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WO2003068738A1 - Derives de pyrrole utilises en tant que ligands de recepteurs de melanocortine - Google Patents

Derives de pyrrole utilises en tant que ligands de recepteurs de melanocortine Download PDF

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Publication number
WO2003068738A1
WO2003068738A1 PCT/US2003/004455 US0304455W WO03068738A1 WO 2003068738 A1 WO2003068738 A1 WO 2003068738A1 US 0304455 W US0304455 W US 0304455W WO 03068738 A1 WO03068738 A1 WO 03068738A1
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substituted
heterocycle
alkyl
compound
carbocycle
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PCT/US2003/004455
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English (en)
Inventor
Brian P. Dyck
Val Goodfellow
Jessica Parker
Teresa Phillips
Warren Wade
Joe Anh Tran
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Neurocrine Biosciences, Inc.
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Priority to AU2003216274A priority Critical patent/AU2003216274A1/en
Publication of WO2003068738A1 publication Critical patent/WO2003068738A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention is generally directed to ligands of a melanocortin receptor, specifically pyrrole-based ligands, and to compositions and methods for using such ligands to alter activity of a melanocortin receptor.
  • MC receptors are members of the family of G-protein coupled receptors. To date, five distinct MC receptors ⁇ i.e., MC1-R, MC2-R, MC3-R,
  • MC4-R and MC5-R have been identified in a variety of tissues and these receptors have been shown to mediate a number of physiological processes.
  • Ligands including peptides and small molecules, have been shown to act as agonists or antagonists at these receptors.
  • MC receptors The role of specific MC receptors in physiological processes has been the object of intense study since their discovery and cloning. These receptors are expressed in a variety of tissues including melanocytes, adrenal cortex, brain, gut, placenta, skeletal muscle, lung, spleen, thymus, bone marrow, pituitary, gonads and adipose tissue. A putative role of MC receptors has been shown in melanocytes, stimulatory actions on learning, attention and memory, motor effects, modification of sexual behavior, facilitation of nerve regeneration, anti-inflammatory and antipyretic effects, and the regulation of food intake and body weight.
  • the pro-opiomelanocortin (POMC) gene product is processed to produce a number of biologically active peptides that are expressed in the pituitary, and two locations in the brain: the arcuate nucleus of the hypothalamus and the solitary tract nucleus of the brain stem. These peptides elicit a range of biological activities.
  • MC4-R melanocortin receptors that respond to POMC peptides (reviewed in Rec. Prog. Hor. Res. 51, 287-318, 1996). Each receptor in this family is pharmacologically distinct in its particular response to the POMC peptides ⁇ -MSH, ⁇ -MSH and ACTH and to two peptide antagonists.
  • MC4-R has the highest affinity for ⁇ -MSH.
  • MC4-R differs from the other MC receptors in that it binds both natural melanocortin antagonists, agouti (Nature 371, 799-802, 1994) and ⁇ g ⁇ wtz-related protein (AgRP) ⁇ Biochem.
  • MCl-R is expressed primarily in melanocytes, while MC2-R is expressed in adrenocortical cells.
  • MC3-R is expressed in brain, placenta and gut, and MC4-R is expressed primarily in the brain where its mRNA can be detected in nuclei that bind ⁇ -MSH.
  • MC4-R is notably absent from adrenal cortex, melanocyte and placental tissues. Both MC3-R and MC4-R are expressed in arcuate and paraventricular neurons.
  • MC5-R is expressed in brain, adipose tissues, muscle and exocrine glands.
  • ⁇ -Melanocyte stimulating hormone is a tridecapeptide whose principal action ⁇ i.e., the activation of a set of G-protein coupled melanocortin receptors), results in a range of physiological responses including pigmentation, sebum production and feeding behavior.
  • Cyclized peptide derivatives of ⁇ -MSH are potent modulators of these receptors.
  • peptides exhibiting MCR-4 antagonist activity increase food intake and body weight.
  • agouti- related peptide AgRP
  • AgRP agouti- related peptide
  • MC4-R antagonists of the MC4-R would selectively enhance the feeding response.
  • MC4-R antagonists have a unique clinical potential because such compounds would stimulate appetite as well as decrease metabolic rate.
