent, such as methanol, with a solution of PLGA in methylene chloride, and adding thereto a continuous phase solution of polyvinyl alcohol under suitable mixing conditions in a reactor.
  • a suitable solvent such as methanol
  • any of a number of injectable and biodegradable polymers, which are preferably also adhesive polymers, may be employed in a time release injectable formulation.
  • the teachings of U.S. Patents 4,938,763, 6,432,438, and 6,673,767, and the biodegradable polymers and methods of formulation disclosed therein, are incorporated here by reference.
  • the formulation may be such that an injection is required on a weekly, monthly or other periodic basis, depending on the concentration and amount of compound, the biodegradation rate of the polymer, and other factors known to those of skill in the art.
  • the injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or other means known in the art.
  • the compounds of this invention may be formulated by any means known in the art, including but not limited to formulation as tablets, capsules, caplets, suspensions, powders, lyophilized preparations, suppositories, ocular drops, skin patches, oral soluble formulations, sprays, aerosols and the like, and may be mixed and formulated with buffers, binders, excipients, stabilizers, anti-oxidants and other agents known in the art.
  • Administration means may thus include administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, pulmonary administration, nasal administration, urethral administration, vaginal administration, and the like.
  • a compound of this invention is administered by means of a time release injectable formulation, such as a compound of this invention in a formulation with a PEG, poly(ortho ester) or PLGA polymer.
  • a compound of this invention is administered by means of an automated delivery device providing subcutaneous delivery, either continuous or intermittent.
  • a compound of this invention may also be administered by transdermal administration.
  • Therapeutically Effective Amount In general, the actual quantity of compound of this invention administered to a patient will vary between fairly wide ranges depending upon the mode of administration, the formulation used, and the response desired.
  • the dosage for treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired therapeutic effect.
  • a therapeutically effective amount includes an amount of a compound or pharmaceutical composition of this invention that is sufficient to induce a desired effect.
  • the compounds of this invention are highly active.
  • the compound can be administered at about 0.01 , 0.05, 0.1 , 0.5, 1 , 5, 10, 50, or 100 ⁇ g/kg body weight, depending on the specific compounds selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.
  • compounds of this invention that are MCR-1 specific can be used as chemoprevention agents against sun-induced, such as by UV radiation, neoplastic activity in human skin.
  • MCR-1 agonist compounds of this invention may be employed to stimulate epidermal melanocytes to produce melanin as well as to convert pheomelanin to eumelanin.
  • Eumelanin which is dark brown or black pigmentation, is considered more photo-protective than pheomelanin, which is yellow or red pigmentation.
  • the process of melanogenesis is believed to involve stimulation of MCR-1 in epidermal melanocytes, thereby mediating the stimulation of tyrosinase enzymes within these pigment cells, inducing the conversion of tyrosine to dopa and then through dopaquinone to eumelanin.
  • Sun tanning due to direct sun exposure is proposed to result from the same pathway by local production of melanotropic peptide from a POMC gene in the epidermis.
  • stimulation of eumelanin production and conversion of pheomelanin to eumelanin may be a desirable chemoprevention modality in blocking sun- or UV-induced neoplastic activity in skin.
  • a potent, high-affinity and highly selective MCR-1 agonist compound of this invention can accordingly be used as a therapeutic chemoprevention agent for combating harmful sun or UV exposure that induces neoplastic activity in skin melanocytes.
  • MCR-1 agonist compounds and/or MCR-3 agonist compounds may be used to treat, prevent or ameliorate the effects of a number of inflammatory diseases and inflammatory conditions.
  • the inflammatory condition results from a disease including a form of arthritis, including but not limited to osteoarthritis, rheumatoid arthritis, septic arthritis, gout and pseudogout, juvenile idiopathic arthritis, Still's disease and ankylosing spondylitis, as well as arthritis secondary to other diseases, such as arthritis secondary to lupus erythematosus, Henoch-Schonlein purpura, psoriatic arthritis, reactive arthritis, haemochromatosis, hepatitis, Wegener's granulomatosis, vasculitis syndromes, Lyme disease, familial Mediterranean fever, hyperimmunoglobulinemia D with recurrent fever, TNF receptor-associated periodic syndrome and inflammatory bowel disease, including Crohn's disease and ulcerative colitis.
  • the inflammatory condition results from a disease including a form of inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, infective colitis and indeterminate colitis.
  • a disease including a form of inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behget's syndrome, infective colitis and indeterminate colitis.
  • the inflammatory condition results from an autoimmune disease, including but not limited to systemic syndromes such as systemic lupus erythematosus, Sjogren's syndrome, scleroderma, rheumatoid arthritis and polymyositis, or a syndrome affecting only a local body system, such as the endocrine system (diabetes mellitus type 1 , Hashimoto's thyroiditis, Addison's disease, etc.), dermatologic system (pemphigus vulgaris), hematologic system (autoimmune hemolytic anemia), or neural system (multiple sclerosis).
  • systemic syndromes such as systemic lupus erythematosus, Sjogren's syndrome, scleroderma, rheumatoid arthritis and polymyositis, or a syndrome affecting only a local body system, such as the endocrine system (diabetes mellitus type 1 , Hashimoto's thyroiditis, Addi
  • autoimmune diseases include, in addition to the general syndromes discussed above, such diseases and conditions as acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, gestational pemphigoid, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, primary biliary cirrhosis, Reiter's syndrome, Sjogren's syndrome, Takayasu's art
  • the inflammatory condition results from or is related to chronic obstructive pulmonary disease (COPD), also known as chronic obstructive airway diseases, including but not limited to diseases characterized by the pathological limitation of airflow in the airway that is not fully reversible, such as for example chronic bronchitis, emphysema, pneumoconiosis, pulmonary neoplasms and other lung disorders.
  • COPD chronic obstructive pulmonary disease
  • Other inflammatory conditions include upper or lower airway diseases and disorders, such as allergic asthma, non-allergic asthma, allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis, non-allergic conjunctivitis, and the like, as well as airway diseases related to external toxins or substances, such as various forms of pneumoconiosis (coalworker's pneumoconiosis, asbestosis, silicosis, bauxite fibrosis, berylliosis, or siderosis), byssinosis or hypersensitivity pneumonitis (farmer's lung or bird fancier's lung).
  • Other lung diseases involving an inflammatory condition include acute respiratory distress syndrome.
  • the compounds and compositions of this invention are of particular utility tor treatment of conditions wherein glucocorticoids are either ineffectual or inadequate to bring about the desired pharmacological response, such as COPD, asthma in individuals who smoke, and other conditions characterized, in whole or in part, by eosinophil accumulation in the lung, neutrophil infiltration and activation, alveolar macrophage recruitment and activation, epithelial cell expression of IL-8 or increased expression of TNF- ⁇ .
  • the compounds of this invention are delivered systemically; in another aspect the compounds of this invention are delivered locally, such as by inhalation administration.
  • the inflammatory condition results from or is related to some form of transplant-related condition or syndrome, such as graft-versus-host disease, hyperacute rejection, acute rejection, or chronic rejection.
  • transplant-related condition or syndrome such as graft-versus-host disease, hyperacute rejection, acute rejection, or chronic rejection.
  • Graft-versus-host disease is a common complication of allogeneic bone marrow transplantation, but can occur with other transplantations, and particularly those with T cells present in the graft, either as contaminants or intentionally introduced.
  • Hyperacute, acute or chronic rejection can occur with bodily organs such as kidneys, liver, pancreas, spleen, uterus, heart or lungs, as well as transplantation of bone, cornea, face, hand, penis or skin.
