WO2010096854A1 - Procédés de modulation de l'activité des récepteurs mc3 et/ou mc4 et traitement des conditions associées aux dits récepteurs - Google Patents

Procédés de modulation de l'activité des récepteurs mc3 et/ou mc4 et traitement des conditions associées aux dits récepteurs Download PDF

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WO2010096854A1
WO2010096854A1 PCT/AU2009/000229 AU2009000229W WO2010096854A1 WO 2010096854 A1 WO2010096854 A1 WO 2010096854A1 AU 2009000229 W AU2009000229 W AU 2009000229W WO 2010096854 A1 WO2010096854 A1 WO 2010096854A1
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methyl
diazepan
oxo
optionally substituted
group
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Mark Arnold Thomas Blaskovich
Peter Joseph Cassidy
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Mimetica Pty Ltd
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Mimetica Pty Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to methods of modulating the activity of a receptor selected from the group consisting of the melanocortin-3 receptor and the melanocortin-4 receptor.
  • the present invention relates to the use of a family of 1 ,4-diazepan-2- ones and derivatives thereof to modulate the activity of the melanocortin-3 and / or melanocortin-4 receptors.
  • the invention also relates to methods and uses of the compounds in the treatment of conditions in which agonism or antagonism of the melanocortin-3 and / or melanocortin-4 receptors is beneficial.
  • the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are G- protein coupled receptors (GPCRs) belonging to the family of melanocortin receptors. There are five melanocortin receptors that have been isolated and cloned to date: MC1 R, MC2R, MC3R, MC4R and MC5R.
  • the melanocortin receptors participate in a variety of physiologic functions, providing a number of opportunities for therapeutic intervention in physiologic processes through alteration (i.e., a statistically significant increase or decrease) or modulation (e.g., up-regulation or down-regulation) of melanocortin receptor signalling activity.
  • the melanocortin receptor family members are regulated by natural peptide agonists such as adrenocorticotropic hormone (ACTH) and the melanocyte stimulating hormones ( ⁇ -, ⁇ -, ⁇ -
  • MSH derived from proopiomelanocortin (POMC), and by peptide antagonists such as Agouti signal protein (ASP) and Agouti-related peptide (AGRP).
  • POMC proopiomelanocortin
  • ASP Agouti signal protein
  • AGRP Agouti-related peptide
  • the MC1 R is widely expressed and is associated with pigmentation in melanocytes and with inflammation responses in many cells involved in the immune system.
  • the MC2R differs from the other melanocortin receptors in that it binds only ACTH but not MSH ligands. It is highly expressed in the adenal gland and controls corticosteroid synthesis.
  • the MC3R is found in the brain, but also elsewhere in the body, and appears to play a role in the regulation of energy homeostasis, and possibly sexual dysfunction.
  • the MC4R is found almost exclusively in the brain, with some reports of its presence elsewhere. It has been strongly associated with feeding control, and also implicated with sexual desire.
  • the MC5R is widely expressed in peripheral tissues, particularly in the exocrine glands, with some receptor also expressed in the brain.
  • MC3R (Gantz 1993a) and MC4R (Gantz 1993b) were first cloned and expressed from humans in 1993. Both MC3R and MC4R play a role in regulating energy balance and food intake (Adan 2006, Bertile 2006, Butler 2006, Emmerson 2007, Foster 2007, Lam 2007,
  • MC4R knockout mice are obese and suffer from hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar 1997). Genetic studies strongly associate MC4R sequence variants with obesity (Thorleifsson 2009, Wilier 2009). MC3R knockout mice have increased fat mass and reduced lean body mass (Chen
  • mice lacking both MC3R and MC4R become more obese than mice lacking only MC4R (Chen 2000).
  • MC3R and MC4R have also been associated with sexual dysfunction, particularly in the control of penile erection (Wessells 2005, King 2007, Shadiach 2007, Wikberg 2008).
  • PT-141 bremelanotide
  • ⁇ -MSH shows immunosuppressive effects in humans, suppressing a variety of inflammation responses, and both MC3R and MC4R have been implicated in these immunomodulating activities (Catania 2004, Lasaga 2008, Getting
  • MC4R has also been linked to depression and anxiety disorders (Chaki
  • peptides e.g. Holder 2002, Holder 2003
  • peptide derivatives e.g. Mutulis
  • Therapeutic regulation of biological signal transduction includes modulation of MC3R- and / or MC4R- mediated cellular events including, inter alia, inhibition or potentiation of interactions among MC3R- and / or MC4R- binding and activating or deactivating molecules, or of other agents that regulate MC3R and / or MC4R activities.
  • An increased ability to so regulate MC3R and / or MC4R may facilitate the development of methods for modulating receptor signalling or other biological processes, and for treating conditions associated with such pathways such as obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
  • the present invention provides a method of modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof comprising exposing the receptor or a fragment or analogue or functional equivalent thereof to a compound of the formula (I):
  • Y is a group of formula -(CR 9 9 IR-)1 ⁇ 0 ⁇ N) n -;
  • R is an amino acid side chain group
  • R 1 is selected from the group consisting of H, optionally substituted C-rC 12 alkyl, optionally substituted CH 2 (C 6 -C 18 aryl) optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted CrC 12 heteroalkyl, optionally substituted C 3 - Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci ⁇ heteroaryl;
  • R 2 and R 3 are each independently selected from the group consisting of H, optionally substituted d-C ⁇ alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -
  • Ci 2 alkynyl optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted CrCisheteroaryl, or
  • R 5a , R 5b and R 6 are each independently selected from the group consisting of H, halogen, hydroxy, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted CrCi 2 heteroalkyl, optionally substituted Ci-Ci 0 heteroalkenyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted
  • Ci ⁇ heteroaryl optionally substituted amino, optionally substituted carboxy, optionally substituted carboxamide, optionally substituted Ci-Ci 2 alkyloxy, and optionally substituted thio;
  • each R 9 and R 10 is independently selected from the group consisting of H, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci- Ci ⁇ heteroaryl;
  • each R 11 and R 12 is independently selected from the group consisting of H, and optionally substituted CrC 12 alkyl;
  • n is an integer selected from the group consisting of 1 , 2, 3 and 4;
  • r is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
  • s is an integer selected from the group consisting of 0, 1 , 2, 3, and 4;
  • the receptor or fragment or analogue or functional equivalent thereof is in a cell and the method comprises exposing the cell to a compound of formula (I).
  • the invention provides a method of modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment or analogue or functional equivalent thereof in a mammal comprising administering a MC3R- and / or MC4R -modulating amount of a compound of the invention to the mammal.
  • the invention provides the use of a compound of the formula (I) in modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of MC3R or fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of MC4R or fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides the use of a compound of formula (I) in the preparation of a medicament for modulating the activity of both MC3R and MC4R or fragment or analogue or functional equivalent thereof in a mammal.
  • the invention provides a method of preventing or treating a condition associated with the activity of a receptor selected from the group consisting of
  • MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal the method comprising administering a therapeutically effective amount of a compound of formula
  • the compound may be administered in any way known in the art although in one aspect the compound is administered topically. In another aspect the compound is administered orally. In another aspect the compound is administered parenterally. In one embodiment of the method the condition is selected from the group consisting of obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
  • the invention provides for the use of a compound of formula (I) in the preparation of a medicament for preventing or treating a condition associated with the activity of a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal.