  • chronic MC4-R blockade causes an increase in lean body mass as well as fat mass, and the increase in lean body mass is independent of the increase in fat mass.
  • Orally active forms of a small molecule MC4-R antagonist would provide a novel therapeutic strategy for indications in which cachexia is a symptom.
  • the MC receptors are also key mediators of steroid production in response to stress (MC2-R), regulation of weight homeostasis (MC4-R), and regulation of hair and skin pigmentation (MCl-R). They may have additional applications in controlling both insulin regulation (MC4-R) and regulation of exocrine gland function (MC5-R) ⁇ Cell 91, 789-798, 1997); the latter having potential applications in the treatment of disorders such as acne, dry eye syndrome and blepharitis. Melanocortin peptides have also been reported to have anti-inflammatory activity, although the receptor(s) involved in mediating these effects have not yet been determined.
  • Endocrine disorders such as Gushing 's disease and congenital adrenal hyperplasia, which are characterized by elevated levels of ACTH, could be effectively treated with ACTH receptor (MC2-R) antagonists.
  • M2-R ACTH receptor
  • Some evidence suggests that depression, which is characterized by elevated levels of glucocorticoids, may also be responsive to these same compounds.
  • elevated glucocorticoids can be an etiological factor in obesity.
  • Synthetic melanocortin receptor agonists have been shown to initiate erections in men (J. Urol. 160, 389-393, 1998).
  • An appropriate MC receptor agonist could be an effective treatment for certain sexual disorders.
  • MCl-R provides an ideal target for developing drugs that alter skin pigmentation.
  • MCl-R expression is localized to melanocytes where it regulates eumelanin pigment synthesis, hi fact, two small clinical trials indicate that broad-spectrum melanocortin agonists induce pigmentation with limited side effects.
  • the desired compound would have a short half-life and be topically applied.
  • Applications include skin cancer prevention, UV-free tanning, inhibition of tanning and treatment of pigmentation disorders, such as tyrosinase-positive albinism.
  • U.S. Patent No. 6,054,556 is directed to a family of cyclic heptapeptides which act as antagonists for MCI, MC3, MC4 and MC5 receptors;
  • U.S. Patent No. 6,127,381 is directed to isoquinoline compounds which act upon MC receptors for controlling cytokine-regulated physiologic processes and pathologies;
  • published PCT Application No. WO 00/74679 is directed to substituted piperidine compounds which act as selective agonists of MC4-R.
  • this invention is directed to compounds which function as melanocortin (MC) receptor ligands.
  • ligand means a molecule that binds or forms a complex with one or more of the MC receptors.
  • This invention is also directed to compositions containing one or more MC receptor ligands in combination with one or more pharmaceutically acceptable carriers, as well as to methods for treating conditions or disorders associated with MC receptors.
  • this invention is directed to MC receptor ligands that may be characterized as "substituted pyrroles” and having the following structure (I):
  • the MC receptor ligands of this invention have utility over a broad range of therapeutic applications, and may be used to treat disorders or illnesses, including (but not limited to) eating disorders, cachexia, obesity, inflammation, pain, skin disorders, skin and hair coloration, sexual disfunction, dry eye, acne and/or Cushing's disease.
  • a representative method of treating such a disorder or illness includes administering an effective amount of a ligand of this invention, preferably in the form of a pharmaceutical composition, to an animal (also referred to herein as a "patient", including a human) in need thereof.
  • the ligand may be an antagonist or agonist or may stimulate a specific melanocortin receptor while functionally blocking a different melanocortin receptor.
  • pharmaceutical compositions are disclosed containing one or more ligands of this invention in combination with a pharmaceutically acceptable carrier.
  • the present invention is generally directed to compounds having the following structure (I):
  • A is a direct bond or -N(R 8 )-; n is 3, 4, 5 or 6;
  • R 3a and R 3b are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl or -COOR] 4 ; or any one of R 3a and the carbon to which it is attached taken together with any one of R 3D and the carbon atom to which it is attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring; or any one of R 3a and the carbon to which it is attached taken together with Ri and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring;
  • R 4 is carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
  • R 8 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle or substituted heterocycle; or R 8 and R 3a on the carbon atom adjacent the nitrogen atom bearing R 8 , taken together form a direct bond;
  • R 9 and R 10 are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
  • R ⁇ , R 12 and R 13 are the same or different and, at each occurrence, independently hydrogen, halogen, cyano, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and R 14 is hydrogen, alkyl or substituted alkyl.
  • Alkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term
  • lower alkyl has the same meaning as alkyl but contains from 1 to 6 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
  • Cyclic alkyls are also referred to herein as a “homocycles” or “homocyclic rings.”
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or
  • alkynyl Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-
  • Carbocycle (also referred to herein as “carbocyclic ring”) means a 3- to 7- membered monocyclic, or a 7- to 10-membered bicyclic, homocyclic ring which is saturated, unsaturated or aromatic. Saturated and unsaturated carbocyclic rings are as defined above for saturated and unsaturated cyclic alkyls. Aromatic carbocyclic rings are as defined below for aryl.
  • Carbocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a carbocycle moiety, such as -CH 2 cyclohexane, benzyl, and the like.
  • Aryl means an aromatic carbocyclic moiety such as phenyl or naphthyl.
  • Arylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, -(CH 2 ) 2 ⁇ henyl, -(CH 2 ) 3 phenyl, -CH(phenyl) 2 , and the like.
  • Heteroaryl means an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
  • heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, oxadiazolyl and quinazolinyl.
  • Heteroarylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH 2 pyridinyl, -CH 2 pyrimidinyl, and the like.
  • Heterocycle (also referred to herein as a “heterocyclic ring”) means a 4- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is saturated, unsaturated, or aromatic, and which contains at least 1 carbon atom and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • Heterocycles include heteroaryls as defined herein.
  • heterocycles also include morpholinyl, pyrrohdinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • Heterocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle moiety, such as -CH 2 morpholinyl, and the like.
  • substituted means any of the above groups ⁇ i.e., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocycle, carbocyclealkyl, heterocycle and heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent.
  • Halogen means fluoro, chloro, bromo and iodo.
  • Haloalkyl means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.
  • Alkoxy means an alkyl moiety attached through an oxygen bridge (i.e., -O-alkyl) such as methoxy, ethoxy, and the like.
  • Thioalkyl means an alkyl moiety attached through a sulfur bridge (i.e., -S-(alkyl)) such as methylthio, ethylthio, and the like.
  • Alkylsulfonyl means an alkyl moiety attached through a sulfonyl bridge
  • -S0 2 -(alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylamino and dialkylamino mean one or two alkyl moiety attached through a nitrogen bridge ⁇ i.e., -N-(alkyl)) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
  • Hydroalkyl means an alkyl substituted with at least one hydroxyl group.
  • “Mono- or di(cycloalkyl)methyl” represents a methyl group substituted with one or two cycloalkyl groups, such as cyclopropylmethyl, dicyclopropylmethyl, and the like.
  • Alkyloxyalkyl represents an alkyl substituted with a -O-(alkyl) group.
  • Alkylthioalkyl represents a alkyl substituted with a -S-(alkyl) group.
  • “Mono- or di(alkyl)amino represents an amino substituted with one alkyl or with two alkyls, respectively.
  • “Mono- or di(alkyl)aminoalkyl” represents an alkyl substituted with a mono- or di(alkyl)amino.
  • Alkylamino and dialkylamino mean one or two alkyl moiety attached through a nitrogen bridge ⁇ i.e., -N-(alky ⁇ )) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
  • A is a direct bond
  • the compounds of this invention have the following structure (II):
  • Ri, R 2 , R 3a , R 3b , t , R 5 , R 6 , R and n are as defined above.
  • A is -N(R 8 )-, and the compounds of this invention have the following structure (III):
  • Ri , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 and n are as defined above.
  • n 3 and the compounds of this invention have the following structure (V):
  • any one of the R 3a moieties, such as those depicted in structure (V), taken together with Ri form a heterocycle or substituted heterocycle.
  • the compounds of this invention have the following structure (VI):
  • the compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
  • Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
  • Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like).
  • the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms.
  • prodrugs are also included within the context of this invention.
  • Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
  • prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I).
  • esters may be employed, such as methyl esters, ethyl esters, and the like.