  • a pharmaceutical composition including one or more of the compounds of this invention is given prophylactically to limit or prevent a transplant-related condition or syndrome, such as immediately before, during or after transplantation of a bodily fluid, organ or part.
  • a transplant-related condition or syndrome such as immediately before, during or after transplantation of a bodily fluid, organ or part.
  • the bodily fluid, organ or part being transplanted is perfused with a solution of a pharmaceutical composition including one or more of the compounds of this invention.
  • one or more of the compounds of this invention are administered in conjunction with, combination with or series with one or more other agents for transplant rejection, such as calcineurin inhibitors including cyclosporin or tacrolimus, mTOR inhibitors including sirolimus or everolimus, anti-proliferatives including azathioprine or mycophenolic acid, corticosteroids including prednisolone or hydrocortisone, antibodies such as monoclonal anti-IL-2R ⁇ receptor antibodies, basiliximab or daclizumab, or polyclonal anti-T-cell antibodies such as anti- thymocyte globulin or anti-lymphocyte globulin.
  • agents for transplant rejection such as calcineurin inhibitors including cyclosporin or tacrolimus, mTOR inhibitors including sirolimus or everolimus, anti-proliferatives including azathioprine or mycophenolic acid, corticosteroids including prednisolone or hydrocortisone, antibodies such as mono
  • Compounds of this invention may also be directed towards the treatment of fibrotic and sclerotic diseases, indications, conditions and syndromes in a subject.
  • fibrotic and sclerotic diseases, indications, conditions and syndromes There are a number of fibrotic and sclerotic diseases, indications, conditions and syndromes which may be so treated.
  • Fibrotic and sclerotic diseases, indications, conditions and syndromes frequently include an inflammatory component, and thus many may similarly be categorized as an inflammatory disease or condition.
  • Fibrotic and sclerotic diseases and conditions, in addition to including an inflammatory component may also be idiopathic, toxic, hereditary and/or pharmacologically-induced disorders.
  • fibrotic disorders are characterized by excessive production of extracellular matrix, primarily type I collagen, which may result in loss of organ function.
  • agonism of MCR-1 can result in suppression of transforming growth factor- ⁇ -Hnduced collagen synthesis by human dermal fibroblasts, thereby providing therapeutic and/or prophylactic benefit for fibrotic and sclerotic diseases, indications, conditions and syndromes.
  • fibrotic and sclerotic diseases and conditions that can be so treated include, but are not limited to, localized scleroderma, systemic sclerosis, sclerodermic graft-versus-host disease of the skin, idiopathic lung fibrosis, bleomycin-induced lung fibrosis, cyclosporine-induced nephropathy, cirrhosis of the liver, hypertrophic scars, keloids and the like.
  • TNF- ⁇ is a pleiotropic cytokine produced mainly by macrophages, and also by other types of cells.
  • the invention is directed to methods of using one or more of the compounds of this invention to decrease pro-inflammatory cytokine production and expression, including decreasing proinflammatory cytokine production and expression secondary to circulatory shock, ischemia, reperfusion injury and the like.
  • the decrease in pro-inflammatory cytokine production and expression including without limitation one or more of TNF- ⁇ , IL-1 and IL-6, occurs instantaneously or within a short time period following administration of a composition comprising one or more of the compounds of this invention.
  • the invention is further directed to methods of using one or more of the compounds of this invention to increase anti-inflammatory cytokine production and expression.
  • the increase in antiinflammatory cytokine production and expression occurs instantaneously or within a short time period following administration of a composition comprising one or more of the compounds of this invention.
  • Certain cancers such as mesothelioma, are reported to be very sensitive to growth-promoting influences of cytokines and growth factors, and may be treatable by means of compounds selective for MCR-1.
  • Canania, A., et al. "Autocrine inhibitory influences of ⁇ -melanocyte-stimulating hormone in malignant pleural mesothelioma," J. Leukoc. Biol. 75:253-259 (2004).
  • Cancers that may be so treated include pleural mesothelioma, known to express mRHA for MCR-1 and the receptor protein, as well as other tumors that express MCR-1 , including but not limited to adenocarcinoma, such as pulmonary adenocarcinoma.
  • ocular diseases there are a number of ocular diseases, indications, conditions and syndromes characterized by inflammation, including but not limited to increased cytokine production.
  • dry eye disease an ocular disease affecting approximately 10-20% of the population.
  • autoimmune diseases e.g. Sjogren's syndrome and systemic lupus erythematosus
  • ocular surgeries including PRK or LASIK
  • many medications environmental conditions, visual tasking such as computer use, ocular fatigue, contact lens wear, and mechanical influences such as corneal sensitivity, partial lid closure, surface irregularities (e.g. pterygium), and lid irregularities (e.g.
  • Uveitis Another inflammatory disease of the eye is uveitis, an ocular disease involving inflammation of the middle layer or uvea of the eye, which may also be understood to include any inflammatory process involving the interior of the eye.
  • Uveitis includes anterior, intermediate, posterior and panuveitic forms, with the majority of uveitis cases anterior in location, involving inflammation of the iris and anterior chamber. This condition can occur as a single episode and subside with proper treatment or may take on a recurrent or chronic nature. Symptoms include red eye, injected conjunctiva, pain and decreased vision.
  • Signs include dilated ciliary vessels, presence of cells and flare in the anterior chamber, and keratic precipitates on the posterior surface of the cornea.
  • Intermediate uveitis includes inflammation and the presence of inflammatory cells in the vitreous cavity
  • posterior uveitis include the inflammation of the retina and choroid.
  • Uveitis may be secondary to any of a number of diseases and disorders, including acute posterior multifocal placoid pigment epitheliopathy, ankylosing spondylitis, Behget's disease, birdshot retinochoroidopathy, brucellosis, herpes simplex, herpes zoster, inflammatory bowel disease, juvenile rheumatoid arthritis, Kawasaki disease, leptospirosis, Lyme disease, multiple sclerosis, psoriatic arthritis, Reiter's syndrome, sarcoidosis, syphilis, systemic lupus erythematosus, toxocariasis, toxoplasmosis, tuberculosis, Vogt-Koyanagi-Harada syndrome, Whipple disease or polyarteritis nodosa.
  • diseases and disorders including acute posterior multifocal placoid pigment epitheliopathy, ankylosing spondylitis, Behget's disease,
  • the invention is directed to methods of using one or more of the compounds of this invention for treatment of any of the foregoing ocular diseases, indications, conditions and syndromes.
  • treatment may include treatment by means of eye drops, ointments, gels, washes, implants, plugs or other means and methods for delivering one or more of the compounds of this invention to an ocular surface.
  • Compounds of this invention that are ligands of MCR-4 are believed to be useful in treating diseases, disorders and/or conditions responsive to modulation of the MCR-4, more particularly activation of the MCR-4, i.e. diseases, disorders and/or conditions which would benefit from agonism (including full or partial agonism) at the MCR-4, including energy homeostasis and metabolism related (such as diabetes, in particular type 2 diabetes; dyslipidemia; fatty liver; gout; hypercholesterolemia; hypertriglyceridemia; hyperuricacidemia; impaired glucose tolerance; impaired fasting glucose; insulin resistance syndrome; and metabolic syndrome), food intake related (such as hyperphagia; binge eating; bulimia; and compulsive eating) and/or energy balance and body weight related diseases, disorders and/or conditions, more particularly such diseases, disorders and conditions characterized by excess body weight and/or excess food intake.
  • agonism including full or partial agonism
  • Compounds of this invention that are ligands of MCR-4 are particularly believed to be useful for treatment of body weight related diseases, disorders and/or conditions conditions characterized by excess body weight, including obesity and overweight (by promotion of weight loss, maintenance of weight loss, and/or prevention of weight gain, including medication-induced weight gain or weight gain subsequent to cessation of smoking), and diseases, disorders and/or conditions associated with obesity and/or overweight, such as insulin resistance; impaired glucose tolerance; type 2 diabetes; metabolic syndrome; dyslipidemia (including hyperlipidemia); hypertension; heart disorders (e.g.
