WO2008017852A1 - Composés pipérazine tétrasubstituée contenant une diamine en tant que modulateurs de récepteur de mélanocortine - Google Patents

Composés pipérazine tétrasubstituée contenant une diamine en tant que modulateurs de récepteur de mélanocortine Download PDF

Info

Publication number
WO2008017852A1
WO2008017852A1 PCT/GB2007/003039 GB2007003039W WO2008017852A1 WO 2008017852 A1 WO2008017852 A1 WO 2008017852A1 GB 2007003039 W GB2007003039 W GB 2007003039W WO 2008017852 A1 WO2008017852 A1 WO 2008017852A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
propan
compound
propionyl
naphthalen
Prior art date
Application number
PCT/GB2007/003039
Other languages
English (en)
Inventor
Shubh D. Sharma
Yi-Qun Shi
Kevin Burris
Papireddy Purma
Yadi Reddy Bonuga
Original Assignee
Palatin Technologies, Inc.
Snodin, Michael, David
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/464,053 external-priority patent/US7968548B2/en
Priority claimed from US11/464,069 external-priority patent/US7727990B2/en
Priority claimed from PCT/US2006/031472 external-priority patent/WO2007021990A2/fr
Application filed by Palatin Technologies, Inc., Snodin, Michael, David filed Critical Palatin Technologies, Inc.
Publication of WO2008017852A1 publication Critical patent/WO2008017852A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to tetra-substituted piperazine compounds with diamine groups that bind to one or more n ⁇ elanocortin receptors and are agonists, antagonists, mixed agonist-antagonists, inverse agonist or antagonists of inverse agonists with respect to one or more melanocortin receptors, and use thereof for the treatment of metabolic, immune, infection-related and other melanocortin receptor-mediated disorders, including treatment of obesity and related energy homeostasis disorders and diseases.
  • melanocortin- 1 receptors MCl-R
  • melanocortin-2 receptors MC2-R
  • ACTH coronase
  • MC3-R and MC4-R melanocortin-3 and melanocortin-4 receptors
  • MC5-R melanocortin-5 receptors
  • compounds specific for MCl-R are believed to be useful for treatment of melanoma.
  • Compounds specific for MC3-R or MC4-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and treatment of other food intake and metabolism-related purposes.
  • Compounds specific for MC3-R and MC4-R can further be used as agents for treatment of sexual dysfunction, including male erectile dysfunction and female sexual dysfunction.
  • melanocortin receptor-specific compounds such as MCR-I agonists
  • MCR-I agonists can be used as tanning agents to increase melanin production in the skin, acting as chemo-preventive agents against harmful effects of UV solar radiation.
  • Compounds specific for MCR-I and MCR-3 may further be useful in regulation of inflammatory processes.
  • high affinity compounds for melanocortin receptors can be used to exploit varied physiological responses associated with the melanocortin receptors, either as agonists or antagonists.
  • melanocortin receptors have an effect on the activity of various cytokines, and high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.
  • piperazine and piperidine compounds known, such as those disclosed in WO 02/070511 (Bristol-Myers Squibb Company), WO 02/059095 (Eli Lilly and Company), and WO 00/74679 (Merck & Co., Inc.), asserted to be specific for melanocortin or related receptors.
  • such compounds have at most two functional substituted groups, have relatively poor affinity and specificity, and are not suitable for use as a drug compound.
  • High affinity compounds for such receptors can be used to exploit varied physiological responses associated with the receptors, either as agonists or antagonists. There is thus a need for compounds that are more selective, including higher affinity and specificity, and in particular for compounds that have at least three or four biologically active substituted groups. This invention addresses that need.
  • WO 02/085925 "Melanocortin Receptor Ligands", to The Proctor & Gamble Company, discloses ketopiperazine structures and methods of synthesis thereof, but does not disclose piperazine structures, piperazine structures with four or more substituted groups, methods to synthesize piperazine structures, methods to synthesize piperazine structures with four or more substituted groups, or methods to synthesize optically pure structures, and further does not disclose structures with a single substituent group that is a single D-Phe or D-NaI residue, or a derivative or homolog thereof, optionally with an amine capping group.
  • R la , R lb , R 2a , and R 2b are independently a C 1 to C 6 aliphatic linear or branched chain and the remaining of R la , R lb , R 2a , and R 2b are hydrogen, provided that at least one of R la and R Ib and at least one of R 2a and R 2b are hydrogen; or one of R la , R lb , R 2a , and R 2b are
  • R a and R 2b is hydrogen
  • y is in each instance an independent index value from 0 to 5;
