EP1363890A2 - Composes de liaison au recepteur de la melanocortine-4 et procedes d'utilisation de tels composes - Google Patents

Composes de liaison au recepteur de la melanocortine-4 et procedes d'utilisation de tels composes

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Publication number
EP1363890A2
EP1363890A2 EP02718920A EP02718920A EP1363890A2 EP 1363890 A2 EP1363890 A2 EP 1363890A2 EP 02718920 A EP02718920 A EP 02718920A EP 02718920 A EP02718920 A EP 02718920A EP 1363890 A2 EP1363890 A2 EP 1363890A2
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EP
European Patent Office
Prior art keywords
phenyl
methoxy
bromo
tetrahydro
ethyl
Prior art date
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Withdrawn
Application number
EP02718920A
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German (de)
English (en)
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EP1363890A4 (fr
Inventor
Martin P. Maguire
Mingshi Dai
Tricia J. Vos
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ore Pharmaceuticals Inc
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Millennium Pharmaceuticals Inc
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Priority claimed from US09/778,468 external-priority patent/US6699873B1/en
Application filed by Millennium Pharmaceuticals Inc filed Critical Millennium Pharmaceuticals Inc
Publication of EP1363890A2 publication Critical patent/EP1363890A2/fr
Publication of EP1363890A4 publication Critical patent/EP1363890A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • 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
    • C07D295/04—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 substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Melanocortins are known to have a broad array of physiological actions (Nakanishi, et al. Nature (1979) 278:423-427). Aside from their well known effects on adrenal cortical functions and on melanocytes, melanocortins have been shown to affect behavior, learning, memory, control ofthe cardiovascular system, analgesia, thermoregulation, and the release of other neurohumoral agents including prolactin, luetinizing hormone, and biogenic amines (De Weid et al. Methods Achiev. Exp. Pathol
  • melanocortins have been identified to have immunomodulatory and neurotrophic properties, and to be involved in events surrounding partition (Cannon, J.G. et al. J. Immunol. (1986) 137:2232-2236; Gispen, W.H. Trends Pharm. Sci. (1992) 11 :221-222; Wilson, J.F. Clin. Endocrinol. (1982) 17:233-242; Clark, D. et al. N ⁇ twre (1978) 273:163-164; Silman, R.E. et al.
  • melanocortins are present in a myriad of normal human tissues including the brain, ovary, lung, thyroid, liver, colon, small intestine and pancreas (Tatro, J.B. et al. Endocrinol. (1987) 121 :1900-1907; Mountjoy, K.G. et al. Science (1992) 257:1248- 1251; Chhajlani, V. et al., FEBS Lett. (1992) 309:417-420; Gantz, L. et al., J. Biol. Chem. (1993) 268:8246-8250; Gantz, L. et al, J.
  • the melanocortin-2 receptor (MC2-R or ACTH receptor) is found in the adrenal glands where it mediates the effects of ACTH (adrenocorticotrophic hormone).
  • the melanocortin-3 receptor (MC3-R) is primarily found in the central nervous system (CNS) (Gantz, L. et al., J. Biol. Chem. (1993) 268:8246-8250), but its physiological function is still unknown.
  • the melanocortin-4 receptor (MC4-R) has been found in the brain, where it is widely distributed in several areas, including the cortex, thalamus, hypothalamus, brain stem, and spinal cord (Gantz, L. et al. J. Biol. Chem.
  • MC4-R has recently been related to weight homeostasis. MC4-R "knock out" mice have been shown to develop obesity (Huszar et al. Cell (1997) 88:131-141). The feeding behavior leading to the obesity can be inhibited by injection of MSH peptides (Vergoni et al. Neuropeptides (1986) 7:153- 158; Vergoni et al. Eur. J. Pharmacol. (1990) 179:347-355; Fan et al. N ⁇ twre (1997) 385:165-168).
  • MSH peptides The melanocortin-5 receptor (MC5-R) has a wide peripheral distribution and is believed to participate in the regulation ofthe exocrine gland function (Chen et al. Cell (1997) 91 :789-798).
  • the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal.
  • the method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • the MC4-R binding compound is ofthe formula (I):
  • B is an anchor moiety
  • Z is a central moiety
  • E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
  • the MC4-R binding compound is ofthe formula (II):
  • B-A-E (II) wherein B is an anchor moiety, A is cyclic moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts, thereof.
  • the invention pertains to another method for treating an MC4-R associated state in a mammal, by administering to a mammal an effective amount of a MC4-R binding compound of formula (III) :
  • B is an anchor moiety
  • L ⁇ and L 2 are linking moieties
  • A is a cyclic moiety
  • E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • the invention also pertains to treating MC4-R associated states with an MC4-R binding compound of formula III, wherein B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, hydroxy, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro; Li is a covalent bond, C ⁇ -C ⁇ 0 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, amino
  • the invention pertains to a method for treating an MC4- R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • the compound is ofthe formula (IV):
  • B is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or heteroaryl;
  • A is aryl, heteroaryl, biaryl, cycloalkyl, heterocyclic, or cycloalkenyl;
  • Li and L 2 are selected from the group consisting of a covalent bond, C ⁇ -C 6 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H;
  • t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H;
  • s is CHR 5 , CR 5 , CR 5 R 6 or absent (e.g., leaving a non- cyclic diamine);
  • R is H, substituted or unsubstituted alkyl,
  • compositions for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound ofthe formula (V):
  • B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, cyano, or nitro;
  • Li is a covalent bond, Ci-Cio branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
  • E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl
  • the invention also pertains to a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal, wherein the compound is an MC4-R antagonist, and is ofthe formula (VI):
  • p i p 2 ⁇ p 3 an( j p 4 ⁇ g optionally substituted carbon, sulfur, or nitrogen, and wherein one of P 1 , P 2 , P 3 and P 4 may represent a covalent bond;
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are optionally substituted carbon or nitrogen;
  • Li is a covalent bond, Cj-Cio branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and
  • J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof.
  • the MC4-R binding compound is of formula (VII):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon
  • P 1 , P 2 , P 3 , P 4 , and P 5 are CH, N or substituted carbon.
  • the MC4-R binding compound is of formula (VIII):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon
  • P 1 , P 2 , P 3 , P 4 , and P 5 are CH, N or substituted carbon.
  • the invention also pertains to MC4-R binding compound ofthe formula (IX):
  • P 2 is CH, CF, CC1, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond;
  • P 3 is CH, CF, CC1, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI
  • P 4 is CH, CC1, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a sulfur atom
  • G 1 and G 2 are each independently CH 2 , S, or O; r is a covalent bond or CH 2 ; t is CH 2 , CHR 3 , or CR 3 R 4 ; s is CH 2 , CHR 5 or CR 5 R 6 ;
  • R is hydrogen, alkyl, alkoxycarbonyl, or alkylcarbonyl;
  • Z 1 is CH, or covalently linked to Z 2 to form a naphthyl ring;
  • Z 2 is CH, C-(C ⁇ CH), CC1, CBr, CI, CF, or covalently linked to Z 1 to form a naphthyl ring;
  • Z 5 is CH, C-alkoxy or C-OMe
  • R 3 , R 4 , R 5 , and R 6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, or amino, or pharmaceutically acceptable salts thereof.
  • the invention also features a pharmaceutical composition for the treatment of a
  • compositions contain a pharmaceutically acceptable carrier and a MC4-R binding compound.
  • the compounds are described herein in the context ofthe description ofthe method but it should be understood that the invention further pertains to pharmaceutical compositions containing the compounds and the compounds per se.
  • pharmaceutical compositions ofthe invention include a pharmaceutically acceptable carrier and an effective amount of at least one MC4-R binding compound ofthe formula (I):
  • B-Z-E (I) wherein B is an anchor moiety, Z is an central moiety, E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • Figures la and lb are bar graphs showing the effects of MT II (a MC4-R agonist) on food intake in lean mice.
  • Figure 2 is a graph depicting the effects of treating lean mice with Compound N and MT II on food intake over a six hour period.
  • Figure 3 is a graph depicting the effects of treating lean mice with Compound O and MT II on food intake over a six hour period.
  • the invention pertains to a method for treating a melanocortin-4 receptor (MC4-R) associated state in a mammal.
  • the method involves administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • the MC4-R binding compound is ofthe formula (I):
  • B is an anchor moiety
  • Z is a central moiety
  • E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • MC4-R includes receptors for ⁇ -melanocyte stimulating hormone.
  • the MC4-R is usually found in the brain where it is widely distributed (Mountjoy et al. Mol. Endocrinol. (1994) 8:1298-1308).
  • Melanocortins are peptide hormones that play an important role in regulating melanocyte pigmentation as well as memory and thermoregulation. They consist of various peptides, such as ⁇ -melanocyte stimulating hormone, that are cleaved from the polypeptide precursor prooptiomelanocortin (POMC).
  • POMC prooptiomelanocortin
  • the effects of melanocortins are mediated via stimulation of adenylate cyclase via the activation ofthe melanocortin receptors.
  • the melancortin-4 receptor (MC4-R) is a G-protein coupled receptor (GPCR) expressed in brain tissue.
  • GPCR G-protein coupled receptor
  • the specific role ofthe MC4-R protein in vivo was investigated by engineering MC4-R "knock out" mice. The mice were unable to produce functional MC4-R protein, because the endogenous MC4-R gene coding sequence was deleted. The knock-out mice were produced by using human MC4-r gene sequences to isolate and clone the murine MC4-r gene. A murine MC4-r targeting construct was then generated which was designed to delete the majority ofthe murine MC4-r coding sequence upon homologous recombination with the endogenous murine MC4-r gene.
  • Embryonic stem (ES) cells containing the disrupted MC4-r gene were produced, isolated and microinjected into murine blastocysts to yield mice chimeric for cells containing a disrupted MC4-r gene.
  • Offspring ofthe chimeric mice resulting from germline transmission ofthe ES genome were obtained and animals heterozygous for the disrupted MC4-R were identified.
  • the animals heterozygous for the MC4-r disrupted gene were bred together, producing litters containing wild-type mice, mice heterozygous for the MC4-r mutation and mice homozygous for the MC4-R mutation. The weight gain ofthe animals was monitored regularly.
  • mice heterozygous null MC4-R mutants showed an increase in weight compared to mice heterozygous for MC4-R deletion and wild type mice as early as 25 days of age.
  • MC4-R deficient mice exhibited, on average, a 55-70% greater weight relative to wild type mice, and an approximately 50% greater weight compared to mice heterozygous for the MC4-R deletion.
  • MC4-R associated states includes those states, disorders, or diseases characterized by aberrant or undesirable activity or expression of MC4-Rs. It also includes those states, disorders and diseases associated with MC4-R ligands (e.g., ⁇ -melanocyte stimulating hormone). The language also includes prevention of states, disorders and diseases characterized by aberrant or undesirable activity of MC4-Rs or its ligands. Examples of MC4-R associated states include, but are not limited to, disorders involving or associated with pigmentation, bones, and weight homeostasis, e.g., weight loss or obesity.