  • coronary heart disease myocardial infarction
  • cardiovascular disorders non-alcoholic fatty liver disease (including non- alcoholic steatohepatitis); joint disorders (including secondary osteoarthritis); gastroesophageal reflux; sleep apnea; atherosclerosis; stroke; macro and micro vascular diseases; steatosis (e.g. in the liver); gall stones; and gallbladder disorders.
  • BMI body mass index
  • the recommended classifications for BMI in humans adopted by the Expert Panel on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults, and endorsed by leading organizations of health professionals, are as follows: underweight ⁇ 18.5 kg/m 2 , normal weight 18.5-24.9 kg/m 2 , overweight 25-29.9 kg/m 2 , obesity (class 1 ) 30-34.9 kg/m 2 , obesity (class 2) 35-39.9 kg/m 2 , extreme obesity (class 3) > 40 kg/m 2 (Practical Guide to the Identification, Evaluation, and Treatment of
  • diabetes men having waist circumferences above 94 cm (cut off for europids) and women having waist circumferences above 80 cm (cut off for europids) are at higher risk of diabetes, dyslipidemia, hypertension and cardivascular diseases because of excess abdominal fat.
  • Another classification is based on the recommendation from the Adult Treatment Panel III where the recommended cut-offs are 102 cm for men and 88 cm for women.
  • the compounds of this invention may also be used for reduction of self-diagnosed overweight and for decreasing the risk of becoming obese due to life style, genetic considerations, heredity and/or other factors.
  • the term "diabetes" includes type 1 diabetes (insulin-dependent diabetes mellitus), latent autoimmune diabetes mellitus of adults (LADA), and type 2 diabetes.
  • compounds of this invention which are MCR-4 agonists or partial agonists, upon administration to an animal, including man, will reduce food intake, body weight and/or body weight gain in that animal. Without being bound by any theory, it is believed that such compounds of this invention act by modulating appetite and/or satiety, increasing metabolic rate, reducing intake of and/or craving for fat and/or carbohydrates.
  • compounds of this invention which are MCR-4 agonists or partial agonists, act by enhancing glucose tolerance and/or decreasing insulin resistance. It is therefore believed that such compounds of this invention can be useful also for treatment of type 2 diabetes in underweight and normal weight individuals as well as in overweight and obese individuals.
  • Compounds of the invention might also be useful for (i) occlusive, haemorrhagic, traumatic or surgical organ and/or tissue damage, such as myocardial infarction and stroke or haemorrhagic or cardiogenic shock.
  • compounds of this invention may be used as a therapeutic agent in eating disorders, such as treatment of anorexia and cachexia, which is malnutrition and wasting due to illness.
  • compounds of this invention may be employed with persons who have below optimal body weight, and in particular with patients desiring to gain additional muscle mass.
  • compounds of this invention can be used as therapeutic agents for treatment of sexual dysfunction, including treatment of both male erectile dysfunction and female sexual dysfunction.
  • compounds of this invention may be used as therapeutic agents for treatment of inflammation, including specifically MCR-1 , MCR-3 and MCR-5 agonists.
  • compounds of this invention that are MCR-5 specific can be used as agents to decrease sebum production, and thus may be efficacious in the treatment of acne and related diseases.
  • the compounds for this application may be conveniently formulated for local administration, as through a gel, lotion, cream or other topical formulation.
  • compounds of this invention may be employed in the treatment of drug or alcohol dependence, depression, anxiety and related conditions and indications. 4. SYNTHETIC METHODS FOR COMPOUNDS OF THE INVENTION
  • PG Refers to a protecting group, and specifically Fmoc, boc, cbz or alloc
  • Scheme A may be employed to make the precursor compound R 1 and R 2a substituted-piperazin-1-yl-piperidin-4-yl-amine of the following general structure:
  • R 1 is a protecting group (PG) as defined herein, or is H, a C 1 to C 17 linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, or a C 1 to C 7 acyl group, in each instance optionally substituted with a terminal amide, amino, monosubstituted amino, disubstituted amino, or nitrile, or is an amide, amino, monosubstituted amino, or disubstituted amino, and R 2a is a C 1 to C 17 linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, or a C 1 to C 7 acyl group, in each instance optionally substituted with one or more substituents, and when one or more substituents are present, such substituents are the same or different and independently halo, amino, monosubstituted amino, disubstituted amino, hydroxy, or carboxy. More broadly, Scheme A may be employed to
  • n 1 or 2
  • m 0, 1 or 2
  • X is CH 2 , N or O
  • R 1 and R 2a are as described above, on the proviso that if X is O, then R 1 is not present.
  • the foregoing general structure thus includes, by way of example and not limitation, amine substituted piperazine precursor compounds such as:
  • An R 2a group may be introduced to (3), (5), (8) or (10) by utilizing equamolar amounts of R 2 - aldehyde and (3), (5), (8) or (10) in a solvent such as methylene chloride, dichloroethane or tetrahydrofuran and adding NaBH(OAc) 3 portionwise (typically at 1.5 times the molar concentration of the R 2 -aldehyde).
  • a solvent such as methylene chloride, dichloroethane or tetrahydrofuran
  • NaBH(OAc) 3 portionwise (typically at 1.5 times the molar concentration of the R 2 -aldehyde).
  • the resulting solution is stirred at room temperature for 16 hours, washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated to yield product.
  • the R 2a group may also be introduced to (3), (5), (8) or (10) (1.0 mmol) by the coupling of an organic acid (1.1 mmol), a dehydrating reagent such as TBTU, EDC, HATU or HBTU (1.1 mmol) and an organic base such as N- methylmorpholine or diisopropyl ethyl amine (2.0 mmol) in a solvent such as methylene chloride, tetrahydrofuran or dioxane.
  • a solvent such as methylene chloride, tetrahydrofuran or dioxane.
  • an R 2a group may be introduced to (3), (5), (8) or (10) by stirring with an activated group (1.2 equivalents), such as an organic acid chloride, isocyanate, chloroformate or sulfonyl chloride (generically R 1 -X) and excess base such as pyridine, diisopropyl ethyl amine, triethylamine or 2,4 lutidine in a solvent such as methylene chloride, dichloroethane or tetrahydrofuran.
  • an activated group 1.2 equivalents
  • an organic acid chloride isocyanate, chloroformate or sulfonyl chloride (generically R 1 -X) and excess base such as pyridine, diisopropyl ethyl amine, triethylamine or 2,4 lutidine in a solvent such as methylene chloride, dichloroethane or tetrahydrofuran.
  • an activated group 1.2 equivalents
  • boc as a PG for (1) and alloc as a PG for (2) results, following introduction of the R 2a group, in compound (11).
  • Compound (11) is selectively deprotected, such as by removal of the alloc group to yield compound (12).
  • compound (11) is treated at room temperature with catalytic tetrakis(triphenylphosphine)palladium in a solvent such as methylene chloride, tetrahydrofuran or dichloroethane in the presence of an excess (10X) of an allyl acceptor scavenger, such as phenylsilane or 1 ,3-dimethylbarbituric acid.
  • an allyl acceptor scavenger such as phenylsilane or 1 ,3-dimethylbarbituric acid.
  • the solution is dried over sodium sulfate and evaporated to give the R 1 and R 2a substituted (13).