  • a receptor selected from the group consisting of MC3R and MC4R or a fragment, analogue or functional equivalent thereof in a mammal.
  • the medicament is adapted to be administered topically.
  • the medicament is adapted to be administered orally.
  • the compound is administered parenterally.
  • the condition is selected from the group consisting of obesity, eating disorders (such as cachexia, anorexia, weight gain, weight loss), metabolic syndrome, diabetes, sexual dysfunction (such as erectile dysfunction and female sexual dysfunction), anxiety, depression, inflammation, addiction and alcohol intake.
  • the term "optionally substituted” as used throughout the specification denotes that the group may or may not be further substituted or fused (so as to form a condensed polycyclic system), with one or more non-hydrogen substituent groups.
  • R a , R b , R c and R d are each independently selected from the group consisting of H, C 1 -C 12 alkyl, C 1 -C 12 haloalkyl, C 2 -Ci 2 alkenyl, C 2 -Ci 2 alkynyl, C 1 -C 1 0 heteroalkyl, C 3 -Ci 2 cycloalkyl, C 3 -Ci 2 cycloalkenyl, C r Ci 2 heterocycloalkyl, C r Ci 2 heterocycloalkenyl, C 6 -Ci 8 aryl, Ci-Ci ⁇ heteroaryl, and acyl, or any two or more of R a , R b , R c and R d , when taken together with the atoms to which they are attached form a heterocyclic ring system with 3 to 12 ring atoms.
  • Examples of particularly suitable optional substituents include F, Cl, Br, I, CH 3 , CH 2 CH 3 , OH, OCH 3 , CF 3 , OCF 3 , NO 2 , NH 2 , and CN.
  • amino acid side chain group represents a natural or unnatural side chain group present in a protein.
  • the term includes side chain moieties present in naturally occurring proteins including the naturally occurring amino acid side chain moieties identified in table 1 below.
  • the term also includes derivatives or analogs thereof.
  • derivative or analogue of an amino acid side chain group includes modifications and variations to naturally occurring side chain groups. With reference to the table above most of the naturally occurring amino acid side chain groups may be classified as alkyl, aryl, arylalkyl or heteroalkyl moieties. As such derivatives of amino acid side chain groups include straight or branched, cyclic or non-cyclic alkyl, aryl, heteroaryl, heteroarylalkyl, arylalkyl or heteroalkyl moieties.
  • Amino acid side chain groups as discussed above also include optionally substituted derivatives of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or heteroalkyl moieties.
  • the optional substituents may be selected from the group defined above.
  • the optional substituents may be selected from but are not limited to OH, Cl, Br, F, COOH, C00R z , CONH 2 , NH 2 , NHR Z , NR Z R Z , SH, SR Z , SO 2 R 2 , SO 2 H and SOR Z wherein R z is an alkyl, aryl or arylalkyl moiety.
  • the group may be a terminal group or a bridging group. This is intended to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
  • alkyl alkyl
  • alkylene alkylene
  • a modifier indicating the number of carbon atoms present in the moiety.
  • the modifier “CrC 6 " in front of the term “alkyl” indicates that the alkyl moiety has from 1 to 6 carbon atoms.
  • the modifier “C 1 -C- I s" in front of the term “heteroaryl” indicates that the heteroaromatic ring may have from 1 to 18 carbon atoms as part of the total number of atoms in the ring system.
  • examples of acyl include acetyl and benzoyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2- 6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • alkenyloxy refers to an alkenyl-O- group in which alkenyl is as defined herein. Preferred alkenyloxy groups are C 1 -C 6 alkenyloxy groups. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C 1 -C 14 alkyl, more preferably a C 1 -C 10 alkyl, most preferably CrC 6 unless otherwise noted.
  • suitable straight and branched CrC 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
  • “Mono-alkylamino” means a Alkyl-NH- group, in which alkyl is as defined herein.
  • “Dialkylamino” means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
  • the alkyl group is preferably a CrC 6 alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxy refers to an alkyl-O- group in which alkyl is as defined herein.
  • the alkyloxy is a C-i-C ⁇ alkyloxy. Examples include, but are not limited to, methoxy and ethoxy.
  • the group may be a terminal group or a bridging group.
  • Alkyloxyalkyl refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Alkyloxyary refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxycycloalkyl refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
  • Alkyloxyheteroary refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
  • Alkyloxyheterocycloalkyl refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the alkyl group is preferably a CrC 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • Alkynyloxy refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C 1 -C 6 alkynyloxy groups.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Aminoalkyl means an NH 2 -alkyl- group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5-7 cycloalkyl or C 5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • an aryl group is a C 6 -C 18 aryl group.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
  • exemplary arylalkenyl groups include phenylallyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a Ci -5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Arylalkyloxy refers to an aryl-alkyl-O- group in which the alkyl and aryl are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein.
  • di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Arylheteroalkyl means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Aryloxy refers to an aryl-O- group in which the aryl is as defined herein.
  • the aryloxy is a C 6 -Ci 8 aryloxy, more preferably a C 6 -Ci 0 aryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • a “bond” is a linkage between atoms in a compound or molecule.
  • the bond may be a single bond, a double bond, or a triple bond.
  • Cyclic group refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system.
  • Examples of cyclic groups include cycloalkyl, cycloalkenyl and aryl.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups.
  • the group may be a terminal group or a bridging group.
  • Cycloalkyl refers to a saturated monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. The group may be a terminal group or a bridging group.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein.
  • Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Cycloalkylheteroalkyl means a cycloalkyl-heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Cycloalkyloxy refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein.
  • the cycloalkyloxy is a CrC ⁇ cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.
  • the group may be a terminal group or a bridging group.
  • the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Cycloalkenyloxy refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein.
  • the cycloalkenyloxy is a Ci-C ⁇ cycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Haloalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • a haloalkyl group typically has the formula C n H (2n+ i- m) X m wherein each X is independently selected from the group consisting of F, Cl, Br and I.
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • m is typically 1 to 6, more preferably 1 to 3.
  • Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.
  • Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
  • Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, Cl, Br and I.
  • Halogen represents chlorine, fluorine, bromine or iodine.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group preferably having from 2 to 14 carbons, more preferably 2 to 10 carbons in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
  • the group may be a terminal group or a bridging group.
  • Heteroaryl either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1 H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, pheno
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heteroarylheteroalkyl means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heteroaryloxy refers to a heteroaryl-O- group in which the heteroaryl is as defined herein.
  • the heteroaryloxy is a Ci-Ci 2 heteroaryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocyclic refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom.
  • heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
  • Heterocycloalkenyl refers to a heterocycloalkyl as defined herein but containing at least one double bond.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkyl refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein.
  • exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heterocycloalkylalkenyl refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heterocycloalkylheteroalkyl means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heterocycloalkyloxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein.
  • the heterocycloalkyloxy is a Cr C 6 heterocycloalkyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocycloalkenyloxy refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein.
  • the heterocycloalkenyloxy is a C 1 -C 6 heterocycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Hydroalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an OH group.