  • MC4-R associated states include the unhealthy decrease in body weight that can occur during an acute inflammatory response or that occurs in a cancer patient as a result of cachexia, radiotherapy or chemotherapy, or to the undesirable decrease in body mass due to simulated or actual weightlessness, such as occurs during space travel.
  • Other examples of unhealthy decreases in weight occur in some patients during advance stages of illnesses such as AIDS. Physiologically, this may be a result from any one of a number of complex factors, such as loss of appetite and possibly abnormal catabolism.
  • This cachexia may be slowed by MC4-R binding compounds.
  • the weight loss is a result of old age, anorexia nervosa, or cachexia (e.g., cachexia associated with cancer or HIV).
  • the MC4-R associated state is not weight loss.
  • the MC4-R associated disorder is a bone associated disorder.
  • MC4-R knockout mice have been shown to have enhanced bone thickness (Ducy et al. Science, (Sept., 2000) 289:1501-1504). Examples of bone associated disorders which may be treated with MC4-R binding compounds ofthe invention include disorders and states where the formation, repair or remodeling of bone is advantageous.
  • bone associated states include osteoporosis (e.g., a decrease in bone strength and density), bone fractures, bone formation associated with surgical procedures (e.g., facial reconstruction), osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, and the depletion of calcium in bone, such as that which is related to primary hyperparathyroidism.
  • Bone associated disorders include all states in which the formation, repair or remodeling of bone is advantageous to the subject as well as all other disorders associated with the bones or skeletal system of a subject which can be treated with the compounds of the invention.
  • MC4-R binding compound includes those compounds which interact with the MC4-R resulting in modulation of the activity ofthe MC4-R. In an embodiment, the MC4-R binding compounds are antagonists ofthe MC4-R.
  • the term "antagonist” includes compounds which interact with the MC4-R and modulate, e.g., inhibit or decrease, the ability of a second compound, e.g., ⁇ -melanocyte stimulating hormone or another MC4-R ligand, to interact with the MC4-R.
  • the MC4-R binding compounds is an agonist ofthe MC4-R.
  • agonists includes compounds which interact with the MCR-4 and modulate, e.g., increase or stimulate, its activity and/or its ability to interact with a second compounds, e.g., ⁇ -melanocyte stimulaturing hormone.
  • MC4-R binding compounds can be identified through both in vitro (e.g., cell and non-cell based) and in vivo methods. These methods are described in detail in Examples 2, 3, 4, and 5.
  • the Scincillation Proximity Assay is a non-cell based in vitro assay, described in Example 2. It can be used to identify compounds that interact with, e.g., bind to MC4-R. Such compounds may act as antagonists or agonists of MC4-R activity and may be used in the treatment of body weight disorders.
  • One example of a qualitative measure of binding affinity of a MC4-R binding compound to MC4-R is its IC 50.
  • the MC4-R binding compound binds to the MC4-R with a binding affinity, for example, of about 50 ⁇ M or less, 20 ⁇ M or less, 10 ⁇ M or less, 5 ⁇ M or less, 2.5 ⁇ M or less, or 1 ⁇ M or less.
  • the IC 50 of a MC4-R binding compounds is about 0.5 ⁇ M or less,, about 0.3 ⁇ M or less, about 0.1 ⁇ M or less, about 0.08 ⁇ M or less, about 0.06 ⁇ M or less, about 0.05 ⁇ M or less, about 0.04 ⁇ M or less, or, preferably, about 0.03 ⁇ M or less.
  • isolated membranes are used to identify compounds that interact with MC4-R.
  • 293 cells may be genetically engineered to express the MC4-R.
  • Membranes are be harvested by standard techniques and used in an in vitro binding assay.
  • I-labeled ligand e.g., I- labeled ⁇ -MSH, ⁇ -MSH, or ACTH
  • I-labeled ligand is bound to the membranes and assayed for specific activity; specific binding is determined by comparison with binding assays performed in the presence of excess unlabelled ligand.
  • membranes are incubated with labeled ligand in the presence or absence of test compound.
  • Compounds that bind to the receptor and compete with labeled ligand for binding to the membranes reduced the signal compared to the vehicle control samples.
  • the screens are designed to identify compounds that antagonize the interaction between MC4-R and MC4-R ligands such as ⁇ -MSH, ⁇ -MSH and ACTH.
  • the MC4-R ligands are labeled and test compounds can be assayed for their ability to antagonize the binding of labeled ligand to MC4-R.
  • Cell based assay systems can also be used to identify MC4-R binding compounds.
  • An example of a cell based assay system is the cAMP assay described in detail in Example 3.
  • Cell based methods may use cells that endogenously express MC4- R for screening compounds which bind to MC4-R.
  • cell lines such as 293 cells, COS cells, CHO cells, fibroblasts, and the like, genetically engineered to express the MC4-R can also be used for screening purposes.
  • host cells genetically engineered to express a functional receptor that responds to activation by melanocortin peptides can be used as an endpoint in the assay; e.g., as measured by a chemical, physiological, biological, or phenotypic change, induction of a host cell gene or a reporter gene, change in cAMP levels, adenylyl cyclase activity, host cell G protein activity, extracellular acidification rate, host cell kinase activity, proliferation, differentiation, etc.
  • the host cells expressing functional MC4-R should give a significant response to MC4-R ligand, preferably greater than 5 -fold induction over background.
  • Host cells should preferably possess a number of characteristics, depending on the readout, to maximize the inductive response by melanocortin peptides, for example, for detecting a strong induction of a CRE reporter gene: (a) a low natural level of cAMP, (b) G proteins capable of interacting with the MC4-R, (c) a high level of adenylyl cyclase, (d) a high level of protein kinase A, (e) a low level of phosphodiesterases, and (f) a high level of c AMP response element binding protein would be advantageous.
  • host cells could be engineered to express a greater amount of favorable factors or a lesser amount of unfavorable factors.
  • alternative pathways for induction ofthe CRE reporter could be eliminated to reduce basal levels.
  • the cells expressing the melanocortin receptor are exposed to a test compound or to vehicle controls (e.g., placebos). After exposure, the cells can be assayed to measure the expression and/or activity of components ofthe signal transduction pathway ofthe melanocortin receptor, or the activity ofthe signal transduction pathway itself can be assayed. For example, after exposure, cell lysates can be assayed for induction of cAMP. The ability of a test compound to increase levels of cAMP, above those levels seen with cells treated with a vehicle control, indicates that the test compound induces signal transduction mediated by the melanocortin receptor expressed by the host cell.
  • vehicle controls e.g., placebos.
  • ligands that activate the MC4-R e.g., ⁇ -MSH, ⁇ -MSH or ACTH, to test for inhibition of signal transduction by the test compound as compared to vehicle controls.
  • the assays described above may be conducted using a panel of host cells, each genetically engineered to express one ofthe melanocortin receptors (MC1-R through MC5-R). Expression ofthe human melanocortin receptors is preferred for drug discovery purposes.
  • host cells can be genetically engineered to express any ofthe amino acid sequences shown for melanocortin receptors 1 through 5.
  • MC1-R and MC2-R Mountjoy., 1992, Science 257: 1248-1251 ; Chhajlani & Wikberg, 1992 FEBS Lett. 309: 417-420
  • MC3-R Roselli-Rehfuss et al., 1993, Proc. Natl. Acad. Sci., USA 90: 8856-8860; Gantz et al., 1993, J. Biol. Chem. 268: 8246-8250
  • MC4-R Gantz et al., 1993, J. Biol. Chem. 268: 15174-15179; Mountjoy et al., 1994, Mol.
  • the activation, or inhibition of MC4- R activation is compared to the effect ofthe test compound on the other melanocortin receptors.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R than at least one other MC receptors, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC1-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC3-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective. In one further embodiment, the MC4-R binding compounds ofthe invention are more selective for the MC4-R than the MC5-R, for example, more than twice as selective, at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective.
  • the MC4-R binding compounds ofthe invention are more selective for the MC4-R receptor than at least one, two or three other MC receptors (such as, for example, MC1-R, MC3-R, or MC5-R).
  • the MC4-R binding compounds are more selective for the MC4-R than MC1-R, MC3-R, and MC5-R.
  • the MC4-R binding compounds as at least ten times as selective, at least twenty times as selective, at least fifty times as selective, or at least one hundred times as selective for the MC4-R than the MC 1 -R, MC3-R and the MC5-R.
  • the MC4-R binding compound includes compounds ofthe formula (I):
  • B is an anchor moiety
  • Z is a central moiety
  • E is a MC4-R interacting moiety
  • anchor moiety includes moieties which interact with the
  • anchor moieties include substituted or unsubstituted alkyl (e.g., branched, straight chain, or cyclic (e.g., cyclohexane, cyclopentane)), alkenyl, alkynyl, aryl (e.g., substituted or unsubstituted phenyl, naphthyl, biphenyl, anthracenyl, fluorenyl, etc.), heterocyclic (e.g., thienyl, morpholinyl, piprazinyl, piperidinyl, etc.), and multicyclic (e.g., indolyl, benzothioenyl, etc.) moieties.
  • Other examples of anchor moieties include carbonyl moieties, thiol groups, cyano groups, amino groups, and hydrogen atoms.
  • the anchor moiety includes substituted or unsubstituted carbocyclic aryl moieties, e.g., phenyl, naphthyl, etc.
  • substituents include halogens (e.g., fluorine, chlorine, iodine, bromine, etc.), alkoxy (e.g., methoxy, ethoxy, isopropoxy, n-propyloxy, n-butyloxy, pentoxy, cyclopentoxy, arylalkyloxy, etc.) hydroxy, alkylcarbonyl, cyano, nitro, thiol, thioether, thioalkyl, alkenyl, alkynyl (e.g., ethynyl, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkoxycarbonyl, aminocarbony
  • the anchor moiety substituent can be substituted itself with one or more halogen, nitro, alkyl, alkenyl, alkynyl, aryl or alkoxy groups, or combinations thereof.
  • the aryl moiety is fused to another ring which can be substituted or unsubstituted, carbocyclic or heterocyclic, aromatic or non-aromatic.
  • the anchor moiety is substituted with at least one halogen, alkoxy group, or alkyl (e.g., substituted or unsubstituted) group.
  • halogen substituted phenyl anchor moieties include ⁇ -iodophenyl, w-iodophenyl, o- bromophenyl, m-bromophenyl, o-chlorophenyl, m-chlorophenyl, ⁇ -fluorophenyl, m- fluorophenyl, ⁇ -fluorophenyl, w-nitrophenyl, or o-methoxy.
  • the anchor moiety may also comprise more than one substituent, e.g.
  • anchor moieties include 2-methoxy-5- bromophenyl, 2-methoxy-5-fluorophenyl, 2-methoxy-5-iodophenyl, 2-methoxy-5- fluorophenyl, 2-ethoxy-5-bromophenyl, 2-methoxy-6-bromophenyl, 3-methoxy-6- bromophenyl, 2-isopropyl-5-bromophenyl, 2- «-propyl-5-bromophenyl, and 2- cyclopentyloxy-5-bromophenyl.