  • Boc protected optionally substituted-phenylalanine (14) (10 mmol), where R 4a is from one to three permitted substitutents, is dissolved in methanol and cooled to 0 0 C in an ice bath. A solution of 2M thionyl chloride (5 ml_, 10 mmol) is slowly added dropwise keeping the temperature below 5 0 C. After 1 hour the solution is allowed to warm to room temperature overnight. The solution is then evaporated, triturated with ether and filtered to give the hydrochloride salt of the resulting ester (15).
  • the substituted-phenylalanine (15) (2.0 mmol) is added slowly to a stirred mixture of boc protected 2-(1 ,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid (16) (2.1 mmol), a dehydrating reagent such as TBTU, EDC, HATU or HBTU (2.1 mmol) and an organic base such as N-methylmorpholine or diisopropyl ethyl amine (6 mmol) in a solvent such as methylene chloride, tetrahydrofuran or dioxane. After stirring for 16 hours the solution is extracted and washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated. The resulting oil is purified on silica gel (40 g) eluted with 40-80% ethyl acetate in heptane.
  • the purified oil of compound (17) is dissolved in methanol (5 ml_) and cooled to 0 0 C.
  • a solution of 4N sodium hydroxide (4 ml_) is slowly added dropwise keeping the temperature below 5 0 C.
  • the reaction is stirred for 30 minutes at 0 0 C, allowed to warm to room temperature and stirred an additional 2 hours.
  • the resulting solution is concentrated under reduced pressure to remove methanol.
  • the aqueous solution is then treated with 4N hydrochloric acid (4 ml_) and brought to pH 1 with 1 N hydrochloric acid.
  • the mixture is extracted into a solvent such as methylene chloride or ethyl acetate and washed with brine, and the organic layer dried over sodium sulfate and evaporated to a solid yielding compound (18).
  • De-protection is accomplished by stirring with excess TFA in a solvent such as methylene chloride for one hour followed by evaporation of the solvent, yielding compound (19).
  • the diastereomers (20) and (21) are separated by HPLC. Each resulting isomer (0.5 mmol) is boc protected by stirring with boc anhydride (0.5 mmol) and excess base such as triethylamine (0.2 ml_) in a solvent such as methylene chloride.
  • R 1 and R 2a substituted (13) (1.0 mmol) is added slowly to a stirred mixture of a boc protected optionally substituted-phenylalanine (14) (1.1 mmol), where R 4a is from one to three permitted substitutents, a dehydrating reagent such as TBTU, EDC, HATU or HBTU (1.1 mmol) and an organic base such as N-methylmorpholine or diisopropyl ethyl amine (2.0 mmol) in a solvent such as methylene chloride, tetrahydrofuran or dioxane.
  • a dehydrating reagent such as TBTU, EDC, HATU or HBTU
  • an organic base such as N-methylmorpholine or diisopropyl ethyl amine (2.0 mmol) in a solvent such as methylene chloride, tetrahydrofuran or dioxane.
  • phenylalanine (14) may be optionally substituted with one or more substituents, including specifically substitutents that are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl.
  • substituents may include protecting groups, which are deprotected to yield final product.
  • protecting groups other than boc including specifically alloc, may be employed.
  • phenylalanine (14) it is possible to employ a protected and optionally substituted 1-naphthylalanine or 2-naphylalanine.
  • R 1 and R 2a substituted (13) (0.1 mmol) is added slowly to a stirred mixture of PG-compound (27) (0.11 mmol), which may, for example, be compound (22) or (23), a dehydrating reagent such as TBTU, EDC, HATU or HBTU (0.11 mmol) and an organic base such as N-methylmorpholine or diisopropyl ethyl amine (0.2 mmol) in a solvent such as methylene chloride, tetrahydrofuran or dioxane. After stirring for 16 hours the solution is extracted and washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated. De-protection is accomplished by stirring with excess TFA in solvent such as methylene chloride for one hour followed by evaporation of the solvent. The residue is dissolved in 35% aqueous methanol and purified by HPLC to yield compound (26).
  • PG-compound (27) (0.11 mmol)
  • Di-substitution can be carried out on fully de-protected materials, such as compound (28) by stirring the TFA salt compound (28) (0.034 mmol) with acetic anhydride (0.034 mmol) and excess base such as triethylamine in a solvent such as methylene chloride, tetrahydrofuran or dioxane (2 ml_). The solution is stirred at room temperature for 2 hours and then washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated. Purification is done by HPLC to yield compound (29).
  • Scheme F Scheme F
  • a dehydrating reagent such as TBTU, EDC, HATU or HBTU (1.1 mmol) and an organic base such as N-methylmorpholine or diisopropyl ethyl amine (2.0 mmol) in a solvent such as methylene chloride, tetrahydrofuran or dioxane.
  • a solvent such as methylene chloride, tetrahydrofuran or dioxane.
  • Selected compounds are tested in assays to determine binding and functional status, and are tested in animal models of feeding behavior as discussed below.
  • the following assays and animal models are employed, with modifications, if any, as discussed in the examples.
  • Competitive Inhibition Assay Using [l 125 ]-NDP- ⁇ -MSH.
  • a competitive inhibition binding assay is performed using membrane homogenates prepared from HEK-293 cells that express recombinant hMCR-1a, hMCR-4, hMCR-3, or hMCR-5, and from B-16 mouse melanoma cells (containing endogenous MCR-1 ). In the examples that follow, all values are for human recombinant receptors unless otherwise noted.
  • Assays are performed in 96 well GF/B Millipore multiscreen filtration plates (MAFB NOB10) pre-coated with 0.5% bovine serum albumin (Fraction V). Membrane homogenates are incubated with 0.2nM (for hMCR-4) 0.4 nM (for MCR-3 and MCR-5) or 0.1 nM (for mouse B16 MCR-1 or hMCR-1a) [l 125 ]-NDP- ⁇ -MSH (Perkin Elmer) and increasing concentrations of test compounds in buffer containing 25 mM HEPES buffer (pH 7.5) with 100 mM NaCI, 2 mM CaCI 2 , 2 mM MgCI 2 , 0.3 mM 1 ,10- phenanthroline, and 0.2% bovine serum albumin. After incubation for 60 to 90 minutes at 37 0 C, the assay mixture is filtered and the membranes washed three times with ice-cold buffer. Filters are dried and counted in a gam
  • Non-specific binding is measured by inhibition of binding of [l 125 ]-NDP- ⁇ -MSH in the presence of 1 ⁇ M NDP- ⁇ -MSH. Maximal specific binding (100%) is defined as the difference in radioactivity (cpm) bound to cell membranes in the absence and presence of 1 ⁇ M NDP- ⁇ -MSH. Radioactivity (cpm) obtained in the presence of test compounds is normalized with respect to 100% specific binding to determine the percent inhibition of [l 125 ]-NDP- ⁇ -MSH binding. Each assay is conducted in duplicate or triplicate and the actual mean values are described, with results less than 0% reported as 0%. Ki values for test compounds are determined using Graph-Pad Prism® curve-fitting software.
  • DELFIA Enhancement solution (PerkinElmer Life Sciences) was added to each well. The plates were incubated on a shaker for 15 minutes and read at 340 nm excitation and 615 nm emission wavelengths. Each assay was conducted in duplicate and mean values were utilized. Ki values were determined by curve-fitting with Graph-Pad Prism® software using a one-site fixed-slope competition binding model.
  • the assay mixture contained 25 mM HEPES buffer (pH 7.5) with 100 mM NaCI, 2 mM CaCI 2 , 2 mM MgCI 2 , 0.3 mM 1 ,10-phenanthroline, 0.5% bovine serum albumin, membrane homogenates, radioligand [I 125 J-AgRP (83-132) (Perkin Elmer) and increasing concentrations of compounds in a total volume of 200 ⁇ L. Binding is measured at radioligand concentrations of 0.2 nM. After incubating for 1 hour at 37 0 C, the reaction mixture is filtered and washed with assay buffer containing 500 mM NaCI. The dried discs are punched out from the plate and counted on a gamma counter.