  • a hydroxyalkyl group typically has the formula C n H( 2n +i- x )(OH) x
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably 1 to 3.
  • x is typically 1 to 6, more preferably 1 to 3.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • the group may be a terminal group or a bridging group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
  • the present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I) wherein one or more atoms have the same atomic number as, but an atomic mass or mass number different from, the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically- labeled reagents in place of the non-labeled reagent previously employed.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • Prodrug means a compound that undergoes conversion to a compound of formula
  • an ester prodrug of a compound of formula (I) containing a hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gestisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • an ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by FJ. Leinweber, Drug Metab. Res., 18:379, 1987.
  • an acyl prodrug of a compound of formula (I) containing an amino group may be convertible by hydrolysis in vivo to the parent molecule.
  • prodrugs for these and other functional groups, including amines are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R.Oliyai, H. Maag and J Tilley; Springer, 2007).
  • terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • the term "functional equivalent” is intended to include variants of the specific receptor described herein. It will be understood that receptors may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given receptor isoform is different to the prototypical receptor; the molecule maintains biological activity as a receptor. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term “functional equivalent” are variants generated at the level of transcription.
  • R 1 , R 2 , R 3 , R 5a , R 5b , R 6 , X, Y and r are as defined above,
  • Z is a group of formula -(CR 13 R 14 ) q -;
  • R 4b is selected from the group consisting of H, optionally substituted CrCi 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted
  • R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic moiety, or
  • R 4a and R 4b when taken together with any R 13 or R 14 and the atoms to which they are attached forms an optionally substituted heterocyclic moiety
  • R 13 and R 14 are each independently selected from the group consisting of H, halogen, OH, Ci-Ci 2 alkyl, C 6 -Ci 8 aryl, Ci-Ci 2 hydroxyalkyl, Ci-Ci 2 haloalkyl, Ci-Ci 2 alkyloxy and d- Ci 2 haloalkyloxy, or when taken together with the carbon to which they are attached R 13 and R 14 form an optionally substituted C 3 -Ci 2 cycloalkyl, or an optionally substituted Ci-Ci 2 heterocycloalkyl group, or
  • R 13 and R 14 when taken together with one of R 4a , and R 4b and the atoms to which they are attached form an optionally substituted heterocyclic moiety, or
  • R 13 and R 14 when taken together with one of R 15 , R 16 , R 17 , R 18 , R 19 or R 20 and the atoms to which they are attached form an optionally substituted cyclic moiety;
  • each R 15 , R 15a , R 16 , R 16a , R 17 , R 17a , R 18 , R 19 and R 20 is independently selected from the group consisting of H, optionally substituted d-Ci 2 alkyl, optionally substituted C 1 -
  • Ci 2 heteroalkyl optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci 8 heteroaryl, or
  • R 15 , R 15a , R 16 , R 16a , R 17 , R 17a , R 18 , R 19 and R 20 when taken together with the atoms to which they are attached form an optionally substituted cyclic group, or
  • R 15 , R 16 , R 17 , R 18 , R 19 and R 20 when taken together with one of R 13 and R 14 and the atoms to w Vhi IiicOhI i t Uh iet/y y a ⁇ rieG a ⁇ tut ⁇ ac ⁇ ihed f iouri m i n a ⁇ in i s ouuubostuitiuutiuedu c oyycoliiico
  • q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5;
  • a particularly useful subset of compounds of formula (I) are compounds where Y is a group of the formula -(CR 9 R 10 X 1 -.
  • n is 1 and Y is -CR 9 R 10 -.
  • n is 2 and Y is -CR 9 R 10 CR 9 R 10 -.
  • each R 9 and R 10 is independently selected from H and CH 3 .
  • R 9 and R 10 are both H.
  • Y is -CH 2 -.
  • Y is - CH 2 CH 2 -.
  • Y is -C(CHs) 2 -.
  • R 2 is H or C-i-C ⁇ alkyl. In a specific embodiment R 2 is H.
  • R 3 is H or CrC 6 alkyl. In a specific embodiment R 3 is H.
  • This provides compounds of formula (Ib).
  • R 1 , R 4 , R 5a , R 5b , R 6 , Z and r are as defined above.
  • R 4 is selected from the group consisting of H, Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, C 3 -
  • Ci 2 cycloalkyl optionally substituted C 6 -Ci 8 aryl, optionally substituted C-linked d-
  • R 4 is optionally substituted Ci-Ci ⁇ heteroaryl. In another embodiment R 4 is optionally substituted C 3 -Ci 2 cycloalkyl. In another embodiment R 4 is Cr Ci 2 alkyl
  • R 15 and R 16 when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, azepan-1-yl, morpholin-4-yl, and piperazin-1-yl.
  • R 16 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
  • R 17 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2, CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
  • r is selected from the group consisting of 0, 1 , 2, 3, and 4. In one specific embodiment r is 0. In another specific embodiment r is 1. In yet a further specific embodiment r is 2. In yet a further specific embodiment r is 3. In an even further specific embodiment r is 4.
  • Z is a group of formula -(CR 13 R 14 ) q -.
  • R 13 and R 14 are independently selected from H and C 1 -C 6 alkyl.
  • R 13 and R 14 are each independently selected from H and CH 3 .
  • R 13 and R 14 are both H.
  • at least one of R 13 and R 14 when taken together with at least one of R 4a and R 4b and the atoms to which they are attached form an optionally substituted heterocycloalkyl group.
  • Z is -(CH 2 ) q -
  • q is an integer selected from the group consisting of 0, 1 , 2, 3, 4, and 5. In one specific embodiment q is 1. In another specific embodiment q is 2, in yet an even further specific embodiment q is 3, and in yet an even further specific embodiment q is 4.
  • R 4b is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2, CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3, CH 2 CH(CH 3 ) 2, C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof.
  • R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted C 2 -Ci 2 heterocycloalkyl group, an optionally substituted C 2 -Ci 2 heterocycloalkenyl group or an optionally substituted Ci-Ci 8 heteroaryl group.
  • R 4a and R 4b when taken together with the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, azepan-1-yl, azetidin-1-yl, piperazin-1-yl, and morpholin-4-yl.
  • the compound of formula (I) is one in which one of R 4a and R 4b when taken together with the nitrogen atom to which it is attached and one of R 13 and R 14 and the carbon atom to which it is attached form an optionally substituted C 2 -Ci 2 heterocycloalkyl group.
  • one of R 4a and R 4b when taken together with the nitrogen atom to which it is attached and one of R 13 and R 14 and the carbon atom to which it is attached form an optionally substituted heterocycloalkyl group selected from the group consisting of piperidinyl, pyrrolidinyl, azepanyl, azetidinyl, morpholinyl, and piperazinyl.
  • the compound of formula (I) used is one in which the stereoisomeric configuration of the diazepanone is (3S,5R), as in formula (Id):
  • R 1 , R 4a , R 4b , R 5a , R 5b , R 6 , and Z are as defined for formula (Ic).
  • the compound of formula (I) used is one in which the stereoisomeric configuration of the diazepanone is (3S,5S), as in formula (Ie):
  • R 1 , R 4a , R 4b , R 5a , R 5b , R 6 , A and Z are as defined for formula (Ic).