  • the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Compounds of structure (I) may also possess axial chirality which may result in atropisomers. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
  • the compounds of this invention may be evaluated for their ability to bind to a MC receptor by techniques known in this field.
  • a compound may be evaluated for MC receptor binding by monitoring the displacement of an iodonated peptide ligand, typically [ 125 I]-NDP- ⁇ -MSH, from cells expressing individual melanocortin receptor subtypes.
  • an iodonated peptide ligand typically [ 125 I]-NDP- ⁇ -MSH
  • cells expressing the desired melanocortin receptor are seeded in 96-well microtiter Primaria-coated plates at a density of 50,000 cells per well and allowed to adhere overnight with incubation at 37°C in 5% CO 2 .
  • test compounds are diluted serially in binding buffer (D-MEM, 1 mg/ml BSA) containing [ 125 I]- NDP- ⁇ -MSH (10 5 cpm/ml). Cold NDP- ⁇ -MSH is included as a control.
  • Cells are incubated with 50 ⁇ l of each test compound concentration for 1 hour at room temperature. Cells are gently washed twice with 250 ⁇ l of cold binding buffer and then lysed by addition of 50 ⁇ l of 0.5 M NaOH for 20 minutes at room temperature. Protein concentration is determined by Bradford assay and lysates are counted by liquid scintillation spectrometry. Each concentration of test compound is assessed in triplicate.
  • ICs 0 values are determined by data analysis using appropriate software, such as GraphPad Prizm, and data are plotted as counts of radiolabeled NDP-MSH bound (normalized to protein concentration) versus the log concentration of test compound.
  • MC receptors based on their coupling to G s proteins.
  • the MC receptors couple to Gs and activate adenylyl cyclase resulting in an increase in cAMP production.
  • Melanocortin receptor activity can be measured in HEK293 cells expressing individual melanocortin receptors by direct measurement of cAMP levels or by a reporter gene whose activation is dependent on intracellular cAMP levels.
  • HEK293 cells expressing the desired MC receptor are seeded into 96-well microtiter Primaria-coated plates at a density of 50,000 cells per well and allowed to adhere overnight with incubation at 37°C in 5% CO 2 .
  • Test compounds are diluted in assay buffer composed of D-MEM medium and 0.1 mM isobutylmethylxanthine and assessed for agonist and/or antagonist activity over a range of concentrations along with a control agonist ⁇ -MSH.
  • medium is removed from each well and replaced with test compounds or ⁇ -MSH for 30 minutes at 37°C.
  • Cells are harvested by addition of an equal volume of 100% cold ethanol and scraped from the well surface.
  • the compounds of this invention function as ligands to one or more MC receptors, and are thereby useful in the treatment of a variety of conditions or diseases associated therewith. In this manner, the ligands function by altering or regulating the activity of an MC receptor, thereby providing a treatment for a condition or disease associated with that receptor.
  • the compounds of this invention have utility over a broad range of therapeutic applications, and may be used to treat disorders or illnesses, including (but not limited to) eating disorders, cachexia, obesity, diabetes, metabolic disorders, inflammation, pain, skin disorders, skin and hair coloration, male and female sexual disfunction, erectile disfunction, dry eye, acne and/or Gushing' s disease.
  • disorders or illnesses including (but not limited to) eating disorders, cachexia, obesity, diabetes, metabolic disorders, inflammation, pain, skin disorders, skin and hair coloration, male and female sexual disfunction, erectile disfunction, dry eye, acne and/or Gushing' s disease.
  • the compounds of the present invention may also be used in combination therapy with agents that modify sexual arousal, penile erections, or libido such as sildenafil, yohimbine, apomorphine or other agents.
  • agents that modify sexual arousal, penile erections, or libido such as sildenafil, yohimbine, apomorphine or other agents.
  • Combination therapy with agents that modify food intake, appetite or metabolism are also included within the scope of this invention.
  • agents include, but are not limited to, other MC receptor ligands, ligands of the leptin, NPY, melanin concentrating hormone, serotonin or B 3 adrenergic receptors.
  • pharmaceutical compositions containing one or more compounds of this invention are disclosed.
  • the compounds of the present invention may be formulated as pharmaceutical compositions.