  • Ki values for test compounds are determined using Graph-Pad Prism ® curve-fitting software.
  • Assay for Agonist Activity Accumulation of intracellular cAMP was examined as a measure of the ability of the compounds this invention to elicit a functional response in a human melanoma cell line, HBL, that express hMCR-1 (see Kang, L., et al., "A slective small molecule agonist of melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice," J. Leuk. Biol.
  • HBL cells that express hMCR-1 or HEK-293 cells that express recombinant hMCR-4 were detached from culture plates by incubation in enzyme-free cell dissociation buffer. Dispersed cells were suspended in Earle's Balanced Salt Solution containing 10 mM HEPES (pH 7.5), 1 mM MgCI 2 , 1 mM glutamine, 0.5% albumin and 0.3 mM 3-isobutyl-1-methyl-xanthine (IBMX), a phosphodiesterase inhibitor.
  • IBMX 3-isobutyl-1-methyl-xanthine
  • the cells were plated in 96-well plates at a density of 0.4 x 10 5 cells per well for HBL cells and 0.5 x 10 5 cells per well for HEK-293 cells and pre-incubated for 10 minutes. Cells were exposed for 15 minutes at 37 0 C to peptides of the present invention dissolved in DMSO (final DMSO concentration of 1 %) at a concentration range of 0.05 - 5000 nM in a total assay volume of 200 ⁇ L. NDP- ⁇ -MSH was used as the reference agonist.
  • cAMP levels were determined by an HTRF® cAMP cell-based assay system from Cisbio Bioassays utilizing cryptate- labeled anti-cAMP and d2-labeled cAMP, with plates read on a Perkin-Elmer Victor plate reader at 665 and 620 nM. Data analysis was performed by nonlinear regression analysis with Graph-Pad Prism ® software. Maximum efficacy (E max ) values were determined for each test compound of the present invention, compared to that achieved by the reference melanocortin agonist NDP- ⁇ -MSH. 6. IN VIVO ANIMAL TESTS FOR COMPOUNDS Food intake after IN and IP dosing. Changes in food intake are evaluated for selected compounds.
  • mice Male C57BL/6 mice are obtained from Jackson labs (Bar Harbor, ME). Animals are individually housed in conventional plexiglass hanging cages and maintained on a controlled 12 hour on/off light cycle. Water and pelleted (Harlan Teklad 2018 18% Protein Rodent Diet) food is provided ad libitum. The mice are dosed IP (by intraperitoneal injection) after a 24 hour fast or IN (by intranasal administration) with vehicle or selected compounds (0.1-3 mg/kg, and in some cases up to 10 mg/kg). All animals are dosed once a day (or up to four consecutive days) at the start of the "lights off" period. The changes in food intake weight for the 4 hour and 20 hour period after dosing relative to control animals administered vehicle is determined.
  • DIO Diet-induced Obese
  • mice are individually housed in conventional plexiglass hanging cages and maintained on a controlled 12 hour on/off light cycle with ad libitum access to water and pelleted food (Research Diets D12451 - 45 Kcal% Fat Rodent Diet). Mice are allowed 5 days to acclimate to the facility prior to experimentation. Mice are dosed orally with vehicle or selected compounds (0.1-50 mg/kg) by oral gavage injection using a 1 mL BD Syringe and a 2OG X 1-1/2" animal feeding needle (dose volumes up to 10 mL/kg). Animals are monitored immediately after dosing for signs of gasping, wheezing or presence of dose solution around the mouth. All animals are dosed once or twice daily, withchanges in food intake weight monitored at 1 , 7, 8 and 24 hours after dosing and expressed relative to vehicle controls. Body weights are collected at 24 hours and daily thereafter and the percent change in body weight calculated from starting body weights.
  • rats are placed into individual polystyrene observational cages (27 cm long, 16 cm wide and 25 cm high) and their behavior is recorded via a high resolution video camera system for 1-2 hours (depending on route of administration). The timing and type of erection (grooming related or sudden awareness) is recorded. Rats are also observed for abnormal behaviors such as gasping or writhing. After the observations are recorded the animals are returned to their home cages.
  • the test sessions also include a negative control (vehicle) and, for IV, SC or ICV administration, a positive control (typically bremelanotide). Only those compounds that demonstrate mean statistically significant higher PE values than mean PE values with vehicle are considered efficacious.
  • Combination Therapy for sexual Dysfunction It is also possible and contemplated to use compounds of this invention in combination with other drugs or agents, such as for treatment of sexual dysfunction. These other drugs and agents may include agents that induce erectile activity, including phosphodiesterase-5 (PDE-5) inhibitors, testosterone, prostaglandin and the like.
  • PDE-5 phosphodiesterase-5
  • compounds of the invention are used in combination with a therapeutically effective amount of a cyclic-GMP-specific phosphodiesterase inhibitor or an alpha-adrenergic receptor antagonist.
  • This invention thus provides methods of treating sexual dysfunction, the methods comprising the step of administering to the patient having or at risk of having sexual dysfunction a therapeutically effective amount of a compounds of this invention in combination with a therapeutically effective amount of a second sexual dysfunction pharmaceutical agent.
  • the compounds of this invention may be administered simultaneously with, prior to or subsequent to administration with a therapeutically effective amount of a second sexual dysfunction pharmaceutical agent.
  • the compounds of this invention is administered within one hour, preferably within less than one-half hour, of administration of a therapeutically effective amount of a second sexual dysfunction pharmaceutical agent.
  • the hormone or hormone-related sexual dysfunction pharmaceutical agent may be administered on an independent schedule, such that there is no set or specific temporal relationship between administration of the compounds of this invention and the hormone or hormone-related sexual dysfunction pharmaceutical agent.
  • the hormone or hormone-related sexual dysfunction pharmaceutical agent may be administered on a daily or other dose, or by means of patches or other continuous administration schedules, with administration of the compounds of this invention when desired or needed by the patient.
  • the sexual dysfunction is female sexual dysfunction.
  • the sexual dysfunction is erectile dysfunction.
  • compositions that comprise a compound of this invention and a second compound useful for the treatment of sexual dysfunction.
  • the additional compounds useful for the treatment of sexual dysfunction are preferably selected from but not limited to the group consisting of a phosphodiesterase inhibitor; a cyclic-GMP- specific phosphodiesterase inhibitor; prostaglandins; apomorphine; oxytocin modulators; ⁇ -adrenergic antagonists; androgens; selective androgen receptor modulators (SARMs); buproprion; vasoactive intestinal peptide (VIP); neutral endopeptidase inhibitors (NEP); and neuropeptide Y receptor antagonists (NPY).
  • VIP vasoactive intestinal peptide
  • NEP neutral endopeptidase inhibitors
  • NPY neuropeptide Y receptor antagonists
  • the second sexual dysfunction pharmaceutical agent is testosterone.
  • the second sexual dysfunction pharmaceutical agent is a type V phosphodiesterase (PDE-5) inhibitor.
  • PDE-5 inhibitor may be Viagra ® , a brand of sildenafil, Levitra ® , a brand of monohydrochloride salt of vardenafil, or Cialis ® , a brand of tadalafil.
  • Other PDE-5 inhibitors are disclosed in U.S. Patent No. 7,235,625, incorporated here by reference.
  • the second compound useful for the treatment of sexual dysfunction is an estrogen agonist/antagonist.