  • R 1 is selected from the group consisting of an optionally substituted amino acid, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 6 -Ci 8 aryl, optionally substituted CH 2 (C 6 - Ci 8 aryl), and optionally substituted Ci-Ci 8 heteroaryl.
  • R 1 - X is an optionally substituted amino acid.
  • R 1 is optionally substituted C 6 -C 18 aryl.
  • the C 6 -C 18 aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C 6 -C 18 aryl is a monocyclic moiety. In certain embodiments the C 6 -Ci 8 aryl is a bicyclic moiety.
  • R 1 is optionally substituted CH 2 (C 6 -Ci 8 aryl).
  • the C 6 -Ci 8 aryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C6-Ci 8 aryl is a monocyclic moiety. In certain embodiments the C 6 -Ci 8 aryl is a bicyclic moiety.
  • R 1 is an optionally substituted C 6 -Ci 8 aryl selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl.
  • R 1 is an optionally substituted CH 2 (C 6 -Ci 8 aryl) with the aryl group selected from the group consisting of optionally substituted phenyl, biphenyl, and optionally substituted naphthyl.
  • the moieties may be unsubstituted or may be substituted with one or more optional substituents. A wide variety of optional substituents may be used as defined above.
  • Such optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2- ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH 2 , cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1-yl, and 3,5-dimethyl-pyrazol-1-yl.
  • substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee.
  • suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-
  • R 1 is optionally substituted biphenyl
  • the point of attachment of R 1 to the remainder of the molecule may be at the 2-, 3- or 4- position relative to the point of attachment of the second phenyl ring.
  • the biphenyl may be an optionally substituted biphen-2-yl, or an optionally substituted biphen-3-yl, or an optionally substituted biphen-4-yl.
  • the optionally substituted biphenyl is an optionally substituted biphen-4-yl.
  • the optionally substituted biphenyl may be substituted in any suitable position.
  • R 1 is optionally substituted naphthyl
  • the point of attachment of R 1 to the remainder of the molecule may be at the 1 or 2 position.
  • the naphthyl may be an optionally substituted naphth-1-yl, or an optionally substituted naphth-2-yl.
  • the optionally substituted naphthyl is an optionally substituted naphth-2-yl.
  • the optionally substituted naphthyl may be substituted in any suitable position.
  • Suitable optionally substituted naphth-2-yls include, but are not limited to, 6-fluoro-naphth-2-yl, 6- bromo-naphth-2-yl, 6-chloro-naphth-2-yl, 1-methoxy-naphth-2-yl, 3-methoxy-naphth-2-yl, 6- methoxy-naphth-2-yl, 1-hydroxy-naphth-2-yl, and 6-amino-naphth-2-yl.
  • R 1 is optionally substituted Ci-Ci 8 heteroaryl.
  • the Ci-Ci 8 heteroaryl may be a monocyclic, bicyclic or polycyclic moiety. In certain embodiments the Ci-Ci 8 heteroaryl is a monocyclic moiety. In certain embodiments the Ci-C-isheteroaryl is a bicyclic moiety.
  • heteroaryl moieties include, but are not limited to, indol-2-yl, indol-3-yl quinolin-2-yl quinolin-3- yl, isoquinolin-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, thiazole-4-yl, benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl, benzo[d]thiazole-6-yl, pyrazole-1-yl, pyrazole-4-yl and thiophen-2-yl. These may also be optionally substituted as discussed above.
  • R 1 is an optionally substituted C 2 -C 12 alkenyl.
  • the optionally substituted alkenyl may contain one or more double bonds with each of the double bonds being independently in the E or Z configuration.
  • the alkenyl contains a single double bond which is in the E configuration.
  • R 1 is an optionally substituted C 2 -Ci 2 alkenyl of the formula:
  • R is selected from the group consisting of H, halogen and optionally substituted d- Ci 2 alkyl;
  • R 1b and R 1c are each independently selected from the group consisting of H, halogen, optionally substituted Ci-Ci 2 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 2 -Ci 2 alkynyl, optionally substituted Ci-Ci 2 heteroalkyl, optionally substituted C 3 -Ci 2 cycloalkyl, optionally substituted C 2 -Ci 2 heterocycloalkyl, optionally substituted C 6 -Ci 8 aryl, and optionally substituted Ci-Ci 8 heteroaryl.
  • R 1a is H. In one form of this embodiment R 1b is H. This provides compounds where R 1 is of the formula:
  • R 1c is optionally substituted Ce- Ci 8 aryl.
  • the C 6 -Ci 8 aryl may be monocyclic, bicyclic or polycyclic moiety. In certain embodiments the C 6 -C 18 aryl is a monocyclic moiety. In certain embodiments the C 6 -C 18 aryl is a bicyclic moiety.
  • R 1c is an optionally substituted C 6 -C 18 aryl selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl.
  • the moieties may be unsubstituted or may be substituted with one or more optional substituents.
  • a wide variety of optional substituents may be used as defined above.
  • Such optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl, hexyl, heptyl, octyl, phenyl, NH 2 , cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol- 1-yl, and 3,5-dimethyl-pyrazol-1-yl.
  • substituents may be located at any substitutable position around the aryl ring available for substitution as would be clear to a skilled addressee.
  • suitable optionally substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3- methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4- trifluoromethyl-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 4-bromo-phenyl, 2- fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl- phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-difluoro-phenyl, 2- chloro-6-
  • R 5a and R 5b are independently selected from H and CrC 6 alkyl. In one embodiment R 5a and R 5b are each independently selected from H and CH 3 . In one specific embodiment R 5a and R 5b are both H. In one embodiment of the compounds suitable for use in the invention R 6 is an optiona allllyy ssuubbssttiittuutteedd aallkkyyll group. In one embodiment invention R 6 is an optionally substituted alkyl group of the formula:
  • R is H.
  • R 6a and R 6c are each independently selected from the group consisting of H, optionally substituted CrC 12 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 6 -Ci 8 aryl and optionally substituted Ci-Ci 8 heteroaryl.
  • R 6a and R 6c are each independently selected from the group consisting of optionally substituted CrC 12 alkyl, optionally substituted C 2 -Ci 2 alkenyl, optionally substituted C 6 -Ci 8 aryl and optionally substituted Ci-Ci 8 heteroaryl.
  • R 6a is selected from the group consisting of ethyl, 2,2,2- trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2- methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted C 1 -C 5 heteroaryl.
  • R 6a is optionally substituted phenyl or optionally substituted C 1 - C 18 heteroaryl.
  • R 6c is selected from the group consisting of ethyl, 2,2,2- trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, 2- methyl-butyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl and optionally substituted C 1 -C 5 heteroaryl.
  • R 6c is methyl, ethyl, phenyl or optionally substituted C 1 -C 5 heteroaryl.
  • r is 1
  • R ,5a is H
  • R 5b is selected from the group consisting of optionally substituted carboxy and optionally substituted carboxamide.
  • R 6 is selected from the group consisting of H, optionally substituted d-C ⁇ alkyl, optionally C 6 -Ci 8 aryl, or optionally substituted d- Ci ⁇ heteroaryl.