  • compositions of the present invention comprise a compound of structure (I) and a pharmaceutically acceptable carrier and/or diluent.
  • the compound is present in the composition in an amount which is effective to treat a particular disorder of interest, and preferably with acceptable toxicity to the patient.
  • the pharmaceutical composition may include a compound of this invention in an amount ranging from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
  • the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound of this invention, dispersing and surface active agents, binders, and lubricants.
  • One skilled in this art may further formulate the compound in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
  • the present invention provides a method for treating a condition related to an MC receptor.
  • Such methods include administration of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition.
  • "treat” includes prophylactic administration.
  • Such methods include systemic administration of compound of this invention, preferably in the form of a pharmaceutical composition as discussed above.
  • systemic administration includes oral and parenteral methods of administration.
  • suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
  • the compounds of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions. The following examples are provided for purposes of illustration, not limitation.
  • HP 1100 series equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (electrospray); - HPLC column: YMC ODS AQ, S-5, 5 ⁇ , 2.0 x50 mm cartridge;
  • HPLC gradients 1.5 mL/minute, from 10 % acetonitrile in water to 90 % acetonitrile in water in 2.5 minutes, maintaining 90 % for 1 minute.
  • the diketone 3 was diluted with ethanol (0.5 mL), treated with the appropriate diamine (0.51 mmol) and toluenesulfonic acid monohydrate (13 mg, 0.068 mmol), and heated at 80 °C in a sealed vial for 20 h. A portion of this mixture was concentrated, diluted with dichloromethane (1 mL), washed with aqueous sodium bicarbonate, and concentrated. The residue was purified by preparative HPLC to afford amine 4. The remainder of the reaction mixture was treated with (lH)-pyrazole-l- carboxamidine hydrochloride (80 mg, 0.55 mmol) and triethylamine (0.5 mL) and heated at 80 °C for 25 min. Another portion of the carboxamidine (80 mg) was added and heating was continued for 25 min. Workup and purification as described above for 4 afforded the guanidine 5.
  • the substituted acetophenone 12 (0.17 mol), paraformaldehyde (23 g, 0.77 mol), and N-methylanilinium trifluoroacetate (TAMA, 51 g, 0.23 mol) were combined in dioxane (210 mL) and the mixture was heated at 90 °C for 20 h. Additional paraformaldehyde (17 g, 0.55 mol) and TAMA (26 g, 0.12 mol) were added and heating was continued for 6 h. The mixture was cooled to room temperature, concentrated under vacuum, taken up in ethyl acetate (200 mL), washed with water and aqueous sodium chloride, and dried (MgSO 4 ). The solution was then concentrated and the residue purified by chromatography to afford the enone 13.
  • TAMA N-methylanilinium trifluoroacetate
  • the aldehyde 28 (.071 mmol) was dissolved in 500 uL of acetonitrile, and the respective amines (0.142 mmol) were added to the solution. The mixtures were stirred for 10 minutes and sodium triacetoxyborohydride (0.142 mmol, 2.0 eq) was added. The reaction mixtures were stirred overnight at ambient temperature in capped vials. The mixtures were then diluted in 1 mL dichloromethane and were washed with 1 mL 10% aqueous sodium bicarbonate. The organic layer was concentrated under a stream of nitrogen, and the residual compound was then diluted in methanol, filtered, and purified via HPLC/MS to afford the desired aminoalkylpyrroles 29.
  • Pyrrole 23 was prepared according to the procedure provided in example 18.
  • Pyrrole 25 was prepared from 23 according to the same procedure as in the above conversion of 15 to 24.
  • the selected N-Boc protected amino acid (0.217 mmol, 1.0 eq) was dissolved in dichloromethane (500 uL). Diisopropylethylamine (0.435 mmol, 2.0 eq) and HBTU (0.228 mmol, 1.05 eq) were added, and the mixture stirred for 30 min. The amine 30 (0.217 mmol, 1.0 eq) was dissolved in the minimum amount of dichloromethane and was added to the mixture. The solution stirred at ambient temperature overnight in a capped vial.
  • the resulting secondary amine 35 (2.7 mmol, 1.5 eq) was dissolved in 10 mL methylene chloride.