  • anchor moieties include, but are not limited to, 2-methoxy-5- cyanophenyl, 2-chloro-5-chlorophenyl, 2-methoxy-6-methoxyphenyl, 2-methoxy-5- nitrophenyl, 2-methoxy-5 -phenyl phenyl, 2-methoxy-5-3'-thiofuranyl phenyl, 2- methoxy-5-methylcarbonyl phenyl, 3,5-dimethyloxy phenyl, 2-methoxyphenyl, 2,5- dimethoxy phenyl, 2-fluoro-6-chlorophenyl, and 3-chloro-4-fluorophenyl.
  • the anchor moiety includes substituted and unsubstituted heterocycles.
  • heterocycles include, but are not limited to, furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, deazapurinyl, morpholine, piprazine, piperidine, thiomorpholine, and thioazolidine.
  • substituents include alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonyla
  • the anchor moiety is a substituted or unsubstituted fused aryl or biaryl moiety.
  • Biaryl moieties include moieties with two or more aromatic rings, which may be fused or connected through one or more covalent bonds. Examples include biphenyl, fluorene, anthracenyl, benzoquinazolinyl, and naphthyl.
  • substituents of biaryl moieties include alkyl (e.g., substituted and unsubstituted, branched or straight chain, methyl, ethyl, propyl, butyl, pentyl, etc.), alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, cyclopentoxy, etc.), alkenyl, alkynyl, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamin
  • Biaryl moieties also include moieties which comprise one or more heterocycles, such as, benzothiofuranyl, benzothienyl, quinolinyl, benzothiophenyl, benzofuranyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, and indolyl.
  • heterocycles such as, benzothiofuranyl, benzothienyl, quinolinyl, benzothiophenyl, benzofuranyl, isoquinolinyl, benzodiozanyl, benzoxazolyl, benzothiazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, and indolyl.
  • biaryl anchor moieties include naphthyl, 2-methoxynaphthyl, 2-methoxy-5-phenyl phenyl, 2-ethoxynaphthyl, 2-methoxy-5-thiofuranyl phenyl, 2-methyl naphthyl, 2-n- propyl naphthyl, benxothiofuranyl, 2-phenyl phenyl, 2-methoxy-5-4'methoxy-phenyl phenyl; 2-methoxy-5-(3'-fluoro-4'-phenyl) phenyl phenyl; 2-cyclopentoxynaphthyl; quinolinyl; and 2-methoxy-5-(3'-chloro-4'fluoro)phenyl phenyl.
  • the anchor moiety can be multicyclic and comprise a combination of one or more aromatic, non-aromatic, heterocyclic, and heteroaryl rings, which can be fused, bridged, or linked together through covalent bonds.
  • the multicyclic anchor moiety may also be substituted with substituents such as alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato
  • central moiety includes moieties which covalently attach the anchor moiety to the MC4-R interacting moiety.
  • central moieties include cyclic moieties, optionally substituted amines (e.g., tertiary amino, aminoalkylamino, dialkylaminoalkylamino, aminocarbonylamino, aminocarbonylamino; arylaminocarbonylamino groups; arylaminothiocarbonylamino), optionally substituted alkyl groups (e.g., carbon atoms with substituted or unsubstituted alkyl, aryl (e.g., phenyl, naphthyl), heterocyclic moieties (e.g., morpholinyl, piprazinyl, etc.), and carbonyl groups, etc.
  • cyclic moieties e.g., optionally substituted amines (e.g., tertiary amino, aminoalkylamino, dialkylaminoalky
  • substituents ofthe central moiety include, for example, alkyl (e.g., straight, branched or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), alkenyl (ethenyl, propenyl, butenyl, etc.), alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g., chlorine, fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy, ethoxy, trifluoromefhoxy, trichloromethoxy, propoxy, butoxy, cyclopropoxy, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate
  • central moiety may further comprise one or more linking moieties.
  • the linking moieties may covalently link the cyclic moiety to the anchor moiety and/or the MC4-R interacting moiety.
  • central moiety also includes moieties ofthe formula (XII):
  • ⁇ is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, carbocyclic, or aryl
  • L 3 is a covalent bond, C ⁇ -C branched, unbranched or cyclic alkyl(wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or aminothiocarbonyl moiety;
  • A is substituted or unsubstituted heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and ⁇ is 0, 1 or 2.
  • ⁇ is a carbon or nitrogen atom.
  • ⁇ is alkyl, carbocyclic, heterocyclic (e.g., piprazinyl, morphonlinyl, piperidinyl, etc.).
  • A is heterocyclic (e.g., non-aromatic, e.g., substituted or unsubstituted, bridged, fused, or monocyclic, morpholinyl, piperidinyl, azetidinyl, piprazinyl, etc. or aromatic, e.g., pyridinyl, pyrimidinyl, pyrrolyl, etc.), aryl e.g., phenyl, naphthyl) or amino (e.g., substituted or unsubstituted, e.g., alkylamino, dialkyl amino, etc.).
  • heterocyclic e.g., non-aromatic, e.g., substituted or unsubstituted, bridged, fused, or monocyclic, morpholinyl, piperidinyl, azetidinyl, piprazinyl, etc. or aromatic, e.g., pyridinyl, pyr
  • cyclic moiety includes heterocyclic and carbocyclic groups, such as substituted or unsubstituted phenyl, heteroaryl, or biaryl moieties.
  • cyclic moieties include those without aromaticity (e.g., cyclohexane, cyclopentane, etc.) and those with aromaticity, e.g. moieties that have at least one aromatic ring.
  • Cyclic moieties may include one or more heteroatoms.
  • Examples include phenyl, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, naphthyl, quinolyl, indolyl, and the like.
  • the cyclic moiety can be substituted at one or more ring positions with such substituents such as, for example, alkyl (e.g., substituted or unsubstituted methyl, ethyl, propyl, butyl), alkenyl (ethenyl, propenyl, butenyl, etc.), alkynyl (e.g., ethynyl, propynyl, etc.), halogen (e.g., chlorine, fluorine, iodine, bromine), hydroxyl, alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, trichloromethoxy, propoxy, butoxy, cyclopropoxy, etc.), aryloxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alky
  • the cyclic moiety ofthe present invention is substituted or unsubstituted phenyl, heteroaryl, or biaryl.
  • the language "cyclic moiety” also includes non-aromatic cyclic moieties, such as, substituted or unsubstituted cyclic alkanes, (e.g., cyclohexane, and cyclopentane), cyclic alkenes (e.g., cyclohexene), and substituted or unsubstituted heterocycles (e.g., thiofuran, pyrimidine, pyrazine, pyrrole, imidazole, quinoxaline, etc.).
  • cyclic moiety comprises not only the heterocyclic or carbocyclic moieties, but also may additionally include moieties which further comprise linking moieties, such as Lj and L 2 which, for example, may link the anchor moiety to the carbocyclic or heterocyclic cyclic portion ofthe cyclic moiety. Furthermore, linking moieties may also link the heterocyclic or carbocyclic cyclic moiety to the MC4-R interacting moiety.
  • cyclic moieties include unsubstituted phenyl, halogenated phenyl (e.g., fluoro, bromo, chloro and iodo phenyl), alkyl substituted phenyl (e.g., methyl, ethyl, propyl, etc.),amino substituted phenyl, heteroaryls (e.g., thiofuran, pyridine, quinoxaline, pyrazine, pyrrole, etc.).
  • halogenated phenyl e.g., fluoro, bromo, chloro and iodo phenyl
  • alkyl substituted phenyl e.g., methyl, ethyl, propyl, etc.
  • amino substituted phenyl e.g., thiofuran, pyridine, quinoxaline, pyrazine, pyrrole, etc.
  • MC4-R interacting moiety (“E") includes moieties which permit the MC4-R binding compound to perform its intended function, e.g., interact with the MC4-R.
  • MC4-R interacting moieties include substituted or unsubstituted alkyl (e.g., substituted with amino, cyano, nitro, hydroxy, etc.), aryl (e.g., phenyl, heteroaryl), amino (e.g., 3-aminopropylamino, dimethyl amino, diethyl amino), amidino, guanidino, carbocyclic and heterocyclic moieties.
  • the language "MC4-R interacting moiety” is not intended to suggest that this moiety is the active pharmacophore ofthe molecule, responsible for the pharmacological, binding or other properties ofthe MC4-R binding compound.
  • the MC4-R interacting moiety is cyclic, e.g., aryl, alkyl, biaryl, polycyclic, heteroaromatic, or heterocyclic.
  • heterocyclic MC4-R interacting moieties include heterocycles which contain nitrogen atoms, such as, substituted and unsubstituted imidazolyl, imidazolinyl, pyridinyl, pyrrolyl, piprazinyl, imidoazopyridinyl, pyrolloimidazolyl, pyrrolyl, azetidinyl, azapanyl, pyrimidinyl, pyridinyl, morpholinyl, diazapanyl, and piperidinyl moieties.
  • the MC4-R interacting moiety may be bicyclic, polycyclic, bridged or a fused ring system. Examples of fused and bridged heterocycles include:
  • the substituent R includes substituted and unsubstituted alkyl (e.g., methyl, ethyl, etc.), arylcarbonyl, alkoxycarbonyl, alkylcarbonyl, arylalkylcarbonyl, and other groups which allow the MC4-R interacting moiety to perform its intended function.
  • the MC4-R interacting moiety can be substituted with substituents such as, but not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, aminoalkyl, and alkylary
  • the MC4-R interacting moiety is not cyclic, e.g., the MC4-R interacting moiety is alkyl, unsubstituted amino, alkylamino, dialkylamino, amidino, guanidino, etc.
  • alkyl MC4-R interacting moieties include straight and branched chain alkyls such as n-butyl, n-pentyl, and n-hexyl.
  • the MC4-R interacting moiety contains one or more nitrogen atoms, e.g., pyridinyl, pyrrolyl, pyrazinyl, imidazolyl, imidazolinyl, quinoxalinyl, or pyrimidinyl.
  • the MC4-R interacting moiety is ofthe formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , CHR 5 , CR 5 R 6 , or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L 2 , R 1 , R 2 , R 3 , R 4 , R 5 . or
  • R 6 to form one or more rings
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each substituted or unsubstituted alkyl, alkenyl, alkynyl, heterocyclic, halogen, thiol, thioether, thioalkyl, hydroxyl, nitro, amino, cyano, or alkoxy, and may optionally be linked to form a carbocyclic or heterocyclic ring.
  • R 3 , R 4 , R 5 , or R 6 may be bridged, fused, or spiro.
  • the MC4-R interacting moiety is represented by the formula
  • the MC4-R interacting moiety may be bicyclic, e.g., biheterocyclic, for example, quinoxalinyl.