  • the optionally substituted alky group is selected from the group consisting of an optionally substituted CH 2 (C 6 -C 18 aryl) group and an optionally substituted CH 2 (C 1 -C 18 heteroaryl) group.
  • the compounds of formula (I) are modulators of the MC3R and / or MC4R and therefore may be used to modulate the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof by exposing MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof to a compound of the invention.
  • This can occur in vitro in assays where the modulation of MC3R and / or MC4R activity is desirable, however it is typically more beneficial when utilised in modulation of MC3R and / or MC4R activity in a patient.
  • the amount of modulation provided by the compounds of the invention will vary from compound to compound and will also be affected by the amount of compound administered.
  • the modulation can consist of upregulation or downregulation. In one embodiment the amount of upregulation or downregulation is at least 10%. In another embodiment the amount of upregulation or downregulation is at least 20%. In an even further embodiment the amount of upregulation or downregulation is at least 50%
  • the methods of the present invention may be used in the treatment of any condition in which modulation of the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof would lead to a beneficial effect on that condition.
  • the compounds suitable for use in the present invention may be used in methods of preventing or treating a condition associated either directly or indirectly with the activity of MC3R and / or MC4R or a fragment or analogue or functional equivalent thereof in a mammal wherein an MC3R and / or MC4R modulating amount of the compound of the invention is administered to the mammal.
  • One condition associated with MC3R and / or MC4R activity is metabolic syndromes and conditions related thereto.
  • the condition is selected from the group consisting of obesity, eating disorders, and diabetes.
  • the eating disorder is selected from the group consisting of cachexia, anorexia, weight gain and weight loss.
  • the condition is Type Il diabetes.
  • Another condition associated with MC3R and / or MC4R activity is sexual dysfunction.
  • the sexual dysfunction is selected from the group consisting of erectile dysfunction and female sexual dysfunction.
  • the condition is erectile dysfunction.
  • the modulation of MC3R and / or MC4R may involve upregulation or downregulation. For example, downregulation of MC4R leads to increased food intake and weight gain and can thus be used in the treatment of cachexia.
  • upregulation of MC4R leads to weight loss and can thus be used in the treatment of obesity.
  • upregulation of MC4R leads penile erection and can thus be used in the treatment of erectile dysfucntion.
  • the methods of the invention may also be useful in prevention or treatment of a number of conditions that relate to biological processes controlled by MC3R and / or MC4R, such as diseases related to inflammation, depression, anxiety and addiction.
  • the compounds of formula (I) may also find application in treatments where reduced weight is desirable such as in dieting.
  • the compounds may thus be used in methods of reducing the weight a mammal, the method comprising administering an effective amount of a compound of formula (I).
  • the compounds of formula (I) may be used in the treatment of conditions in any species in which MC3R and / or MC4R is present, most typically mammals.
  • Examples of species in which MC3R and / or MC4R are found and hence species in which the compounds may be used include humans, rats, mice, dogs, and rhesus monkey.
  • the mammal is a human.
  • Administration of compounds within Formula (I) to a patient such as humans can be by topical administration, by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
  • the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
  • the compounds of formula (I) can be administered in any form or mode which makes the compound bioavailable.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19 th edition, Mack Publishing Co. (1995) for further information.
  • the compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • the compounds of formula (I) while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
  • compositions which are formulated depending on the desired mode of administration.
  • compositions are prepared in manners well known in the art.
  • a compound of formula (I) is typically combined with the carrier to produce a dosage form suitable for the particular patient being treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of the compound of the invention, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition.
  • Representative dosage forms will generally contain between from about 1 mg to about 500 mg of a compound of the invention, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • Compounds of the present invention may also be formulated for topical delivery in formulations such as solutions, ointments, lotions, gels, creams, microemulsions or transdermal patches.
  • these topical formulations may contain from 0.005 to 5% (wt/wt or wt/vol) of a compound of the invention.
  • the compounds of formula (I) may be used or administered in combination with one or more additional drug (s), either concurrently or sequentionally.
  • the compounds of the present invention may be used in combination with one or more other pharmaceutically-active compounds, such as other metabolism altering, sexual dysfunction, anti-inflammatory, antianxiety, or antiaddiction medications. These components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).
  • compositions suitable for use in the invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and non aqueous carriers, diluents, solvents or vehicles 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.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the 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. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • the dosage form 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 sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents 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, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming 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, aluminium metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • the active agent may be in the form of an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.
  • the composition may be delivered via a liposome, nanosome, rivosome, or nutri-diffuser vehicle.
  • a formulation may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • compositions used for topical administration typically contain a pharmaceutically acceptable carrier which may be any vehicle that is toxicologically and pharmaceutically acceptable.
  • Typical pharmaceutically acceptable carriers that can be used in compositions of the present invention include water, ethanol, acetone, isopropyl alcohol, stearyl alcohol, freons, polyvinyl pyrrolidone, propylene glycol, polyethlyene glycol, fragrances, gel-producing materials, mineral oil, stearic acid, spermaceti, sorbitan, monoleate, polysorbates, "Tweens," sorbitol, methyl cellulose, petrolatum, a mineral oil (vaseline oil), which may be any petroleum based product; modified or unmodified vegetable oils such as peanut oil, wheatgerm oil, linseed oil, jojoba oil, apricot kernel oil, walnut oil, palm oil, pistachio oil, sesame oil, colza oil, cade oil, corn germ oil, peach kernel oil, poppy
  • compositions for topical administration may be formulated in numerous forms. However, the composition may often take the form of an aqueous or oily solution or dispersion or emulsion or a gel or a cream.
  • An emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.
  • the oil phase of water-in-oil or oil-in-water emulsions may comprise for example: a) hydrocarbon oils such as paraffin or mineral oils; b) waxes such as beeswax or paraffin wax; c) natural oils such as sunflower oil, apricot kernel oil, shea butter or jojoba oil; d) silicone oils such as dimethicone, cyclomethicone or cetyldimethicone; e) fatty acid esters such as isopropyl palmitate, isopropyl myristate, dioctylmaleate, glyceryl oleate and cetostearyl isononanoate; f) fatty alcohols such as cetyl alcohol or stearyl alcohol and mixtures thereof (eg cetearyl alcohol); g) polypropylene glycol or polyethylene glycol ethers, eg PPG-14 butyl ether; or h) mixtures thereof.
  • hydrocarbon oils such as paraffin or
  • Emulsifiers used may be any emulsifiers known in the art for use in water-in-oil or oil- in-water emulsions.
  • Known cosmetically acceptable emulsifiers include: a) sesquioleates such as sorbitan sesquioleate, available commercially for example under the trade name Arlacel 83 (ICI), or polyglyceryl-2-sesquioleate; b) ethoxylated esters of derivatives of natural oils such as the polyethoxylated ester of hydrogenated castor oil available commercially for example under the trade name Arlacel 989 (ICI); c) silicone emulsifiers such as silicone polyols available commercially for example under the trade name ABIL WS08 (Th.