  • Di-tert-butyl dicarbonate (1.8 mmol, 1.0 eq) was dissolved in a minimum amount of methylene chloride and was added to the reaction mixture. The reaction stirred under nitrogen at ambient temperature for 3 hours. The mixture was concentrated in vacuo to afford 36.
  • the aldehyde 37 (0.05 mmol, 1.0 eq) was dissolved in 500 uL acetonitrile, and the respective amine (O.lOmmol, 2.0eq) was added to the solution. The mixture stirred for 10 minutes and sodium triacetoxyborohydride (0.10 mmol, 2.0 eq) was added. The reaction mixture stirred 15 hours at ambient temperature in a capped vial. The mixture was then diluted in 1 mL methylene chloride and washed with 1 mL 10% sodium bicarbonate. The organic layer was concentrated under a stream of nitrogen to afford the desired oil.
  • the compound was dissolved in 1 mL methylene chloride and 1 mL trifluoroacetic acid and stirred for 30 minutes, then concentrated under a stream of nitrogen. The compound was then diluted in methanol, filtered, and purified via HPLC/MS to produce diamine 38.
  • the diamine 38 (0.198 mmol, 1.0 eq) was dissolved in 1 mL ethanol and was cooled to 0 °C.
  • Cyanogen bromide (0.219 mmol, 2.0 eq) was dissolved in the minimum amount of ethanol and added slowly to the reaction solution under nitrogen. The reaction mixture was warmed over one half hour to 85 °C and then stirred for 2 hours.
  • the resulting secondary amine 40 (0.333 mmol, 1.0 eq) was dissolved in 500 uL DMF.
  • Dusopropylethylamine (0.667 mmol, 2.0 eq) was added to the solution.
  • 1H- pyrazole-1-carboxamidine-HCl (0.667 mmol, 2.0 eq) was added to the mixture, and the reaction stirred 15 hours in a capped vial at 50 °C.
  • the mixture was diluted with 3 mL methylene chloride and washed with 10% sodium bicarbonate.
  • the organic layer was concentrated in vacuo and the resulting oil was diluted with acetonitrile, filtered and purified via HPLC/MS to yield the substituted guanidine 41.
  • the piperidine 42 (1.31 mmol, 1.0 eq) was dissolved in 6 mL methylene chloride. To this solution, triethylamine (2.63 mmol, 2.0 eq) and dimethylaminopyridine (1.31 mmol, 1.0 eq) were added. Cyanogen bromide (1.98mmol, 1.5eq) was dissolved in a minimum amount of methylene chloride and added to the above mixture at 0 °C. The reaction was allowed to warm to room temperature and then was stirred for 15 hours under nitrogen atmosphere. The compound was concentrated in vacuo and purified via silica gel chromatography (1:1 hexanes: ethyl acetate) to afford the cyanamide 43 .
  • Cyanamide 43 (0.108 mmol, 1.0 eq) was dissolved in 500 uL dry toluene.
  • the appropriate amine (0.108 mmol, 3.0 eq) and p-toluenesulfonic acid (0.108 mmol, 1.0 eq) were added to the solution and the reaction was stirred at 85 °C in a capped vial for three days.
  • the reaction mixture was concentrated under a stream of nitrogen, dissolved in acetonitrile, filtered and purified via HPLC/MS to yield substituted guanidine 44.
  • Cyanamide 63 (0.128 mmole) was dissolved in toluene (500 uL) and 2.5 mmoles of the appropriate amine was added. The reaction was stirred at 50 °C for 72 hours. The reaction mixture was then concentrated in vacuo and purified by preparative
  • Amine 46 (0.120 mmol, 1.0 eq) was dissolved in 1 mL DMF to which sodium hydride (0.598 mmol, 5.0 eq) was added. The reaction stirred for 5 min. and the appropriate N-(n-bromoalkyl)-phthalimide (0.180 mmol, 1.5 eq) was added. The reaction stirred overnight in a capped vial at ambient temperature. Another portion of both sodium hydride (5.0 eq) and bromoalkyl phthalimide (1.5 eq) was added and the reaction stirred for an additional 48 hours. The reaction was then diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under nitrogen.