  • the language "linked to form a ring” refers to moieties covalently connected through a chain of atoms (e.g., carbon atoms and/or heteroatoms).
  • the chain of atoms can comprise any number of atoms, which allow the MC4-R binding moiety to perform its intended function.
  • the chain of atoms is selected such that a ring with three, four, five, six, seven, or eight members are formed.
  • the ring that can be formed may be spiro (e.g., connected through the same carbon atom), fused (connected through adjacent carbon atoms), or bridged (e.g., connected through carbon atoms which are neither identical nor adjacent).
  • R and t are linked, e.g., to for a bicyclic moiety.
  • bicyclic moieties include, but are not limited to, imidazopyridinyl, pyrolloimidazolyl, cyclopentaimidazolyl, pyridopyrimidinyl, etc.
  • R is H, alkyl, benzocarboxy, alkylcarboxy, or arylalkylcarboxy.
  • s is CR 5 R 6 and R 5 and R 6 are each methyl.
  • r is a covalent bond, and at least one oft and s are CH 2 .
  • t, r, and s are each CH 2 .
  • r is a covalent bond, and t and s are linked through a 4 carbon chain.
  • at least one R group is OH.
  • r is a covalent bond
  • t is CR 3 R 4
  • s is CR 5 R 6
  • R 3 , R 4 , R 5 and R 6 are each independently hydrogen or alkyl (e.g., methyl, ethyl, propyl, or butyl).
  • MC4-R interacting moieties include, but are not limited to, the following structures:
  • the invention pertains to a method for treating an MC4- R associated state in a mammal, by administering an effective amount of a MC4-R binding compound to a mammal, such that the MC4-R associated state is treated.
  • MC4-R binding compounds include compounds comprising the formula (II):
  • B is a anchor moiety; A is a cyclic moiety; and E is a MC4-R interacting moiety, and pharmaceutically acceptable salts thereof.
  • the MC4-R binding compounds of formula (II), may further comprise linking moieties, Li and L 2 .
  • Such MC4-R binding compounds include compounds ofthe formula (III):
  • B is an anchor moiety (as described above), Li and L 2 are linking moieties, A is a cyclic moiety (as described above), and E is a MC4-R interacting moiety.
  • Pharmaceutically acceptable salts ofthe MC4-R binding compound are also included.
  • linking moiety includes moieties which link, preferably covalently, the MC4-R interacting moiety, the cyclic moiety, and the anchor moiety of the invention.
  • linking moieties include covalent bonds, 1-10 atom chains which may be branched or unbranched, substituted or unsubstituted alkyl, heterocyclic, alkenyl, or alkynyl. The chains may be substituted with 0-3 heteroatoms or other moieties which allow the MC4-R binding compound to perform its intended function. Examples of suitable heteroatoms include sulfur, oxygen, nitrogen, and phosphorous.
  • the invention contemplates MC4-R binding compounds which comprises more than two linking moieties.
  • ⁇ is a chain of 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms.
  • Lj is selected from the group consisting of a covalent bond, C ⁇ -C 6 , CrC 5 , C ⁇ -C 4 , C 1 -C 3 , C ⁇ - C 2 , branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with any combination of substituted or unsubstituted oxygen, sulfur or nitrogen atoms.
  • Li is a thioether (e.g., -S-CH 2 -, S- CH(CH 3 )-, -CH 2 -S-CH 2 , -S-, or -S-CH-(C 6 H 5 )-.), an ether (e.g., -O-CH 2 or -CH 2 -O- CH 2 -), a sulfoxide, a sulfone, an amine (e.g., -NH-, -NH-CH 2 -, -NMe-CH 2 -, CH 2 -NH- CH 2 -, etc.) or alkyl (e.g., -CH 2 -CH 2 -, -CH 2 -, or -CH 2 -CH 2 -CH 2 - ).
  • a thioether e.g., -S-CH 2 -, S- CH(CH 3 )-, -CH 2 -S-CH 2 , -S-,
  • Li in another embodiment, comprises a sulfonyl group.
  • Li can be substituted or unsubstituted (e.g., a hydrogen can be replaced by another moiety), such that the MC4-R binding compound is capable of performing its intended function, e.g., bind to or interact with the MC4-R.
  • substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino),
  • examples of L 2 include a covalent bond, a chain of 1-10 atoms (e.g., such as carbon, nitrogen, oxygen, or sulfur atoms), e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms.
  • ⁇ is selected from the group consisting of a covalent bond, CpC , C)-C 5 , C ⁇ -C 4 , C ⁇ -C 3 , Cj-C 2 , branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with any combination of substituted or unsubstituted oxygen, sulfur or nitrogen atoms..
  • L 2 is a covalent bond, -CH 2 - or -NH-.
  • L 2 may also comprise one or more carbonyl groups.
  • L 2 can be substituted with any substituent such that the
  • MC4-R binding compound is capable of performing its intended function.
  • substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkyl (e.g., substituted or unsubstituted, branched straight chain or cyclic, e.g., methyl, ethyl, propyl, butyl, pentyl, etc.), alkenyl, alkynyl, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino
  • the MC4-R binding compound is of formula (III) (e.g., B-L ! -A-L 2 -E), wherein B is substituted or unsubstituted biaryl (e.g., substituted or unsubstituted biphenyl, naphthyl, fluorenyl), unsubstituted or substituted heteroaryl (e.g., thienyl, benzothienyl, furanyl, pyrazinyl, pyrrolyl, pyrrolidinyl, etc.), unsubstituted or substituted phenyl, wherein one or more of said substituents are selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl
  • B is substitute
  • Li is a covalent bond, Ci-Cio branched or unbranched alkyl, wherein one or more ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • A is a substituted or unsubstituted phenyl, heteroaryl (e.g., pyrrolyl, pyrazinyl, thienyl, pyridinyl, etc.), bicyclic (e.g., methylenedioxyphenyl, isoindole, indole, and indan )or biaryl (e.g., naphthyl, quinoxalinyl, purinyl, etc.) wherein said substituent is selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, iso
  • Li is selected from the group consisting of a covalent bond, C ⁇ -C 6 , C ⁇ -C 5 , C 1 -C 4 , C 1 -C 3 , Ci- C 2 , branched or unbranched alkyl, wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms, substituted or unsubstituted amino (e.g., -NH-, -NH-CH 2 ), ether, thioether, or alkyl (e.g., C1-C10, -CH 2 -, -CH 2 -CH 2 -, or -CH 2 -CH 2 -CH 2 -, etc.);
  • E is unsubstituted amino, unsubstituted and substituted alkylamino (e.g., 3- aminopropylamino), dialkylamino (e.g., dimethyl amino, diethyl amino), amidino, guanidino, heterocyclic (e.g., substituted and unsubstituted imidazolyl, imidazolinyl, piprazinyl, morpholinyl, piperidinyl, imidoazopyridinyl, pyrolloimidazolyl, pyridinyl, or pyrimidinyl) moieties, aryl (e.g., phenyl, heteroaromatic, e.g., substituted and unsubstituted pyrazinyl, imidazolyl, quinoxalinyl, or pyrimidinyl), wherein said substituents include, but are not limited to, amino (e.g., unsubstituted amino, alkylamin
  • the invention pertains to a method for treating an MC4-
  • the compound is ofthe formula (IV):
  • A is a substituted or unsubstituted phenyl, heteroaryl (e.g., pyrrolyl, pyrazinyl, pyridinyl, etc.), or biaryl (e.g., naphthyl, quinoxalinyl, purinyl, etc.) wherein said substituent is selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n- butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy
  • B is substituted or unsubstituted biaryl (e.g., substituted or unsubstituted biphenyl, naphthyl, fluorenyl), unsubstituted or substituted heteroaryl (e.g., thienyl, benzothienyl, furanyl, pyrazinyl, pyrrolyl, pyrrolidinyl, etc.), unsubstituted or substituted phenyl, wherein one or more of said substituents are selected from the group consisting of halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy,
  • Li and L 2 are selected from the group consisting of a covalent bond, C C 4 branched or unbranched, substituted or unsubstituted alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms; r is a covalent bond, CH, CH 2 , CHR 1 , CR ⁇ 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CHR 5 , CR 5 R ⁇ or absent (e.g., leaving a non-cyclic diamine); R is H, substituted or unsubstituted alkyl, arylalkyl, or heteroalkyl, and may optionally be linked to A, B, Li, or L ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each substituted or unsubstituted alkyl, halogen, thiol, thioether, thioalkyl, alkoxy, and may be optionally linked to each other to form additional ring moieties, e.g., quinoxalinyl.
  • Pharmaceutically acceptable salts of the MC4-R binding compounds are also included.
  • A is substituted or unsubstituted phenyl. Examples of substituents include halogens (e.g., fluorine, chlorine, iodine, bromine), alkoxy, alkyl (e.g., methyl, trifluoromethyl), and amino moieties.
  • A is heteroaromatic, (e.g., thienyl), or biaryl, (e.g., napthyl or quinoxalinyl).
  • biaryl e.g., napthyl or quinoxalinyl.
  • B is substituted or unsubstituted biaryl, unsubstituted or substituted heterocyclic, or unsubstituted or substituted phenyl, wherein one or more of said substituents are halogens, alkyl, alkynyl, alkoxy, aryl, amino, thiol, thioether, thioalkyl, cyano, or nitro;
  • L ⁇ is a covalent bond, C ⁇ -C 10 branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
  • E is substituted or unsubstituted alkyl, amino, amidino, guanidino, heterocyclic, or aryl, wherein said substituents are amino, arylalkyl, aminoalkyl, alkyl, aryl, alkenyl, or alkynyl;
  • ⁇ is a covalent bond, a carbon atom, a nitrogen atom, heterocyclic, alkyl, carbocyclic, or aryl;
  • L 3 is a covalent bond, C ⁇ -C 6 branched, unbranched or cyclic alkyl (wherein one, two or three ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms), carbonyl, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, or an aminothiocarbonyl moiety;
  • A is substituted or unsubstituted heterocyclic, aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, or hydrogen; and ⁇ is 0, 1 or 2, and pharmaceutically acceptable salts thereof.
  • MC4-R binding compounds with this structure include, but are not limited to, compounds, wherein ⁇ is a carbon atom, L 3 is aminocarbonyloxy, A is substituted aryl, ⁇ is one, Li and L 2 are each CH 2 , and B and E are each pipridinyl.
  • substituents for A include but are not limited to, alkoxy (e.g., Ci-Cio alkoxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy), cyano, halogens (e.g., fluorine, chlorine, bromine, iodine), alkyl (e.g., straight or branched chain, etc.), aryl, alkenyl, alkynyl, nitro, amino, or any other substituents which enables the MC4-R binding compound to perform its intended function, e.g., treat an MC4-R associated state.
  • alkoxy e.g., Ci-Cio alkoxy, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy
  • compounds of formula (V) include, but are not limited to, compounds wherein ⁇ , L and L 3 together are a single covalent bond, E is alkyl, and B is substituted or unsubstituted heterocyclic.