  • emulsifiers such as fatty acid soaps e.g. potassium stearate and fatty acid sulphates e.g. sodium cetostearyl sulphate available commercially under the trade name Dehydag (Henkel); e) ethoxylated fatty alcohols, for example the emulsifiers available commercially under the trade name Brij (ICI); f) sorbitan esters, for example the emulsifiers available commercially under the trade name Span (ICI); g) ethoxylated sorbitan esters, for example the emulsifiers available commercially under the trade name Tween (ICI); h) ethoxylated fatty acid esters such as ethoxylated stearates, for example the emulsifiers available commercially under the trade name Myrj (ICI); i) ethoxylated mono-, di-, and triglycerides, for example the
  • Gels for topical administration may be aqueous or non-aqueous. Aqueous gels are preferred.
  • the gel will contain a thickening agent or gelling agent in order to give sufficient viscosity to the gel.
  • a variety of thickening agents may be used according to the nature of the liquid carrier and the viscosity required and these are recited hereinafter.
  • a particularly suitable thickener is a copolymer of acryloyl dimethyl tauric acid (or a salt thereof), preferably a copolymer of that monomer with another vinylic monomer.
  • the thickening agent is a copolymer of a salt of acryloyl dimethyl tauric acid with another vinylic monomer.
  • the salt may be a salt of a Group I alkali metal, but is more preferably an ammonium salt.
  • suitable copolymer thickening agents are: i) Ammonium acryloyl dimethyl taurate I vinyl pyrrolidone copolymer, ie a copolymer of ammonium acryloyl dimethyl taurate and vinyl pyrrolidone (1-vinyl-2-pyrrolidone).
  • composition may additionally comprise other components which will be well known to those skilled in the art such as emollients, humectants, emulsion stabilising salts, preservatives, chelating agents or sequestering agents (sequestrants), abrasives, antioxidants, stabilisers, pH adjusters, surfactants, thickeners, diluents, perfumes and colourings.
  • the topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the amount of compound administered will preferably treat and reduce or alleviate the condition.
  • a therapeutically effective amount can be readily determined by an attending diagnostician by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount a number of factors are to be considered including but not limited to, the species of animal, its size, age and general health, sex, diet, the specific condition involved, the severity of the condition, the response of the patient to treatment, the particular compound administered, the mode of administration, the bioavailability of the preparation administered, the dose regime selected, the use of other medications and other relevant circumstances.
  • a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
  • a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
  • a suitable dose can be administered in multiple sub-doses per day.
  • the resulting secondary amine is acylated under standard peptide coupling conditions with the protected amino acid, P 2 -NHCH(U)-CO 2 H, where U represents either the final R side chain, a protected final side chain R-P 3 , or a precursor that requires chemical modification to form the final R side chain.
  • the ring system is generated by deprotection of the P 4 and P 5 protecting groups, followed by amide bond formation using standard peptide coupling reagents.
  • the P 4 protecting group is removed and cyclization achieved by thermal or base-induced cyclization with the P 5 - protected ester.
  • the cyclization produces a mixture of two diastereomers, A and B, from which the preferred diastereomers A can be separated by chromatography.
  • R 5a R 5b W ⁇ J, ⁇ r R 6
  • HPLC analyses were carried out on an Agilent 1100 Series Purification System with a Phenomenex Synergi 4 ⁇ Max-RP 8OA, 50 x 2.00 mm analytical HPLC column, with peak detection by UV.
  • the standard analysis employed a 1 mL/min flow rate of 0.05% trifluoroacetic acid (TFA) in water (Solvent A) and 0.05% TFA in 90:10 acetonitrile:water
  • the organic phase is then washed with 1 N HCI (3 x 100 ml_), H 2 O (3 x 100 ml_), saturated NaHCO 3 aqueous solution (3 x 100 ml.) and brine (1 x 10 ml_).
  • the organic phase is then dried (MgSO 4 ) and the EtOAc removed to give the Weinreb amide (2) as a white solid or an oil.
  • HCI 200 ml_
  • the aqueous mixture is extracted with DCM (3x 100 ml.) and the organic layers combined and washed with 1 M HCI (2x 200 ml.) and H 2 O (3x 100 ml_).
  • the organic phase is dried (MgSO 4 ) to provide a solution of the ⁇ , ⁇ -unsaturated ketone (3).
  • the ⁇ , ⁇ - unsaturated ketone (3) may be isolated by rotary evaporation or it may be used in solution without further purification. If the intention is to use the ⁇ , ⁇ -unsaturated ketone (3) in solution the volume is reduced to 100 ml. by rotary evaporation and stored for later use.
  • the DIC may be replaced with HATU (15 mmol) and DIPEA (15 mmol).
  • the reaction is stirred at room temperature overnight.
  • the DCM is removed by rotary evaporation and the residue is taken up in EtOAc (100 ml_).
  • the organic layer is washed with saturated sodium bicarbonate solution (2 x 100 ml_), saturated ammonium chloride solution (2 x 100 ml.) and brine (2 x 100 ml_).
  • the organic phase is dried and the solvent removed under reduced pressure.
  • the residue is subjected to column chromatography on silica gel using petroleum ethe ⁇ EtOAc to give 5.
  • Example 5 General Procedure - P 2 Deprotection and Cyclization
  • the procedure adopted for the removal of the P 2 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.
  • P 2 Fmoc: To compound 5 (2 mmol) in DCM (3 ml.) is added diethylamine (20 mmol). The reaction is stirred at room temperature for 1 hr. The DCM and diethylamine is then removed by rotary evaporation. DCM (5 ml.) and sodium triacetoxyborohydride (3 mmol) are then added, and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml_), dried (MgSO 4 ) and the DCM removed to give the cyclised product A. This may be purified by flash chromatography on silica gel or used without purification.
  • the procedure adopted for the removal of the P1 protecting group will vary depending upon the exact nature of the protecting group. As will be appreciated by a skilled addressee a large number of possible protecting groups may be used and a skilled worker in the art will readily be able to determine an appropriate procedure for the removal of any particular protecting group from procedures known in the art. Nevertheless in order to assist the reader general procedures for the removal of the more common protecting groups are provided.
  • the reaction mixture is stirred at room temperature for 1.5 hrs, after which DCM (20 ml.) is added, the organic layer washed with saturated sodium bicarbonate solution (20 ml.) and H 2 O (20 ml_), dried (MgSO 4 ) and evaporated.
  • the residue may be purified by preparative HPLC to give the piperidinyl product.
  • the purified product is isolated as the TFA salt, but is readily converted into the free base via neutralisation with aqueous NaHCOs and extraction into an organic solvent, or further converted into the HCI salt by acidification with 1 N HCI.
  • the amino ketone 12 (44 mg, 0.053 mmol) in DCM (2 ml.) was cyclized by addition of NaBH(OAc)3 (40mg, 0.18 mmol) in one portion at room temperature. The resulting mixture was stirred for 3 hrs, followed by addition of saturated NaHCO 3 aqueous solution (3 ml_). The aqueous layer was extracted with DCM (3 x 3 ml.) and the combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was filtered through a short plug of silica gel eluting with DCM followed by EtOAc then EtOAc/IPA (9:1 ) to give the desired product 13 as a white solid. It was used in the next step without further purification. MS (ESI) 807 (M+1 ); HPLC f R 7.75 min.