  • the alkylated product (0.08 mmol) was dissolved in 1 mL ethanol, and 6 drops hydrazine was added. The mixture stirred at 80 °C for 15 hours. The reaction was then diluted with methylene chloride, washed with 10% sodium bicarbonate solution, brine, and then was dried over anhydrous sodium sulfate.
  • the methyl picolinimidate (0.132 mmol, 1.2 eq) was dissolved in 250 uL methanol, to which the amine 42 (0.103 mmol, 1.0 eq) was then added. The reaction was stirred overnight in a capped vial at ambient temperature. Another 1.2 eq of methyl picolinimidate was added and the reaction was stirred for 2 hours at 50 °C. The mixture was diluted with methylene chloride, washed with 10% sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated under nitrogen. The resulting oil was diluted in methanol, filtered and purified via HPLC/MS to yield amidine 48.
  • Weinreb amides 53 were formed by dissolving the appropriate carboxylic acid in CH 2 C1 2 (-25 mL/g) and treating with three equivalents of DIEA followed by the addition of HBTU (1.0 eq). After 10 minutes N,O-dimethylhydroxylamine hydrochloride (1 eq) was added and the reaction stirred overnight at room temperature. The reaction mixture was diluted with CH 2 C1 2 and washed with saturated NaHCO 3 solution. The bicarbonate layers were extracted with CH 2 C1 2 ; all organic layers were collected, dried over anhydrous Na 2 SO and concentrated in vacuo to provide 53.
  • Weinreb amides 53 were dissolved in dry THF (40 mL/g) and cooled to -78 °C.
  • (l,3-Dioxan-2-ylethyl)magnesium bromide 1.3 eq of a 0.5 M solution in THF
  • the reaction stirred at -78 °C for two hours, and was then quenched by the addition of water, followed by extraction with ethyl acetate.
  • the organic layer was dried over anhydrous Na SO 4 and concentrated in vacuo to provide ketones 54.
  • Ketones 54 were suspended in 80 % acetic acid/ H 2 O ( ⁇ 3 mL/g) and were heated in a sealed tube with stirring at 100 °C for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with H 2 O and saturated NaHC0 3 , then the organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to provide keto- aldehydes 55.
  • the crude keto-aldehydes 55 were dissolved in EtOH (30 mL/g ) in a sealed tube with the appropriate amine (1.3 eq) and p-toluene sulfonic acid (0.2 eq). The reaction was heated for 15 hours at 80 °C. Evaporation of solvent, extractive work-up, and purification by LC-MS provided the desired 2-aryl substituted pyrroles 56.
  • the benzyl protected pyrrole 63 was dissolved in dry THF (10 mL/g) and was cooled to -78 °C. n-Butyllithium (1.3 eq) was added dropwise and the reaction mixture was stirred at -78 °C for 60 minutes. Quenching with water and extractive work- up followed by preparative HPLC-MS chromatography provided the desired N-benzyl, 2- aryl-5 benzyl pyrrole 64.
  • Aminopyrrole 65 (0.082 mmol), the appropriate ketone (0.080 mmol), and toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) were dissolved in toluene and heated at reflux for 16 h.
  • the material was concentrated under a stream of nitrogen, taken up in dichloromethane (1 mL), and washed with aqueous sodium bicarbonate.
  • the organic layer was concentrated and the residue was taken up in acetonitrile, treated with TFA (0.020 mL, 0.026 mmol) and sodium borohydride (25 mg, 0.67 mmol), and stirred for 3 h.
  • Compound 70 Aldehyde 70 was prepared from 14 using the same procedure as in the conversion of 14 to 17.
  • Pyrrole 74 was prepared from the appropriate substituted hydrazine using the same procedure as in the conversion of 14 to 15.
  • 3-Phenoxyphenyl bromide 78 (16.2 g, 64.8 mmol) was added to a clean flame-dried roundbottom flask along with 65 mL of dry tetrahydrofuran.
  • magnesium 1.7 g, 71.3 mmol
  • 25 mL of dry tetrahydrofuran were added.
  • the phenoxyphenyl bromide-THF solution (prepared above) was added drop wise at room temperature.
  • the reaction was heated to reflux and continued stirring under N 2 atmosphere for 4 hours.