  • the estrogen agonist/antagonist is (-)-cis-6-phenyl-5-[-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-napth- thalene-2-ol (also known as lasofoxifene) or an optical or geometric isomer thereof; a pharmaceutically acceptable salt, N-oxide, ester, quaternary ammonium salt; or a prodrug thereof.
  • the estrogen agonist/antagonist is in the form of a D-tartrate salt.
  • the estrogen agonist/antagonist is selected from the group consisting of tamoxifen, 4-hydroxy tamoxifen, raloxifene, droloxifene, toremifene, centchroman, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-napthalen-2-ol, ⁇ 4- [2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl ⁇ -[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiopehn-3- yl]-methanone, EM-652, EM-800, GW 5368, GW 7604, TSE-424 and optical or geometric isomers thereof; and pharmaceutically acceptable salts, N-oxides, esters, quaternary ammonium salts, and prodrugs thereof.
  • tamoxifen 4-
  • kits for the treatment of sexual dysfunction comprising: a first pharmaceutical composition including a compound of this invention; a second pharmaceutical composition comprising a second compound useful for the treatment of sexual dysfunction; and, a container for the first and second compositions.
  • One or more compounds of this invention may be combined with at least one other pharmacologically active agent that is useful in the treatment of diabetes, such as other anti-diabetic drugs.
  • One or more compounds of the invention may also be combined with at least one other pharmacologically active agent that is useful in the treatment of obesity and/or overweight, such as other anti-obesity drugs that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or gastrointestinal motility.
  • One or more compounds of this invention may in addition or alternatively further be combined with at least one other pharmacologically active agent that is useful in the treatment of diseaeses, disorders and/or conditions associated with obesity and/or overweight, such as insulin resistance; impaired glucose tolerance; type 2 diabetes; metabolic syndrome; dyslipidemia (including hyperlipidemia); hypertension; heart disorders (e.g. coronary heart disease, myocardial infarction); cardiovascular disorders; non-alcoholic fatty liver disease (including non-alcoholic steatohepatitis); joint disorders (including secondary osteoarthritis); gastroesophageal reflux; sleep apnea; atherosclerosis; stroke; macro and micro vascular diseases; steatosis (e.g. in the liver); gall stones; and gallbladder disorders.
  • pharmacologically active agent that is useful in the treatment of diseaeses, disorders and/or conditions associated with obesity and/or overweight, such as insulin resistance; impaired glucose tolerance; type 2 diabetes; metabolic syndrome; dyslipidemia (including hyperlipidemia); hypertension;
  • a combination treatment comprising the administration of a pharmacologically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from:
  • insulin secretagogues including sulphonylureas (e.g. glipizide) and prandial glucose regulators (sometimes called “short-acting secretagogues”), such as meglitinides (e.g. repaglinide and nateglinide);
  • sulphonylureas e.g. glipizide
  • prandial glucose regulators sometimes called "short-acting secretagogues”
  • meglitinides e.g. repaglinide and nateglinide
  • DPP-4 dipeptidyl peptidase IV
  • GLP-1 glucagon-like peptide-1
  • exenatide glucagon-like peptide-1
  • insulin sensitising agents including peroxisome proliferator activated receptor gamma (PPARY) agonists, such as thiazolidinediones (e.g.
  • agents with any combination of PPAR alpha, gamma and delta activity • agents that modulate hepatic glucose balance, for example biguanides (e.g. metformin), fructose
  • agents designed to reduce/slow the absorption of glucose from the intestine such as alpha- glucosidase inhibitors (e.g. miglitol and acarbose);
  • agents which antagonise the actions of or reduce secretion of glucagon such as amylin analogues (e.g. pramlintide);
  • agents that prevent the reabsorption of glucose by the kidney such as sodium dependent glucose transporter 2 (SGLT-2) inhibitors (e.g. dapagliflozin); • agents designed to treat the complications of prolonged hyperglycaemia, such as aldose reductase inhibitors (e.g. epalrestat and ranirestat); and agents used to treat complications related to micro-angiopathies;
  • SGLT-2 sodium dependent glucose transporter 2
  • agents designed to treat the complications of prolonged hyperglycaemia such as aldose reductase inhibitors (e.g. epalrestat and ranirestat); and agents used to treat complications related to micro-angiopathies;
  • anti-dyslipidemia agents such as HMG-CoA reductase inhibitors (statins, e.g. rosuvastatin) and other cholesterol-lowering agents; PPAR ⁇ agonists (fibrates, e.g. gemfibrozil and fenofibrate); bile acid sequestrants (e.g. cholestyramine); cholesterol absorption inhibitors (e.g. plant sterols
  • cholesteryl ester transfer protein (CETP) inhibitors i.e. phytosterols, synthetic inhibitors
  • CETP cholesteryl ester transfer protein
  • IBAT inhibitors inhibitors of the ileal bile acid transport system
  • bile acid binding resins nicotinic acid (niacin) and analogues thereof; anti-oxidants, such as probucol; and omega-3 fatty acids; • antihypertensive agents, including adrenergic receptor antagonists, such as beta blockers (e.g. atenolol), alpha blockers (e.g. doxazosin), and mixed alpha/beta blockers (e.g. labetalol); adrenergic receptor agonists, including alpha-2 agonists (e.g. clonidine); angiotensin converting enzyme (ACE) inhibitors (e.g. lisinopril), calcium channel blockers, such as dihydropyridines
  • ACE angiotens
  • nifedipine phenylalkylamines
  • verapamil phenylalkylamines
  • benzothiazepines e.g. diltiazem
  • angiotensin Il receptor antagonists e.g. candesartan
  • aldosterone receptor antagonists e.g. eplerenone
  • centrally acting adrenergic drugs such as central alpha agonists (e.g. clonidine); and diuretic agents (e.g. furosemide);
  • haemostasis modulators including antithrombotics, such as activators of fibrinolysis; thrombin antagonists; factor Vila inhibitors; anticoagulants, such as vitamin K antagonists (e.g. warfarin), heparin and low molecular weight analogues thereof, factor Xa inhibitors, and direct thrombin inhibitors (e.g. argatroban);
  • antiplatelet agents such as cyclooxygenase inhibitors (e.g. aspirin), adenosine diphosphate
  • ADP ADP receptor inhibitors
  • phosphodiesterase inhibitors e.g. cilostazol
  • glycoprotein IIB/IIA inhibitors e.g. tirofiban
  • adenosine reuptake inhibitors e.g. dipyridamole
  • anti-obesity agents such as appetite suppressant (e.g. ephedrine), including noradrenergic agents (e.g. phentermine) and serotonergic agents (e.g. sibutramine), pancreatic lipase inhibitors (e.g. orlistat), microsomal transfer protein (MTP) modulators, diacyl glycerolacyltransferase (DGAT) inhibitors, and cannabinoid (CB1 ) receptor antagonists (e.g. rimonabant);
  • appetite suppressant e.g. ephedrine
  • noradrenergic agents e.g. phentermine
  • serotonergic agents e.g. sibutramine
  • pancreatic lipase inhibitors e.g. orlistat
  • MTP microsomal transfer protein
  • DGAT diacyl glycerolacyltransferase
  • CBD1 cannabinoid receptor antagonists
  • feeding behavior modifying agents such as orexin receptor modulators and melanin- concentrating hormone (MCH) modulators; • glucagon like peptide-1 (GLP-1 ) receptor modulators;
  • neuropetideY NPY
  • NPY receptor modulators NPY receptor modulators
  • PDK pyruvate dehydrogenase kinase
  • monoamine transmission-modulating agents such as selective serotonin reuptake inhibitors
  • SSRI noradrenaline reuptake inhibitors
  • NARI noradrenaline reuptake inhibitors
  • SNRI noradrenalineserotonin reuptake inhibitors
  • MAOI monoamine oxidase inhibitors
  • a combination treatment comprising the administration of a pharmacologically pharmacologically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier, with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low-calorie diets (LCD).