  • ⁇ is a nitrogen atom
  • L 2 , Li and L 3 are each alkyl
  • E is substituted amino (e.g., alkyl substituted), or heterocyclic (e.g., piprazinyl, piperidinyl, morpholinyl, etc.)
  • B and A are each aryl (e.g., phenyl, anthracenyl, biaryl, e.g., naphthyl).
  • the invention pertains to yet another method for treating an MC4-R associated state in a mammal by administering to a mammal an effective amount of a
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are optionally substituted carbon or nitrogen;
  • L 1 is a covalent bond, Cj-C branched or unbranched alkyl, wherein one or two ofthe carbons are optionally replaced with oxygen, sulfur or nitrogen atoms;
  • L 2 is a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl;
  • J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group, and pharmaceutically acceptable salts thereof.
  • substituents of P 1 , P , P 3 , P 4 , Z 1 , Z , Z , Z 4 , and Z 5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n- propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substitute
  • P 1 , P 2 , P 3 , and P 4 are each substituted or unsubstituted carbon (e.g., CH).
  • P 1 and P 3 may be CH.
  • P 2 and P 4 are each CH, CF, CCl, CBr, CI, C-aryl, C-alkyl (e.g., C-Me, C-ethyl, C-propyl, etc.) C-alkoxy (e.g., C-OMe, C-O-ethyl, C-OCF 3, etc.).
  • P 2 is CH and P 4 is CCl or CF.
  • P 1 is a covalent bond
  • P 2 and P 3 are each optionally substituted carbon
  • P 4 is S (e.g., thienyl).
  • Z 3 and Z 4 are each CH.
  • Z 1 is CH, or covalently linked to Z 2 to form a naphthyl ring.
  • Z 2 include CH, C-(C ⁇ CH), CCl, CBr, CI, and CF.
  • Z 2 may be substituted with a chain of atoms which covalently links it to Z 1 to form a naphthyl ring.
  • Z 5 examples include, but are not limited to, CH and C-alkoxy.
  • C- alkoxy includes carbon atoms covalently bound to an alkoxy group, as described below.
  • alkoxy groups include methoxy, ethoxy, propoxy, butoxy, etc.
  • L 2 is a covalent bond.
  • J examples include, but are not limited to, substituted or unsubstituted piprazinyl, imidoazopyridinyl, pyrolloimidazolyl, pyrrolyl, azetidinyl, azapanyl, diazapanyl, pyrimidinyl, pyridinyl, mo ⁇ holinyl, or piperidinyl. Furthermore, J may be a substituted or unsubstituted fused ring or bridged heterocycle.
  • each of P 1 , P 2 , P 3 , and P 4 are each optionally substituted carbon; Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each also optionally substituted carbon (e.g., alkoxy substituted, halogen substituted or linked to form a ring); wherein Li is either -S-CH -, or CH 2 -CH 2 .
  • L 2 is a covalent bond and J is a moiety of formula XIII, as described above.
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, ⁇ , or substituted carbon
  • P 1 , P 2 , P 3 , P 4 , and P 5 are CH, ⁇ or substituted carbon.
  • substituents of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , P 1 , P 2 , P 3 , P 4 , and P 5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsub
  • P 1 , P 2 , P 3 , P 4 and P 5 are each substituted or unsubstituted carbon (e.g., CH).
  • P and P may be CH.
  • P 2 and P 4 are each CH, CF, CCl, CBr, or CI.
  • P 1 , P 2 , P 3 , and P 4 can be linked covalently to form a bicyclic ring.
  • Z 3 and Z 4 are each CH.
  • Z is CH, or covalently linked to Z to form a naphthyl ring.
  • Z 2 include CH, C-(C ⁇ CH), CCl, CBr, CI, and CF.
  • Z may be substituted with a chain of atoms which covalently links it to Z to form a naphthyl ring.
  • P 5 is C-L 2 -J, wherein C is a carbon atom, L 2 is a linking moiety, e.g., a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group.
  • L is a covalent bond and J is a moiety of formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , alkenyl, CHR 5 , CR 5 R 6 , or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • compounds of formula VII also include compounds
  • J is wherein R is alkyl (e.g., methyl, ethyl, propyl, butyl, etc.) or hydrogen.
  • the compounds include those in which P 1 , P 2 , and P 3 are each CH, and P 4 is CCl.
  • the compounds also include those wherein Z 1 , Z 3 , and Z 4 are each CH, Z 5 is COMe, and Z 2 is CBr, as well as those wherein Z 1 is covalently linked to Z 2 to form a naphthyl ring, and Z 3 , Z 4 and Z 5 are each CH.
  • the MC4-R binding compound is of formula (VIII):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; and P 1 , P 2 , P 3 , P 4 , and P 5 are CH, N or substituted carbon.
  • substituents of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , P 1 , P 2 , P 3 , P 4 , and P 5 include halogens (e.g., bromine, fluorine, chlorine, iodine, etc.), alkyl groups (e.g., branched, straight chain or cyclic, substituted or unsubstituted, methyl, ethyl, propyl, butyl, etc.), alkoxy groups (e.g., substituted or unsubstituted alkoxy, e.g., methoxy, ethoxy, isopropoxy, n-propoxy, isobutoxy, n-butoxy, pentoxy, cyclopentoxy, methylenedioxy, ethylenedioxy, etc.), aryl groups (e.g., substituted or unsubstituted phenyl, heterocyclic groups), alkenyl, alkynyl, hydroxyl, alky
  • P 1 , P 2 , P 3 , and P 4 are each substituted or unsubstituted carbon (e.g., CH).
  • P and P may be CH.
  • P 2 and P 4 are each CH, CF, CCl, CBr, or CI.
  • P 1 , P 2 , P 3 , and P 4 can be linked covalently to form a bicyclic ring.
  • Z 3 and Z 4 are each CH.
  • Z 1 is CH, or covalently linked to Z 2 to form a naphthyl ring. Examples of Z 2 include CH, C-(C ⁇ CH), CCl, CBr, CI, and CF. 1
  • Z may be substituted with a chain of atoms which covalently links it to Z to form a naphthyl ring.
  • P 5 is C-L 2 -J, wherein C is a carbon atom, L 2 is a linking moiety, e.g., a covalent bond, substituted or unsubstituted amino, ether, thioether, or alkyl; and J is an unsubstituted or substituted nitrogen containing heterocycle or a substituted or unsubstituted amino group.
  • L 2 is a covalent bond and J is a moiety of formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , alkenyl, CHR 5 , CR 5 R 6 , or absent; R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to A, B, Li, L 2 , R 1 , R 2 , R 3 , R 4 , R 5 j or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, aryl, hydroxyl, nitro, amino, cyano, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention pertains to MC4-R binding compounds of formulae VII and VIII.
  • Examples of MC4-R binding compound of these formulae include, for example, compounds wherein P 5 is a carbon covalently bonded to a moiety of formula XIII.
  • the moiety of formula XIII is not benzoimidazole.
  • Z 3 is not ethoxy.
  • the invention pertains to both methods of using and MC4-R binding compounds of formula (IX):
  • I P 2 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, CI, or a covalent bond;
  • P 3 is CH, CF, CCl, CBr, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI
  • P 4 is CH, CCl, CBr, CF, C-alkyl, C-aryl, C-alkoxy, C-CN, C-OH, or CI
  • G 1 and G 2 are each independently CH 2 , S, or O
  • r is a covalent bond or CH 2
  • t is CH 2 , CHR 3 , or CR 3 R 4
  • s is CH 2 , CHR 5 or CR 5 R 6
  • R is hydrogen alkyl, alkoxycarbonyl, or alkylcarbonyl;
  • Z is CH, or covalently linked to Z to form a naphthyl ring
  • Z 2 is CH, C-(C ⁇ CH), CCl, CBr, CI, CF, or covalently linked to Z 1 to form a naphthyl ring;
  • Z 5 is CH, C-alkoxy (e.g., C-OMe);
  • R 3 , R 4 , R 5 , and R 6 are methyl, ethyl, hydroxyl, alkoxy, halogen, cyano, nitro, amino, or pharmaceutically acceptable salts thereof.
  • the language "linked to form a naphthyl ring” includes moieties which join Z 1 and Z 2 to form a naphthyl (fused) ring system.
  • Z 1 is CH; Z 2 is CBr; and Z 5 is C-OMe.
  • P 2 is CH.
  • P 4 is CCl or CF.
  • G' and G 2 are each CH 2 .
  • G 1 and G 2 together are -CH 2 -CH 2 -, -CH 2 -O-, -O-CH 2 -, -CH 2 -
  • r is a covalent bond
  • s is CR 5 R 6
  • t is CR 3 R 4
  • R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or alkyl (e.g., methyl, ethyl, propyl, or butyl).
  • R is hydrogen or alkyl (e.g., methyl, ethyl, propyl or butyl, etc.)
  • Z , Z , Z , Z , and Z are CH, ⁇ , or substituted carbon
  • P ⁇ P 2 , P 3 , and P 4 are CH, ⁇ or substituted carbon
  • P 5 is C-L 2 -J, wherein L 2 is a covalent bond, alkyl (e.g., C 1 -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention also relates to the invention.
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; P 1 , P 2 , P 3 , and P 4 are CH, N or substituted carbon; and P 5 is C-L 2 -J, wherein L 2 is a covalent bond, alkyl (e.g., C ⁇ -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR'R 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , CHR 5 , CR 5 R 6 , or absent;
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 ; or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioalkyl, thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention also relates to the invention.
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; P 1 , P 2 , P 3 , and P 4 are CH, N or substituted carbon; and
  • P 5 is C-L 2 -J, wherein L 2 is a covalent bond, alkyl (e.g., C 1 -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • r is a covalent bond, CH, CH 2 , CHR 1 , CR ⁇ 2 , or H; t is CH, CH 2 , CHR 3 , CR 3 R 4 , or H; s is CH, CH 2 , CHR 5 , CR 5 R 6 , or absent;
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioalkyl, thioether, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl, optionally linked to form a ring with R, R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 .
  • the invention also pertains to MC4-R binding compound ofthe formula (XVI):
  • Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are CH, N, or substituted carbon; P 1 , P 2 , P 3 , and P 4 are CH, N or substituted carbon; and P 5 is C-L2-J, wherein L 2 is a covalent bond, alkyl (e.g., C 1 -C 3 ), amino, ether, carbonyl, etc., and wherein J is a moiety ofthe formula (XIII):
  • R is hydrogen, alkyl, alkenyl, arylalkyl, arylcarbonyl, alkoxycarbonyl, arylalkylcarbonyl, alkylcarbonyl, optionally linked to R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 to form one or more rings; and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each halogen, thiol, thioether, thioalkyl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, hydroxyl, nitro, amino, cyano, aryl
  • the invention includes compounds wherein P 1 , P 2 , P 3 , and P 4 of any one of formulas VII, VIII, XV, or XVI are each substituted or unsubstituted carbon.