  • fe/t-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate 34 (Boc-Gly Weinreb amide, 1.4 g, 6.4 mmol) in DCM (5 ml.) and TFA (3 ml.) were stirred at room temperature 1 hr. The solvent was removed under reduced pressure, followed by addition of
  • Example 36 Synthesis of Compound 104 N-(((3S,5S)-3-(3-aminopropyl)-1-(2,2- diphenylethyl)-4-methyl-2-oxo-1 ,4-diazepan-5-yl)methyl)-6-bromo-2-naphthamide
  • Example 54 Synthesis of Compound 46 bis (Cbz) 1-(3-((2S,7RS)-7-((S)-1-amino-2- (naphthalen-2-yl)ethyl)-4-(2,2-diphenylethyl)-3-oxo-1 ,4-diazepan-2-yl)propyl)guanidine
  • Examples 58-66 Synthesis via Scheme 2: Preparation of all Four Diastereomers of N- ((1 -(2,2-diphenylethyl)-3-(3-guanidinopropyl)-2-oxo-1 ,4-diazepan-5-yl)methyl)-2- naphthamide 52
  • the Alloc/allyl protected derivative 56 (840 mg, 1.1 1 mmol) was dissolved in a minimum of DCM. 1 ,3-Dimethylbarbituric acid (346 mg, 2.22 mmol) and catalytic Pd(PPh 3 ) 4 were added, and the reaction degassed under vacuum, sealed and stirred overnight. The reaction was diluted to 50 ml. with DCM, DIPEA (430 mg, 3.33 mmol) and BOP (540 mg, 1.22 mmol) were added, and the reaction stirred for 30 min.
  • Example 64 Synthesis of Compounds 96 and 97 (3S,5R)-5-(N-Boc aminomethyl)-3-(N- Cbz 3-aminopropyl)-1-(2,2-diphenylethyl)-1 ,4-diazepan-2-one and (3S,5S)-5-(N-Boc aminomethyl)-3-(N-Cbz 3-aminopropyl)-1 -(2,2-diphenylethyl)-1 ,4-diazepan-2-one
  • Example 65 Synthesis of Compounds 62-65 5-(N-Boc aminomethyl)-3-(N,N'-Cbz 2 3- guanidinopropyl)-1 -(2,2-diphenylethyl)-1 ,4-diazepan-2-one
  • frozen hMC3R and hMC4R plasma membranes were prepared as described below from transfected mammalian cells (prepared as in Example 76, using plasmid DNA containing the human MC3R or MC4R gene in a plasmid vector with a mammalian origin of replication.
  • the cell suspension was centrifuged again as previously and the pellet resuspended in 5 ml. of 0.25 M sucrose containing protease inhibitors.
  • the cells were homogenised by a 10 second pulse with an lka disperser followed by 30 seconds on ice. The homogenisation and ice incubation was repeated three times. The mixture was then centrifuged at 1260 x g for 5 mins. The supernatant was decanted into another centrifuge tube, to which a buffer containing 50 mM Tris, pH 7.4, 12,5 mM MgCI 2 , 5 mM EGTA and protease inhibitors was added to make the volume up to 30 ml_.
  • NDP-MSH radiolabeled in house and purified by HPLC:
  • Na 125 I (0.5 mCi, 17.4 Ci/mg) was added to 50 ⁇ l_ sodium phosphate (50 mM, pH 7.4) in an eppendorf tube precoated with IODOGEN. After incubation for 10 mins the phosphate buffer containing the iodine was added to NDP-MSH (10 ul at 1 mg/ml_) in a separate eppendorf tube. This was incubated for a further 10 mins. The iodinated NDP-MSH was purified by HPLC on a Zorbax SB 300 column using solvent A: 0.05% TFA and solvent B: 90% acetonitrile 0.045% TFA with a linear gradient, 0-67% B over 60 mins.
  • the 125 I NDP-MSH eluted at 52 mins after the unlabeled starting material (48 min) and was counted and stored in the freezer. It was used within 48 hrs, as radioactive decay and ligand decomposition resulted in greatly reduced specific binding observed after 72 hrs.
  • Incubation buffer 25 mM HEPES-KOH (pH 7.0), 1.5 mM CaCI 2 , 1 mM MgSO 4 , 0.1 M NaCI, 1 mM 1 ,10-phenanthroline, and 1 CompleteTM protease inhibitor tablet/100 mL (Roche, catalog number 1873580)
  • Perkin Elmer frozen hMC3 or hMC4 membranes catalog number RBXMC3M400UA / RBHMC4M400UA, 0.4 mL/vial; 400 microassays/vial, 0.78 mg/mL protein concentration
  • Vials of frozen membranes were thawed rapidly immediately before use, diluted with binding buffer and vortexed. Resuspended membranes were kept on ice until they were added to the wells of the plate.
  • ice-cold wash buffer (the above incubation buffer without 1 ,10- phenanthroline and CompleteTM protease inhibitor tablet).
  • the filters were dried in a 37 0 C oven, placed in a sample bag and 5 ml. Betaplatescint (Wallac) was added. Prepared filters were counted in cassettes in a Microbeta Trilux (Wallac) for 1 min. Non-specific binding just under 5%.
  • Representative compounds of the present invention were tested for binding in the hMC3R and hMC4R assays as in Example 74, as listed in Table 4. The compounds were tested as their trifluoroacetate or hydrochloride salts, or as their free base.
  • Example 76 Inhibition or stimulation of cAMP signal in cells expressing human MC4R Transient transfection of mammalian cell lines:
  • the mammalian cell line human embryonic kidney cells (HEK 293), were maintained in Dulbeccos Modified Eagle's medium (DMEM) with 5% fetal bovine serum, L- glutamine, high glucose and antibiotics/antimycotics.
  • DMEM Dulbeccos Modified Eagle's medium
  • cells were passaged using trypsin/EDTA and seeded into 75 cm 2 flasks so that they would be approximately 90% confluent the next day.
  • the next day, the cell media was replaced with fresh antibiotic/antimycotic-containing DMEM.
  • Approximately 100 ⁇ l of the transfection lipid Turbofectin 8.0 (Origene Technologies, MD, USA), was diluted in 1.0 ml.
  • OptiMEM serum and antibiotic/antimycotic-free OptiMEM in a sterile 15 ml. tube and incubated for 5 mins at room temperature. Following incubation, approximately 10-20 ⁇ g of plasmid DNA expressing the gene of interest (for example: Homo sapiens melanocortin 4 receptor) was diluted into the transfection mix and incubated for a further 30 mins at room temperature. The DNA/lipid solution was then added drop-wise to the media covering the cells while rocking the flask gently. 24 hrs post-transfection, the cells were passaged and seeded directly into two, 75cm 2 flasks and left to recover. 48 hrs post transfection, cells were harvested for use in assays with cell dissociation solution.
  • the gene of interest for example: Homo sapiens melanocortin 4 receptor
  • Cyclic-Adenosine Monophosphate [cAMP] stimulation assay HEK 293 cells transiently expressing the melanocortin MC4 receptor were suspended in stimulation buffer (Hanks buffered saline solution (HBSS), 0.1 % bovine serum albumin, protease inhibitors and 0.5 mM 3-lsobutyl-1 -methylxanthine) at 4 x 10 6 cells/mL. 5 ⁇ l of cells, plus the compounds/peptides as described below, were added to wells of a 384-well plate as soon as possible after resuspension.