  • VLCD very low calorie diets
  • LCD low-calorie diets
  • a method of treating obesity and/or overweight and therewith associated complications in a mammal, such as man, in need of such treatment which comprises administering to said animal a pharmacologically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier, in simultaneous, sequential or separate administration with a pharmacologically effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier.
  • a method of treating diabetes, in particular type 2 diabetes, in a mammal, such as man, in need of such treatment which comprises administering to said animal a pharmacologically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier, in simultaneous, sequential or separate administration with a pharmacologically effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises a compound of this invention, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable carrier.
  • kits comprising a compound of this invention, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • Combination Therapy with Anti-Inflammatory Agents For the treatment of inflammation-related diseases, indications, conditions and syndromes, compounds of this invention may be used in combination therapy, including by means of coadministration, with one or more anti-inflammatory agents.
  • glucocorticoids including but not limited to cortisone, including cortisone acetate, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate and aldosterone.
  • anti-inflammatory agents that may be used in combination therapy, including by means of coadministration, include aspirin, non-steroidal antiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin), TNF- ⁇ inhibitors (such as tenidap and rapamycin or derivatives thereof), or TNF- ⁇ antagonists (e.g., infliximab, OR1384), cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as Naproxen® or Celebrex®), CTLA4-lg agonists/antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate (CellCept®), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1 , prostaglandin synthesis inhibitors, budesonide, clofazimine, p38 mitogen-activated protein kinase inhibitor
  • NF- ⁇ B inhibitors such as corticosteroids, calphostin, CSAIDs, 4-substituted imidazo [1 ,2-A]quinoxalines as disclosed in U.S. Pat. No. 4,200,750; lnterleukin-10, salicylates, nitric oxide, and other immunosuppressants; and nuclear translocation inhibitors, such as deoxyspergualin (DSG).
  • DSG deoxyspergualin
  • Phosphodiesterase Inhibitors For certain applications and indications, it is desirable to increase production of and maintain levels of cyclic adenoise 3', 5' monophosphate (cAMP), a nucleotide messenger associated with inflammatory cell activity.
  • Certain compounds of this invention increase intracellular levels of cAMP, and can be coadministered with compounds or substances that inhibit the degradation of cAMP.
  • cAMP is hydrolyzed to an inactive form by phosphodiesterase (PDE); compounds or substances that inhibit PDE may thereby result in maintenance of and/or an increase in available cAMP.
  • PDE inhibitors A class of compounds known as PDE inhibitors has been extensively studied for use in treatment of inflammatory diseases, such as asthma, COPD and acute respiratory distress syndrome.
  • the methods and compositions of this invention may comprise use of one or more cAMP-PDE inhibitors.
  • an ophthalmic dosage form may include one or more active ingredients in addition to one or more of the compounds of this invention, such as for example artificial tear components, topical corticosteroids, non-steroidal anti-inflammatory drugs, or calcineurin inhibitors such as cyclosporine-A (Restasis® - Allergan).
  • active ingredients such as for example artificial tear components, topical corticosteroids, non-steroidal anti-inflammatory drugs, or calcineurin inhibitors such as cyclosporine-A (Restasis® - Allergan).
  • coadministration includes administration of one or more additional compounds given separately from a compound of this invention, such as separate administration of an ophthalmic dosage form including an artificial tear component, a topical corticosteroid, a non-steroidal anti-inflammatory drugs, a calcineurin inhibitor such a cyclosporine-A, or a combination of any of the foregoing.
  • ophthalmic solutions may be employed, including specifically solutions including more than one active pharmaceutical ingredient.
  • NSAID non-steroidal anti-inflammatory drug
  • NSAIDs suitable for use in combination ophthalmic solutions include agents, their esters and pharmaceutically acceptable salts thereof that inhibit the cycloxygenase (COX)-I and/or -2 enzyme, including but not limited to propionic acid compounds such as naproxen, flurbiprofen, oxaprozin, ibuprofen, ketoprofen, fenoprofen; ketorolac tromethamine; acetic acid derivatives such as sulindac, indomethacin, and etodolac; phenylacetic acids such as diclofenac, bromfenac, and suprofen; arylacetic prodrugs such as nepafenac, and amfenac; salicyclic acids, such as aspirin, salsalate, diflunisal, choline magnesium trisalicylate; para-aminophenol derivatives such as acetaminophen; naphthylalkanones such as nabumet
  • the ophthalmic solutions may additionally comprise other active ingredients, including, but not limited to, vasoconstrictors, anti-allergenic agents, anti-infectives, steroids, anesthetics, anti-inflammatories, analgesics, dry eye treatment agents (e.g. secretagogues, mucomimetics, polymers, lipids, antioxidants), and the like, or be administered in conjunction (simultaneously or sequentially) with pharmaceutical compositions comprising other active ingredients, including, but not limited to, vasoconstrictors, anti-allergenic agents, anti-infectives, steroids, anesthetics, anti-inflammatories, analgesics, dry eye treatment agents (e.g. secretagogues, mucomimetics, polymers, lipids, antioxidants), and the like.
  • active ingredients including, but not limited to, vasoconstrictors, anti-allergenic agents, anti-infectives, steroids, anesthetics, anti-inflammatories, analgesics, dry eye treatment
  • the invention provides a compound of the formula I: or an enantiomer, stereoisomer or diastereoisomer thereof, or a pharmaceutically acceptable salt thereof, where the variables are as defined in the Summary of the Invention and Claims.
  • X may be N, O, C or CH
  • n may be 1 or 2
  • m may be 0, 1 or 2.
  • R 1 may be H, a C 1 to C 17 linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, or a C 1 to C 7 acyl group, in each instance optionally substituted with a terminal amide, amino, monosubstituted amino, disubstituted amino, or nitrile, or R 1 may be an amide, amino, monosubstituted amino, or disubstituted amino.
  • R 2a is H, a C 1 to C 17 linear or branched alkyl, cycloalkyl, or alkylcycloalkyl, or a C 1 to C 7 acyl group, in each instance optionally substituted with one or more substituents, and when one or more substituents are present, such substituents are the same or different and independently halo, amino, monosubstituted amino, disubstituted amino, hydroxy, or carboxy.
  • R 2a may be: -H, -CH 3 , -CH 2 -CH 3 , -CH-(CH 3 ) 2 ,
  • R 3 is one or two cyclic radicals, and if two cyclic radicals, may in one aspect be fused cyclic radicals, optionally substituted with one or more ring substituents, and when one or more substituents are present, such substituents are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl.
  • the cyclic radicals comprising R 3 may be have a covalent bond attachment to the remainder of the compound of the invention at any chemically permissible position.
  • R 3 may be:
  • R 3 may be two cyclic radicals joined by a bond or linking group, such as L 3 , including, by way of example and not limitation, the following where the two cyclic radicals are phenyl:
  • R is a suitable substituent, including but not limited to oxo.
  • R 3 is two cyclic radicals joined by a bond or linking group, one or both of the cyclic radicals may optionally be substituted with one or more ring substituents, and when one or more substituents are present, such substituents are the same or different and independently alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, aryl, alkylaryl, aryloxy, amino, monosubstituted amino, disubstituted amino, sulfonamide, hydroxy, carboxy, or alkoxy-carbonyl.