  • P 1 is CH.
  • at least one of P 2 , P 3 and P 4 is a substituted carbon.
  • P 2 , P 3 and P 4 are selected from the group consisting of CH, CF, Cl, CBr, C-alkyl, C-alkoxy, or CI.
  • the compounds of formulae VII, VIII, XV, or XVI include compounds wherein Z 3 and Z 4 are each CH.
  • Z 1 is CH.
  • Z 1 is covalently linked to Z 2 to form a naphthyl ring.
  • Z 2 is CH, C-(C ⁇ CH), CCl, CBr, CI, and CF.
  • the compounds ofthe invention include compounds of formulae VII, VIII, XV, or XVI, wherein L 2 is a covalent bond. Also included are compounds wherein R is H, alkyl, benzocarboxy, alkylcarboxy, or arylalkylcarboxy.
  • the compounds ofthe invention include compounds of formulae VII, VIII, XV, or XVI, wherein s is CR 5 R 6 and R 5 and R 6 are each methyl.
  • r is a covalent bond.
  • each of t, r and s may be CH 2 .
  • the MC4-R binding compounds of the invention of formula VII do not include benzoimadazole as the moiety of formula XIII, when P , P , P 3 , P 4 , Z 1 , Z 2 , Z 4 , Z 3 , and Z 5 are each CH.
  • the compounds ofthe invention do not include compounds wherein the moiety of formula XIII is tetrahydropyrimidine, when P 1 , P 2 , P 3 , P 4 , Z 1 , Z 2 , Z 4 , and Z 5 are each CH and Z 3 is C-OEt or CH.
  • the MC4-R binding compounds ofthe invention of formula VIII do not include compounds wherein the moiety of formula XIII is benzoimidazolyl. In another further embodiment, the MC4-R binding compounds ofthe
  • the compounds of formula VIII ofthe invention do not include compounds wherein the moiety of formula is 4,5-dihydro-lH-imidazole, when P 1 , P 2 , P 3 , and P 4 are each CH, and wherein one or two of Z 1 , Z 2 , or Z 3 is CCl, and the remaining Z groups are CH.
  • the MC4-R binding compounds of formula VIII ofthe invention do not include compounds wherein the moiety of formula XIII is tetrahydropyrimidine, and when P 1 , P 2 , P 3 , and P 4 are each CH, and Z 2 is CCl and the remaining Z groups are CH.
  • the compounds of formula VIII ofthe invention do not include compounds wherein when the moiety of formula XIII is tetrahydropyrimidine, and when P 1 , P 2 , P 3 , and P 4 are each CH, and Z 1 and one of Z 4 or Z 5 are CCl and the remaining Z groups are CH.
  • the MC4-R binding compounds ofthe invention do not include compounds of formula XV, wherein the moiety of formula VIII is not benzoimidazole if P 1 , P 2 , P 3 , P 4 are each CH, and wherein Z 2 is CMe and the remaining Z groups are CH.
  • the MC4-R binding compounds ofthe invention do not include compounds of formula XVI, wherein the moiety of formula XVI, wherein L 2 is not NH (e.g., amino), if P 1 , P 2 , P 3 , P 4 , Z 1 , Z 2 , Z 4 , Z 3 , and Z 5 are each CH.
  • the MC4-R binding compounds of formula XVI ofthe invention do not include compounds wherein P groups are substituted to form a naphthyl ring.
  • the invention features a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal.
  • Compounds of formula (X) are also included in the invention. In this embodiment, the compound is ofthe formula (X):
  • Ar and Ar' are aromatic groups
  • R 11 is selected independently for each position capable of substitution from the group hydrogen, cyano, nitro, alkoxy, halogen, alkyl, amino, or aryloxy.
  • R 12 is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
  • R 13 is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl (e.g., C J -C I Q alkyl, e.g., methyl, ethyl, etc.) acyl, carbonyl, or SO 2 CH 3 , and may optionally be linked to an R 16 or an R 16' group;
  • R 16 and R 16 are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, carbonyl, or acyl, and may optionally be connected through an alkyl chain to R 13 or another R 16 or R 16 group, to form a fused or spiro ring system;
  • X is NR 17 , S, O or a covalent bond
  • R 17 is hydrogen, alkyl, alkenyl, alkynyl, acyl, heterocyclic, or carbonyl;
  • R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroaromatic, halogen, nitro, cyano, amino, or aryl, for each occurrence; w is O, 1, 2, 3, or 4; e is O, 1, 2, or 3; f is 0, 1, 2, or 3, and pharmaceutically acceptable salts thereof.
  • Ar groups examples include:
  • R is acyl, alkyl or hydrogen.
  • Ar is, ,
  • R 1 1 is selected independently for each aromatic position capable of substitution.
  • exemplary R 11 groups include, but are not limited to, hydrogen, halogen (e.g., fluorine, chlorine, or bromine), alkyl, amino, and benzyloxy.
  • halogen e.g., fluorine, chlorine, or bromine
  • alkyl e.g., benzyloxy
  • Ar' groups include:
  • R 19 is hydrogen, alkyl, acyl, aryl, alkenyl, or alkynyl.
  • each R group is selected independently from the group consisting of hydrogen, alkoxy, halogen (e.g., fluorine, bromine, chlorine, or iodine), and cyano.
  • alkoxy groups include C ⁇ -C ⁇ 0 alkoxy, such as, methoxy, ethoxy, n-propoxy, i-propoxy, and cyclopentoxy.
  • Examples of X include covalent bond, S, O and NR .
  • Examples of R include hydrogen, alkyl (e.g., Ci-Cio alkyl, e.g., methyl), or acyl.
  • R 16 and R 16 include alkyl and hydrogen. Each R 16 and R 16 group is selected independently for each occurrence. In a further embodiment, at least one of R 16 or R 16 are at least once hydrogen. In another embodiment, at least one of R 16 or R 16' are at least once C ⁇ -C ⁇ 0 alkyl, e.g., methyl or ethyl.
  • R 14 and R 15 are each independently hydrogen, alkyl (e.g., Ci-Cio, e.g., methyl) or phenyl for each occurrence.
  • R is hydrogen, acyl, alkyl (e.g., Ci-Cio alkyl, e.g., methyl, ethyl, etc.) acyl, carboxy, or SO 2 CH 3 .
  • acyl group include, but are not limited to, optionally substituted C ⁇ -C ⁇ oalkyl acyl (e.g., i- propylcarbonyl and benzylcarbonyl).
  • w is 2 or 3. In yet another further embodiment, e is 0 or 1. In yet another further embodiment, f is 0 or 1.
  • the invention features a method for treating an MC4-R associated state in a mammal by administering an effective amount of a MC4-R binding compound to a mammal.
  • the compound is ofthe formula (XI): wherein
  • Ar and Ar' are aromatic groups, as described above; R 1 ' is selected independently for each position capable of substitution from the group hydrogen, halogen, alkyl, amino, cyano, or aryloxy.
  • R is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
  • X is NR 17 , S, O or a covalent bond
  • R 17 is hydrogen, alkyl, acyl, heterocyclic, or carbonyl
  • R 14 and R 15 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, or aryl, for each occurrence;
  • R 20 and R 21 are each independently selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, hydrogen, or carbonyl, and may optionally be linked to form a heterocycle (e.g., mo ⁇ honlinyl, piperazinyl, piperidinyl, etc.); v is 0, 1, 2, 3, 4, 5, or 6; e is O, 1, 2, or 3; f is 0, 1, 2, or 3, and pharmaceutically acceptable salts thereof.
  • Examples of Ar, Ar', R 1 ', R 12 , R 14 , R 15 and X moieties include those described for formula (X).
  • MC4-R binding compounds include compounds ofthe formula (XVII
  • Ar and Ar' are aromatic groups
  • R 1 ' is selected independently for each position capable of substitution from the group hydrogen, cyano, alkoxy, nitro, halogen, alkyl, amino, or aryloxy;
  • R 12 is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl;
  • R is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl, acyl, carbonyl, or SO 2 CH 3 , and may optionally be linked to an R or an R group;
  • R 16 and R 16 are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, cyano, aryl, heterocyclic, carbonyl, or acyl, and may optionally be connected through an alkyl chain to R 13 or another R 16 or R 16 group, to form a fused or spiro ring system;
  • X is NR 17 , S, O or a covalent bond;
  • R 17 is hydrogen, alkyl, or carbonyl;
  • R 14 and R 15 are each independently hydrogen, halogen, or alkyl; w is 1, 2, 3, or 4; e is 0 or 1 ; f is 0 or 1, wherein both e and fare not both 0 if X is a covalent bond, and pharmaceutically acceptable salts thereof.
  • Ar, Ar', R 11 , R 12 , R 14 , R 15 , R 16 and R 16' and X moieties include those described for formula (X).
  • the invention also pertains to the following compounds:
  • the invention also pertains to methods of using these compounds in methods for treating MC4-R associated states in a mammal by administering an effective amount of the compound to a mammal, such that the MC4-R associated state is treated, as well as pharmaceutical compositions comprising these compounds.
  • MC4-R binding compounds include compounds ofthe formulae:
  • the invention also includes MC4-R binding compounds such as:
  • 1-carboxylic acid tert-butyl ester l-(2- ⁇ 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-phenyl ⁇ -4,5-dihydro- imidazol- 1 -yl)-2,2-dimethyl-propan- 1 -one; l-(5-Bromo-2-methoxy-benzyl)-2,3-dihydro-lH-isoindole; 1 -(2-Methoxy-benzyl)-2-methyl-2,3-dihydro- 1 H-isoindole;
  • the methods ofthe invention do not include methods wherein 2-[2-(2,5-dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound A); 2[2-(2-chloro- 6-fluoro-benzylsulfanyl)-phenyl]- 1, 4, 5, 6-tetrahydropyrimidine (Compound B); l-(6-bromo-2-chloro-quinolin-4-yl)-3-
  • the compounds claimed as MC4-R binding compounds do not include those listed above.
  • the methods ofthe invention do not include methods wherein 2-naphthalen- 1 -ylmethyl-4,5-dihydro- 1 H-imidazole (NAPHAZOLINE; Compound AS); 10-[2-(l-methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl-10H- phenothiazine (THORADIAZINE; THIODIAZINE; Compound AP); (2,6-dichloro- phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; Compound AY); or 2-benzyl-4,5- dihydro-1 H-imidazole (TOLAZOLINE; Compound AZ) are used as MC4-R binding compounds.
  • the invention pertain to compounds other than those listed above as MC4-R binding compounds.
  • the methods ofthe invention do not include 5-(4- chloro-phenyl)-2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol (MASPINDOL; Compound DT) as an MC4-R binding compound.
  • MASPINDOL 5-(4- chloro-phenyl)-2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol
  • the compounds ofthe invention include MC4-R binding compounds other than MASPINDOL.
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., Ci-Cio for straight chain, C 3 -C 10 for branched chain), and more preferably 6 or fewer.