  • the reaction was monitored by quenching a small aliquot of the grignard and analyzed by GC-MS. After the reaction was completed, the grignard reagent 79 was stored under N atmosphere at room temperature for later use.
  • D-Pyroglutamic acid ethyl ester (12 g, 76.4 mmol) was dissolved in 150 mL of dichloromethane along with triethylamine (12.64 mL) and 4-(dimethylamino)pyridine (9.3 g, 76.4 mmol).
  • di-t-butyl dicarbonate (33.3 g, 152.7 mmol) was added in several portions and the reaction was allowed to stir at room temperature under N 2 atmosphere for 10 hours.
  • 2-Bromothiazole (90.1 uL, 1 mmol) was added to a clean flame-dried reaction vial along with 1 mL of dry tetrahydrofuran.
  • the reaction mixture was allowed to cool to -78°C and n-butyllithium (1.6M in hexanes, 812.5 uL, 1.3 mmol) was added.
  • the reaction was allowed to stir under N 2 atmosphere for 10 minutes then warmed to 0°C.
  • a solution of compound 85 (260 mg, 0.5 mmol) in 1 mL of tetrahydrofuran was added dropwise at 0°C. After the addition, the reaction was stirred at 0°C for 15 minutes, warmed to room temperature, and stirred for an additional 30 minutes.
  • the reaction was then quenched with a small amount of trifluoroacetic acid and evaporated to dryness.
  • the crude oil was dissolved in 2 mL of dichloromethane followed by 2 mL of trifluoroacetic acid. The reaction was allowed to stir at room temperature for 15 minutes then solvent and excess trifluoroacetic acid were removed by evaporation under vacuum.
  • the crude pyrrole piperidine was dissolved in 4 mL of dichloromethane, washed with 3 x 5 mL of saturated NaHCO 3 solution, 5 mL of saturated NaCl solution, and dried over anhydrous Na 2 SO . The organic layer was filtered and solvent removed in vacuo. The residue was divided into two equal portions.
  • the first portion was dissolved in 1 mL of methanol, filtered, and purified using preparative HPLC to yield compound 86.
  • the second portion was dissolved in 1.2 mL of 1:1 ethanol/triethylamine along with lH-pyrazole-1-carboxamidine hydrochloride (64 mg, 0.44 mmol) and stirred at 80°C for 30 minutes. After 30 minutes, a second portion of lH-pyrazole-1-carboxamidine hydrochloride (64 mg, 0.44 mmol) was added and stirring was continued at 80°C for an additional 30 minutes. The solvent was then evaporated under a stream of nitrogen and the residue was dissolved in 4 mL of dichloromethane.
  • compound 88 was prepared according to the procedures provided above.
  • Compound 88 (0.12 g, 0.27 mmol) was dissolved in 0.55 mL of dichloromethane and diispropylethylamine (94 uL, 0.54 mmol).
  • the reaction mixture was cooled to 0°C and cyanogen bromide (28.6 mg, 0.27 mmol) was added in one portion.
  • the reaction was allowed to stir at 0°C for 1 hour then room temperature for 1 hour.
  • Compound 89 a brown oil, was isolated in quantitative yield (0.13g).
  • EXAMPLE 29 The representative compounds listed in the following Table were made according the above procedures.
  • the column titled “Ex” indicates the synthesis route by the corresponding Example number.
  • “Ex. 2” means that the compounds were made according to the procedure of Example 2 above.

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Abstract

L'invention concerne des composés fonctionnant en tant que ligands de récepteurs de mélanocortine et présentant une utilité dans le traitement de troubles associés aux récepteurs de mélanocortine. Ces composés sont de formule (I), et comprennent des stéréoisomères, des promédicaments, des sels pharmaceutiquement acceptables de ceux-ci, A, n, R1, R2, R3a, R3b, R4, R5, R6 et R7 sont définis dans la description. L'invention concerne également des compositions pharmaceutiques contenant un composé de formule (I), ainsi que des méthodes associées à l'utilisation de celui-ci.
PCT/US2003/004455 2002-02-11 2003-02-11 Derives de pyrrole utilises en tant que ligands de recepteurs de melanocortine WO2003068738A1 (fr)

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