  • R 3 may be a group of the structure
  • R 5 is H or one or two cyclic radicals, and if two cyclic radicals, fused cyclic radicals or cyclic radicals joined by L 3 , the one or two cyclic radicals optionally substituted with one or more ring substituents, where R 6 is an amine, an amine substituted with one or two linear or branched Ci to Ci 7 alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkene, alkenyl, or aralkyl chains, a Ci to C 7 acyl group, a C 1 to C 7 alkylamine group, wherein the alkyl is linear, branched or cyclic and the amine is optionally substituted with one or two C 1 to C 17 linear or branched alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkene, alkenyl, or aralkyl chains, or an N-acylated linear or branched C 1 to C 17
  • R 5 may be one or two cyclic radicals, and if two cyclic radicals, then fused cyclic radicals or cyclic radicals joined by L 3 .
  • R 5 may include an aryl group, a cycloalkyl group, a heterocycloalkyl group, a heteroaryl group or a combination of two or more thereof, optionally with L 3 where R 5 includes two cyclic radicals.
  • the compound was synthesized using the methods of the foregoing synthetic schemes.
  • the compound had the structural formula:
  • the compound was prepared as the TFA salt, and had a molecular weight of 609.24 without salt, and 951.30 with TFA salt.
  • the compound had a Ki of 1 nM at MCR-4 and 220 nM at MCR-1.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 78%, with an EC 50 value of 2 nM.
  • the compound was synthesized using the methods of the foregoing synthetic schemes.
  • the compound had the structural formula:
  • the compound was prepared as the TFA salt, and had a molecular weight of 595.22 without salt, and 937.28 with TFA salt.
  • the compound had a Ki of 1 nM at MCR-4 and 40 nM at MCR-1.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 80%, with an EC 50 value of 0.85 nM.
  • the compound was synthesized using the methods of the foregoing synthetic schemes.
  • the compound had the structural formula:
  • the compound was prepared as the TFA salt, and had a molecular weight of 637.25 without salt, and 865.29 with TFA salt.
  • the compound had a Ki of 0.5 nM at MCR-4 and 85 nM at MCR-1.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 62%, with an EC 50 value of 0.15 nM.
  • the compound was prepared as the TFA salt, and had a molecular weight of 660.30 without salt, and 894.34 with TFA salt.
  • the compound had a Ki of 1 nM at MCR-4 and 210 nM at MCR-1.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 94%, with an EC 50 value of 1 nM.
  • the compound was prepared as the TFA salt, and had a molecular weight of 667.28 without salt, and 895.32 with TFA salt.
  • the compound had a Ki of 3 nM at MCR-4.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 92%, with an EC 50 value of 25 nM.
  • the compound was prepared as the TFA salt, and had a molecular weight of 673.31 without salt, and 901.35 with TFA salt.
  • the compound had a Ki of 6 nM at MCR-4.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 94%, with an EC 50 value of 12 nM.
  • the compound was prepared as the TFA salt, and had a molecular weight of 651.28 without salt, and 879.32 with TFA salt.
  • the compound had a Ki of 3 nM at MCR-4.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 26%, with an EC 50 value of 0.3 nM.
  • the compound was synthesized using the methods of the foregoing synthetic schemes.
  • the compound had the structural formula: and a molecular formula of 0 24 H 38 CIN 5 O 2 .
  • the compound was prepared as the TFA salt, and had a molecular weight of 464.04 without salt, and 692.08 with TFA salt.
  • the compound had a Ki of 23 nM at MCR-4.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 21 %, with an EC 50 value of 71 nM.
  • the compound was synthesized using the methods of the foregoing synthetic schemes.
  • the compound had the structural formula:
  • the compound was prepared as the TFA salt, and had a molecular weight of 611.22 without salt, and 839.26 with TFA salt.
  • the compound had a Ki of 3 nM at MCR-4.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 45%, with an EC 50 value of 8 nM.
  • the compound had a Ki of 1 nM at MCR-4.
  • the compound had a relative efficacy, compared to NDP- ⁇ -MSH, of 26%, with an EC 50 value of 0.95 nM.

Abstract

L’invention concerne un composé représenté par LA formule dans laquelle R1, R2a, R2D, R3, L1, L2, Q, J, X, m et n sont tels que définis dans la spécification, ou un énantiomère, un stéréoisomère ou un diastéréoisomère de celui-ci, ou un sel de celui-ci pharmaceutiquement  acceptable, et l’utilisation de celui-ci pour traiter des maladies, des syndromes et des états modulés par des récepteurs de la mélanocortine.
PCT/US2009/066671 2008-12-04 2009-12-04 Composés de pipérazine spécifiques des récepteurs de la mélanocortine substitués par un amine WO2010065801A1 (fr)

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WO2013102047A1 (fr) 2011-12-29 2013-07-04 Rhythm Pharmaceuticals, Inc. Méthode de traitement de troubles associés au récepteur 4 de la mélanocortine dans des porteurs hétérozygotes
US8697739B2 (en) 2010-07-29 2014-04-15 Novartis Ag Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof
US9018395B2 (en) 2011-01-27 2015-04-28 Université de Montréal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
WO2019195756A1 (fr) 2018-04-06 2019-10-10 Rhythm Pharmaceuticals, Inc. Compositions pour le traitement d'une rénopathie
WO2020060983A3 (fr) * 2018-09-18 2020-07-23 Palatin Technologies, Inc. Composés du récepteur 4 de la mélanocortine oralement actifs
EP4029513A1 (fr) 2015-09-30 2022-07-20 Rhythm Pharmaceuticals, Inc. Agonistes du récepteur de melanocortin-4 pour le traitement des désordres characterisés par une hyperméthylation du gène pomc

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US9789118B2 (en) 2010-07-29 2017-10-17 Novartis Ag Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof
US8697739B2 (en) 2010-07-29 2014-04-15 Novartis Ag Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof
US9018395B2 (en) 2011-01-27 2015-04-28 Université de Montréal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
US9493456B2 (en) 2011-01-27 2016-11-15 Universite De Montreal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
EP3988108A1 (fr) 2011-12-29 2022-04-27 Rhythm Pharmaceuticals, Inc. Procédé de traitement de troubles associés au récepteur de la mélanocortine-4 dans des porteurs hétérozygotes
US9845339B2 (en) 2011-12-29 2017-12-19 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US10167312B2 (en) 2011-12-29 2019-01-01 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
EP3539551A1 (fr) 2011-12-29 2019-09-18 Rhythm Pharmaceuticals, Inc. Procédé de traitement de troubles associés au récepteur de la mélanocortine-4 dans des porteurs hétérozygotes
US10954268B2 (en) 2011-12-29 2021-03-23 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
WO2013102047A1 (fr) 2011-12-29 2013-07-04 Rhythm Pharmaceuticals, Inc. Méthode de traitement de troubles associés au récepteur 4 de la mélanocortine dans des porteurs hétérozygotes
US11702448B2 (en) 2011-12-29 2023-07-18 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
EP4029513A1 (fr) 2015-09-30 2022-07-20 Rhythm Pharmaceuticals, Inc. Agonistes du récepteur de melanocortin-4 pour le traitement des désordres characterisés par une hyperméthylation du gène pomc
WO2019195756A1 (fr) 2018-04-06 2019-10-10 Rhythm Pharmaceuticals, Inc. Compositions pour le traitement d'une rénopathie
WO2020060983A3 (fr) * 2018-09-18 2020-07-23 Palatin Technologies, Inc. Composés du récepteur 4 de la mélanocortine oralement actifs
US20210198201A1 (en) * 2018-09-18 2021-07-01 Palatin Technologies, Inc. Orally Active Melanocortin Receptor-4 Compounds
US20220204450A1 (en) * 2018-09-18 2022-06-30 Palatin Technologies, Inc. Orally Active Melanocortin Receptor-4 Compounds

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