  • preferred cycloalkyls have from 4-7 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids. Examples of halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromefhyl, dichloromethyl, trichloromethyl, perfluoromethyl, perchloromethyl, perfluoroethyl, perchloroethyl, etc.
  • aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, imidazoline, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, isoindole, indan or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamin
  • alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, de
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C5 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both "unsubstituted alkenyls" and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C5 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons ofthe hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • acyl includes compounds and moieties which contain the acyl radical
  • substituted acyl includes acyl groups where one or more ofthe hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons ofthe hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups and may include cyclic groups such as cyclopentoxy. Examples of substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom such as alkyl aminos, alkenyl aminos, dialkyl aminos, aryl aminos, acyl aminos, etc.
  • alkyl amino includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group and is included in the term "amino.”
  • dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups and is included in the term “amino.”
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively, and are included in the term “amino.”
  • alkylarylamino alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group and is included in the term “amino.”
  • amide or "aminocarboxy” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof.
  • moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • carboxy moiety refers to groups such as “alkylcarbonyl” groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl” groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl” groups wherein an alkynyl group is covalently bound to a carbonyl group, “arylcarbonyl” groups wherein an aryl group is covalently attached to the carbonyl group.
  • the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety.
  • the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon ofthe carbonyl group, e.g., an amide), aminocarbonyloxy moieties, wherein an oxygen and a nitrogen atom are both bond to the carbon ofthe carbonyl group (e.g., also referred to as a "carbamate").
  • aminocarbonylamino groups e.g., ureas
  • heteroatoms e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms.
  • heteroatom can be further substituted with one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.
  • thiocarbonyl or “thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • thiocarbonyl moiety includes moieties which are analogous to carbonyl moieties.
  • thiocarbonyl moieties include aminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include, oxythiocarbonyls (oxygen bound to the carbon atom), aminothiocarbonylamino groups, etc.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • thiol includes groups with an -SH group. In certain embodiments, it may also include thioethers, thioalkyls, thioaryls, thiocarbonyl s, as described above.
  • hydroxy or “hydroxyl” includes groups with an -OH or -O " .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • polycyclyl or “polycyclic radical” include moieties with two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each ofthe rings ofthe polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • heterocycle or “heterocyclic” includes saturated, unsaturated, aromatic (“heteroaryls” or “heteroaromatic”) and polycyclic rings which contain one or more heteroatoms.
  • heterocycles include, for example, benzodioxazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, benzoxazole, deazapurine, furan, indole, indolizine, imidazole, isooxazole, isoquinoline, isothiaozole, methylenedioxyphenyl, napthridine, oxazole, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, tetrazole, thiazole, thiophene, and triazole.
  • heterocycles include mo ⁇ holine, piprazine, piperidine, thiomo ⁇ holine, and thioazolidine.
  • the heterocycles may be substituted or unsubstituted.
  • substituents include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylary
  • the structure of some ofthe compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • the compound is an antagonist ofthe MC4-R. In another embodiment, the compound is an agonist ofthe MC4-R. Compounds which are agonists of MC4-R can be identified using the cAMP assay given in Example 5. The term "administering" includes routes of administration which allow the
  • MC4-R binding compound to perform its intended function, e.g. interacting with MC4- Rs and/or treating a MC4-R associated state.
  • routes of administration which can be used include parental injection (e.g., subcutaneous, intravenous, and intramuscular), intraperitoneal injection, oral, inhalation, and transdermal.
  • the injection can be bolus injections or can be continuous infusion.
  • the MC4-R binding compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function.
  • the MC4-R binding compound can be administered alone or wfth a pharmaceutically acceptable carrier.
  • the MC4-R binding compound can be administered as a mixture of MC4-R binding compounds, which also can be coadministered with a pharmaceutically acceptable carrier.
  • the MC4-R binding compound can be administered prior to the onset of a MC4-R associated state, or after the onset of a MC4-R associated state.
  • the MC4-R binding compound also can be administered as a prodrug which is converted to another form in vivo.
  • the invention includes methods of treating an MC4-R associated state by administering the MC4-R binding compound ofthe invention in combination with art recognized compounds, e.g., therapeutic agents.
  • a patient suffering from cachexia resulting from HIV may be treated using both the MC4-R binding compounds ofthe invention in combination with art recognized compounds for treating the cachexia or HIV itself.
  • the term "combination with” includes both simultaneous administration as well as administration ofthe MC4-R binding compound before the art recognized compound or after the compound.
  • the period between administrations ofthe MC4-R binding compound and the other agent may be any length of time which allows the compositions to perform their intended function, e.g., the interval may be between few minutes, an hour, more than one hour, etc.
  • the MC4-R binding compounds may also be administered in combination with other MC4-R binding compounds ofthe invention.
  • the invention also features a pharmaceutical composition for the treatment of a MC4-R associated state in a mammal.
  • the pharmaceutical composition includes a pharmaceutically acceptable carrier and an effective amount of an MC4-R binding compound ofthe formula (I):
  • compositions ofthe invention include MC4-R binding compounds of formulae II, III, IV, V, VI, VII, VIII, IX, X, and/or XI.
  • Pharmaceutical compositions comprising pharmaceutically acceptable salts of at least one MC4-R binding compound are also included.
  • the language "effective amount" ofthe compound is that amount necessary or sufficient to treat or prevent a MC4-R associated state, e.g. prevent the various mo ⁇ hological and somatic symptoms of a MC4-R associated state.
  • the effective amount can vary depending on such factors as the size and weight ofthe subject, the type of illness, or the particular MC4-R binding compound. For example, the choice of the MC4-R binding compound can affect what constitutes an "effective amount".
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount ofthe MC4-R binding compound without undue experimentation.
  • An in vivo assay as described in Example 4 below or an assay similar thereto (e.g., differing in choice of cell line or type of illness) also can be used to determine an "effective amount" of a MC4-R binding compound.
  • the ordinarily skilled artisan would select an appropriate amount of a MC4-R binding compound for use in the aforementioned in vivo assay.
  • the effective amount is effective to treat a disorder associated with pigmentation, bones (e.g., osteoporosis, osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, bone formation, bone remodeling, bone healing, or the depletion of calcium in bone, such as that which is related to primary hype ⁇ arathyroidism) or weight loss, e.g., weight loss is a result of anorexia nervosa, old age, cancer cachexia, or HIV cachexia.
  • bones e.g., osteoporosis, osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, bone formation, bone remodeling, bone healing, or the depletion of calcium in bone, such as that which is related to primary hype ⁇ arathyroidism
  • weight loss e.g., weight loss is a result of anorexia
  • the regimen of administration can affect what constitutes an effective amount.
  • the MC4-R binding compound can be administered to the subject either prior to or after the onset of a MC4-R associated state. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages ofthe MC4-R binding compound(s) can be proportionally increased or decreased as indicated by the exigencies ofthe therapeutic or prophylactic situation.
  • treatment includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
  • treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • pharmaceutical composition includes preparations suitable for administration to mammals, e.g., humans. When the compounds ofthe present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • phrases "pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds ofthe present invention to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion ofthe body, to another organ, or portion ofthe body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients ofthe formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • Formulations ofthe present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount ofthe compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound ofthe present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound ofthe present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations ofthe invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound ofthe present invention as an active ingredient.
  • a compound ofthe present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; abso ⁇ tion accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms ofthe pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical -formulating art. They may also be formulated so as to provide slow or controlled release ofthe active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more ofthe above-described excipients.
  • Liquid dosage forms for oral administration ofthe compounds ofthe invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and e
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • Formulations ofthe pharmaceutical compositions ofthe invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds ofthe invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations ofthe present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound ofthe present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Abso ⁇ tion enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds ofthe invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood ofthe intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged abso ⁇ tion ofthe injectable pharmaceutical form may be brought about by the inclusion of agents which delay abso ⁇ tion such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as
  • the abso ⁇ tion ofthe drug in order to prolong the effect of a drug, it is desirable to slow the abso ⁇ tion ofthe drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amo ⁇ hous material having poor water solubility. The rate of abso ⁇ tion ofthe drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed abso ⁇ tion of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly (anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the preparations ofthe present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • any suitable route of administration including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • Actual dosage levels ofthe active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity ofthe particular compound ofthe present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion ofthe particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history ofthe patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount ofthe pharmaceutical composition required.
  • the physician or veterinarian could start doses ofthe compounds ofthe invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound ofthe invention will be that amount ofthe compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses ofthe compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is that amount treats an MC4-R associated state. If desired, the effective daily dose ofthe active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • certain embodiments ofthe present compounds can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts is art recognized and includes relatively non-toxic, inorganic and organic acid addition salts of compounds ofthe present invention. These salts can be prepared in situ during the final isolation and purification ofthe compounds ofthe invention, or by separately reacting a purified compound ofthe invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • the compounds ofthe present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts in these instances includes relatively non-toxic, inorganic and organic base addition salts of compounds ofthe present invention. These salts can likewise be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • esters refers to the relatively non-toxic, esterified products ofthe compounds ofthe present invention. These esters can be prepared in situ during the final isolation and purification ofthe compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
  • Carboxylic acids can be converted into esters via treatment with an alcohol in the presence of a catalyst.
  • Hydroxyls can be converted into esters via treatment with an esterifying agent such as alkanoyl halides.
  • the term also includes lower hydrocarbon groups capable of being solvated under physiological conditions, e.g., alkyl esters, methyl, ethyl and propyl esters.
  • a preferred ester group is an acetomethoxy ester group.
  • the amount ofthe MC4-R binding compound is effective to treat a pigmentation or weight loss disorder, e.g., weight loss associated with anorexia nervosa, old age, cachexia, HIV or cancer.
  • the invention also pertains to packaged MC4-R binding compounds.
  • the packaged MC4-R binding compounds include, an MC4-R binding compound (e.g., of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, and/or XI), a container, and directions for using said MC4-R binding compound to treat an MC4-R associated state, e.g., weight loss, etc.
  • an MC4-R binding compound e.g., of formulae I, II, III, IV, V, VI, VII, VIII, IX, X, and/or XI
  • a container e.g., directions for using said MC4-R binding compound to treat an MC4-R associated state, e.g., weight loss, etc.
  • Naphthalene-2-sulfonic acid (2-dimethylamino-ethyl)-naphthalen- 1 -ylmethyl-amide; l-[2-(5-Bromo-2-methoxy-benzylsulfanyl)-3-chloro-benzyl]-2-methoxymethyl- pyrrolidine;
  • the pharmaceutical compositions ofthe invention include compositions wherein the MC4-R binding compound is not 5-(4-chloro-phenyl)- 2,5-dihydro-3H-imidazo[2,l-a]-isoindol-5-ol (MASPINDOL; Compound DT).