  • stimulation buffer Hors buffered saline solution (HBSS), 0.1 % bovine serum albumin, protease inhibitors and 0.5 mM 3-lsobutyl-1 -methylxanthine
  • test compounds at varying concentrations were diluted in stimulation buffer at four times concentrate and 2.5 ⁇ l was added to wells containing cells. 2.5 ⁇ l of a four times required concentration of NDP-MSH or alpha-MSH was added to all wells containing compounds. Negative control wells contained two times concentrated NDP-MSH or alpha-MSH alone without compound. The concentration of NDP-MSH or alpha-MSH employed was calculated to give a response equivalent to approximately 60% of the maximal stimulation.
  • test compounds at varying concentrations were diluted in stimulation buffer at two times concentrate and 5 ⁇ l was added to wells containing cells.
  • Positive control wells contained NDP-MSH or alpha-MSH alone (no compound) at two times concentrate.
  • Basal level (of cAMP) control wells contained stimulation buffer only (no agonist or compounds).
  • Known concentrations of cAMP (standards) in stimulation buffer were included on the plate, but no cells were added to these wells. The plate was then incubated for 30 mins at 37 0 C with gentle shaking.
  • lysis buffer (10 % Tween 20, 1 M HEPES, 0.1 % BSA, protease inhibitors, ddH 2 O) was added to all wells to be measured. Detection of cAMP was then achieved using the Alphascreen cAMP kit (Perkin Elmer, USA), briefly described as follows. A dilution of 10 ⁇ l acceptor beads/mL of lysis buffer was prepared in low light conditions. 5 ⁇ l of diluted acceptor beads were added to each well to be measured, then the plate was incubated for 30 mins at room temperature, in the dark, with gentle shaking.
  • donor beads were diluted at 10 ⁇ l/mL of lysis buffer, to which 0.75 ⁇ l biotinylated cAMP/ml_ of lysis buffer was added. This mixture was allowed to incubate for 30 mins at room temperature (in the dark) before proceeding with the assay. Following incubation, 5 ⁇ l/mL of biotinylated cAMP/Donor bead mix were added per well in low light conditions and the plate was incubated in the dark, at room temperature, for a further hr. Plates were read on an Envision plate reader (Perkin Elmer) after 1 hr and ⁇ 16hrs incubation. cAMP concentration in the cells was determined by the use of a 'standard curve' generated from the output of known cAMP concentrations as described below.
  • Each assay plate contained a "standard curve" of known concentrations of cAMP, in
  • Antagonists for the Treatment of Depression and Anxiety Disorders Chen, A.S.; Marsh, DJ.; Trumbauer, M. E.; Frazier, E.G.; Guan, X.-M.; Yu, H.; Rosenblum, C. I.; Vongs, A.; Feng, Y.; Cao, L.; Metzger, J. M.; Strack, A.M.; Camacho, R. E.; MeIMn, T.N.; Nunes, C. N.; Min, W.; Fisher, J.; Gopal-Truter, S.; Maclntyre, D. E.; Chen, H.Y.; Van der Ploeg, L. HT.
  • M4R Receptor

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Abstract

La présente invention porte sur les composés de la formule (I), utiles pour moduler l'activité biologique du récepteur 3 de la mélanocortine (MC3R) et/ou du récepteur 4 de la mélanocortine (MC4R). Les composés de la présente invention peuvent être utilisés pour traiter des maladies et/ou conditions dans lesquelles la modulation de MC3R et/ou de MC4R est avantageuse. De telles maladies et/ou conditions peuvent inclure notamment, mais non exclusivement, l'obésité, les troubles de l'alimentation (notamment cachexie, anorexie, gain de poids, perte de poids), le syndrome métabolique, le diabète, les dysfonctionnements sexuels (notamment dysfonctionnement érectile et dysfonctionnement sexuel féminin), l'anxiété, la dépression, l'inflammation, l'addiction et la consommation d'alcool.
PCT/AU2009/000229 2009-02-27 2009-02-27 Procédés de modulation de l'activité des récepteurs mc3 et/ou mc4 et traitement des conditions associées aux dits récepteurs Ceased WO2010096854A1 (fr)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2013102047A1 (fr) 2011-12-29 2013-07-04 Rhythm Pharmaceuticals, Inc. Méthode de traitement de troubles associés au récepteur 4 de la mélanocortine dans des porteurs hétérozygotes
WO2019195756A1 (fr) 2018-04-06 2019-10-10 Rhythm Pharmaceuticals, Inc. Compositions pour le traitement d'une rénopathie
EP4029513A1 (fr) 2015-09-30 2022-07-20 Rhythm Pharmaceuticals, Inc. Agonistes du récepteur de melanocortin-4 pour le traitement des désordres characterisés par une hyperméthylation du gène pomc
WO2022247783A1 (fr) * 2021-05-24 2022-12-01 中国科学技术大学 Utilisation d'un récepteur de mélanocortine mc5r
JP7288554B1 (ja) 2020-06-09 2023-06-07 ファイザー・インク メラノコルチン４受容体アンタゴニストとしてのスピロ化合物およびそれらの使用

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3988108A1 (fr) 2011-12-29 2022-04-27 Rhythm Pharmaceuticals, Inc. Procédé de traitement de troubles associés au récepteur de la mélanocortine-4 dans des porteurs hétérozygotes
US9845339B2 (en) 2011-12-29 2017-12-19 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US10167312B2 (en) 2011-12-29 2019-01-01 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
EP3539551A1 (fr) 2011-12-29 2019-09-18 Rhythm Pharmaceuticals, Inc. Procédé de traitement de troubles associés au récepteur de la mélanocortine-4 dans des porteurs hétérozygotes
US10954268B2 (en) 2011-12-29 2021-03-23 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
WO2013102047A1 (fr) 2011-12-29 2013-07-04 Rhythm Pharmaceuticals, Inc. Méthode de traitement de troubles associés au récepteur 4 de la mélanocortine dans des porteurs hétérozygotes
US11702448B2 (en) 2011-12-29 2023-07-18 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
EP4029513A1 (fr) 2015-09-30 2022-07-20 Rhythm Pharmaceuticals, Inc. Agonistes du récepteur de melanocortin-4 pour le traitement des désordres characterisés par une hyperméthylation du gène pomc
EP4711004A2 (fr) 2015-09-30 2026-03-18 Rhythm Pharmaceuticals, Inc. Methode de traitement de troubles associes a la voie du recepteur de la melanocortine 4
WO2019195756A1 (fr) 2018-04-06 2019-10-10 Rhythm Pharmaceuticals, Inc. Compositions pour le traitement d'une rénopathie
JP7288554B1 (ja) 2020-06-09 2023-06-07 ファイザー・インク メラノコルチン４受容体アンタゴニストとしてのスピロ化合物およびそれらの使用
JP2023525394A (ja) * 2020-06-09 2023-06-15 ファイザー・インク メラノコルチン４受容体アンタゴニストとしてのスピロ化合物およびそれらの使用
WO2022247783A1 (fr) * 2021-05-24 2022-12-01 中国科学技术大学 Utilisation d'un récepteur de mélanocortine mc5r

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