  • compositions ofthe invention include compositions wherein the MC4-R binding compound is not 2-naphthalen-l- ylmethyl-4,5-dihydro-l H-imidazole (NAPHAZOLINE; Compound AS); 10-[2-(l- methyl-piperadin-2-yl)-ethyl]-2-methylsulfanyl- 1 OH-phenothiazine (THORADIAZINE; THIODIAZINE; Compound AP); (2,6-dichloro-phenyl)-imidazolidin-2-ylidene-amine (CLONIDINE; Compound AY); or 2-benzyl-4,5-dihydro-l H-imidazole (TOLAZOLINE; Compound AZ).
  • NAPHAZOLINE 2-naphthalen-l- ylmethyl-4,5-dihydro-l H-imidazole
  • THORADIAZINE THIODIAZINE
  • CLONIDINE (2,6-dichloro-pheny
  • the pharmaceutical compositions ofthe invention includes compositions wherein the MC4-R binding compound is not 2-[2-(2,5- dichlorothiophen-3-ylmethylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound A); 2[2-(2-chloro- 6-fluoro-benzylsulfanyl)-phenyl]-l, 4, 5, 6- tetrahydropyrimidine (Compound B); l-(6-bromo-2-chloro-quinolin-4-yl)-3-(2- diethylaminoethyl)-urea (Compound AN); 2-[2-(2,6-difluorobenzylsulfanyl)-phenyl]- 1 , 4, 5, 6-tetrahydropyrimidine (Compound AO); l-(4-hydroxy-l, 3, 5-trimethyl-piperadin- 4-yl)-ethanone (Compound AR); 4,6-di
  • the compounds ofthe present invention can be synthesized using standard methods of chemical synthesis and/or can be synthesized using schemes described herein. Synthesis of specific compounds is discussed in detail in the Example sections below. Examples of syntheses of several classes of compounds ofthe invention are outlined in the schemes below. Scheme 1 depicts a method of synthesizing thiomethylene compound ofthe invention.
  • 2-hydroxy or 2-mercapto benzoic acid is heated with the diamine in refluxing 1 ,2-dichlorobenzene to form the corresponding heterocyclic compound.
  • the desired thioether or ether is formed by treating the thiol or alcohol with a corresponding halogenated compound.
  • Scheme 2 depicts a general preparation of ethanyl-linked compounds ofthe invention.
  • Scheme 2 shows a method of synthesizing ethanyl linked compounds by treating ⁇ -tolunitrile with a lithium base in THF at -78 °C. A halogenated alkylaryl compound is then added to form the ethanyl linkage. To form the heterocycle, hydrogen sulfide gas is bubbled through a solution ofthe nitrile and 1,3 diaminopropane. After formation, the product can then be obtained and purified using standard techniques.
  • Scheme 3 depicts a method of preparing methylenethio linked compounds ofthe invention.
  • the methylenethio compounds ofthe invention can be prepared by adding anhydrous K 2 CO 3 to a thiophenol compound (Ar-SH) in DMF. The solution is then stirred and bromomethyl-benzonitrile is subsequently added. The thioether is then converted to the heterocyclic compound by bubbling hydrogen sulfide through a solution ofthe thioether and 1,3 diaminopropane. After formation, the product can then be obtained and purified using standard techniques.
  • cyclic amidines ofthe invention can be prepared by reacting 2-substituted benzonitrile with hydrogen sulfide to form a thiobenzamide.
  • the resulting thiobenzamide is then treated with iodoethane to give a thiobenzimidic acid ethyl ester.
  • the thiobenzimidic acid ethyl ester is suspended in tetrahydrofuran and treated with hydrogen sulfide.
  • the resulting dithiobenzoic acid ethyl ester is then heated with various diamines, in the presence or absence of an added catalyst such as silver trifluoroacetate, to give cyclic amidines.
  • the reaction was capped and heated to 40 °C for 12 hours.
  • the mixture was subsequently diluted with 5 mL of water and extracted with ethyl acetate (2x1 OmL).
  • the organic extracts were washed with water (3xl0mL), brine (2xl0mL), and dried (Na 2 SO 4 ).
  • the solvent was evaporated and the product was purified on silica gel (eluting with 9:1 of hexane/ethyl acetate) to afford 102 mg ofthe product as a colorless oil.
  • the reaction was heated to 45 °C and stirred overnight in a sealed tube.
  • the reaction mixture was diluted with water and extracted with methylene chloride once.
  • the organic layer was washed with brine, dried (MgSO 4 ), filtered and evaporated to give a crude orange oil.
  • the oil was partially purified by chromatography through a short column of silica gel (eluting with 5:95 ethyl acetate/hexanes) which resulted in 1.8 g of an orange powder which was used directly in the next step.
  • MC4-R cells were stable recombinant K293 cells overexpressing the MC4-R.
  • the cells were routinely cultured and passaged in a growth medium composed of DMEM base medium: 10% fetal bovine serum (FBS), IX Glutamine, and 0.5 mg/ml G418.
  • Terminal cultures i.e., those which will be processed to produce plasma membranes
  • the media contained 0.2 mg/ml G418.
  • harvested cells were pelleted and immediately washed with 25 mL of PBS.
  • the washed cells were resuspended in two volumes of STM buffer (0.25 M sucrose, 5 mM Tris, 1 mM MgCl 2 , pH 7.5), containing Boehringer CompleteTM protease inhibitors.
  • Cell breakage was accomplished using a Dounce homogenizer. After 20-30 strokes, nuclei and unbroken cells were pelleted by centrifugation at 1100 rpm for 5 minutes. The supernatant was saved and the pellet was resuspended in 1 volume of STM/protease inhibitors, and then a further lysis step was carried out by the Dounce homogenizer (10-20 strokes).
  • the membrane suspension obtained from the sucrose interface was collected and diluted with 5 mM Tris and 1 mM MgC - Membranes were collected by a further round of centrifugation at 33,000 rpm for 30 minutes (SW-41 Ti rotor).
  • the pellet of membranes was subsequently resuspended in a small (0.5 mL) volume of STM, using a 2 mL Dounce homogenizer, and immediately frozen.
  • the resulting membranes were stable to both freeze-thaw cycles and temperatures around 4°C for at least 6 hours.
  • SPA scincillation proximity assay
  • the membranes from the MC4-R mammalian cells were bound to wheat germ agglutinin (WGA) coated SPA beads.
  • WGA wheat germ agglutinin
  • the membrane coated SPA beads were added to screening plates, which contained the test compounds pre-dissolved in 30 ⁇ L of 10% DMSO. After pre-equilibration ofthe receptor coated beads with the test compounds (1 hour), 2nM of radioactive ligand ([ rl25 I]NDP- ⁇ -MSH) was added. Since the binding ofthe radioactive ligand to the receptor causes the scincillation ofthe beads, blockage ofthe binding ofthe radioactive ligand by a small molecule causes a reduction in scincillation.
  • the membranes were mixed with the SPA beads to make a 2X stock of membrane and beads.
  • the following assay was performed with automation using a Titertec MultiDrop with plate stacker.
  • Binding was initiated by adding 20 ⁇ L of radioactive ligand (a 20 nM solution of [ 125 I]-NDP- ⁇ -MSH) to each test well. The plates were incubated overnight at room temperature and read the following morning.
  • radioactive ligand a 20 nM solution of [ 125 I]-NDP- ⁇ -MSH
  • Results from the SPA are summarized in Table 4.
  • Table 4 * indicates good inhibition ofthe MC4-R, ** indicates very good inhibition ofthe MC4-R, and *** indicates exemplary inhibition ofthe MC4-R.
  • the present invention pertains to the compounds and methods described herein provided that the compound is not selected from the group consisting of those depicted in Table 5.
  • Method MC4 Receptors are expressed in stably transfected K293 cells.
  • the cells are incubated in DMEM base medium (10% FBS, IX glutamine, and 0.4 mg/ml G418) at 37°C, in an atmosphere of 6.0% CO 2 and 90% relative humidity. Two days before the experiment, the cells are trypsinized and 200 ⁇ l ofthe cell suspension (138,000 cells/ml) is deposited into 96-well Costar cell culture plates.
  • test compounds are then dissolved in DMSO creating a 30mM stock solution, which is subsequently diluted to 180, 650, 20, 6.6, 2.2 ⁇ M in OPTI-MEM (GIBCO-BRL) media with 50 ⁇ M IBMX (isobutylmethylxanthine, Sigma) minutes before the experiment.
  • OPTI-MEM GENERAL-BRL
  • IBMX isobutylmethylxanthine, Sigma
  • the media is then thoroughly removed from the cell culture plates through a 12-channel straight manifold.
  • 90 ⁇ l of OPTI-MEM media with 50 ⁇ M IBMX is added to each well (McHale et al. FEBS Letters 345 (1994) 147-150).
  • the plate is then placed in an incubator set at 37 °C, 6.0% CO and 90% relative humidity. After 15 minutes of incubation, 90 ⁇ l ofthe test compound solutions (or a control solution of OPTI-MEM and IBMX) are added and the plates are incubated for another 10 minutes. 20 ⁇ l ofthe ligand MSH solution in OPTI-MEM is then added. The cell plates are incubated for an additional hour at 37 °C.
  • the media mixture is removed by 12-channel straight manifold. 60 ⁇ l of 70% ethanol is added to each well. The plates are then placed on a shaker for 30 minutes to extract the cAMP. The amount of cAMP is
  • mice Male lean C57BL/6J mice were individually housed in macrolon cages
  • Figure 2 shows that administration of 15 nmol of Compound N partially reverses the effect ofthe administration ofthe MC4-R agonist, MT II.
  • Figure 3 shows that administration of Compound O did not significantly effect the food intake of mice treated with MT II.
  • the cAMP assay identifies compounds which have agonist activity against MC receptors. It is used to identify the selectivity of agonist which selectively antagonize receptors of interest. The following method is outlined for MC4-R, but corresponding procedures were used for the other MC receptors, MC1-R, MC3-R, and MC5-R.

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Abstract

L'invention se rapporte à des composés de liaison au récepteur de la mélanocortine-4 (MC4-R) qui sont représentés par la formule: B-Z-E (I) dans laquelle B est une fraction d'ancrage, Z est une fraction centrale et E est une fraction interagissant avec le récepteur MC4-R. L'invention se rapporte également à des procédés d'utilisation de ces composés pour traiter des troubles associés au récepteur MC4-R tels que des troubles associés à une perte de poids.
EP02718920A 2001-02-07 2002-02-07 Composes de liaison au recepteur de la melanocortine-4 et procedes d'utilisation de tels composes Withdrawn EP1363890A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US778468 2001-02-07
US09/778,468 US6699873B1 (en) 1999-08-04 2001-02-07 Melanocortin-4 receptor binding compounds and methods of use thereof
PCT/US2002/003566 WO2002062766A2 (fr) 2001-02-07 2002-02-07 Composes de liaison au recepteur de la melanocortine-4 et procedes d'utilisation de tels composes

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