  • W is a diamine heteroatom unit with at least one cationic center, hydrogen bond donor or hydrogen bond acceptor;
  • L 2 is abond or (CH 2 ) z ;
  • z is an index value from 1 to 6;
  • R 9 is hydrogen or N(R 10a )R 10b ;
  • R 1Oa and R 3Ob are independently hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butanoyl, pentanoyl, heptanoyl, cyclopropyl, cyclopropyhnethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexyknethyl, or polyethylene glycol; v is an index value from 0 to 2; and
  • Q and J are the same and represent an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl;
  • carbon atoms marked with an asterisk can have any stereochemical configuration.
  • polyethylene glycol may have a formula molecular weight of between 100 and 50,000.
  • Q may be:
  • R 3a , R 3b and R 3c are optional ring substituents, and when one or more are present, are the same or different and independently hydroxyl, halogen, alkyl, -O-alkyl, aryl, or -O-aryl.
  • At least one of R 3a , R 3b or R 3c is -CH 3 or -0-CH 3 . In another aspect, at least one of R 3a , R 3b or R 3c is -Cl or -CF 3 .
  • W may include an amine, amide, alcohol, carboxylic acid, ether, ester, or urea. Thus in one aspect W is
  • R 4 is NH
  • R 5 comprises a diamine, CH 2 , provided that R 5 comprises a diamine, C 6 H 5 , provided that R 5 comprises a diamine, N(-CH 2 )z, where N(CH 2 ) Z together with R 5 forms a ring, N(-(CH 2 ) y -CH 3 ),
  • R 5 comprises a diamine
  • R 4 comprises a diamine
  • R 4 comprises a diamine
  • R 4 comprises a diamine
  • positions 1 to 5 are a heteroatom selected from N for position 1 and S, O or NH for positions 2 to 5, provided that only one N is present if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 comprises a diamine,
  • positions 1 to 5 are a heteroatom selected from N for position 1 and for the position to which R is bound if such position does not comprise C, and otherwise S, O or NH, provided that R 5 including R 6 comprises only one N if R 4 comprises an N 5 no N is present if R 4 comprises a diamine and otherwise R 5 including R comprises a diamine,
  • At least one bond between adjacent ring atoms is a double bond, and none or one or more of positions 1 to 5 are a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH for positions 2 to 5, provided that not more than one position is S or O, and further provided that only one N is present if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 comprises a diamine,
  • positions 1 to 5 are optionally a heteroatom selected from N for position 1, the position to which R 6 is bound if such position does not comprise C, and any double bond position and otherwise S, O or NH for positions 2 to 5, provided that not more than one position is S or O, and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine, where at least one bond between adjacent ring atoms is a double bond, the oxo is bound to a ring carbon, and one or more of the remaining of positions 1 to 5 are optionally a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH for positions 2 to 5, provided that not more than one ring position is S or O, and further provided that only one N is present if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise
  • positions 1 to 5 are optionally a heteroatom selected from N for position 1, the position to which R 6 is bound if such position does not comprise C, and any double bond position and otherwise S, O or NH for positions 2 to 5, provided that not more than one position is S or O, and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • positions 1 to 6 are a heteroatom selected from N for position 1 and S, O or NH for positions 2 to 6, provided that R 5 together with R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • positions 1 to 6 are a heteroatom selected from N for position 1 and the position to which R is bound if such position does not comprise C, and otherwise S 5 O or NH, provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • At least one bond between adjacent ring atoms is a double bond, and one or more of positions 1 to 6 are a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH or N- (CH 2 ) y -CH 3 for positions 2 to 6, provided that not more than two positions are S or O, and further provided that R 5 together with R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • positions 1 to 6 are optionally a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH for positions 2 to 6, provided that not more than two positions are S or O, and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • the oxo is bound to a ring carbon, and one or more of the remaining of positions 1 to 6 are optionally a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH for positions 2 to 6, provided that not more than two positions are S or O 3 and further provided that only one N is present if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 comprises a diamine, or where at least one bond between adjacent ring atoms is a double bond, the oxo is bound to a ring carbon, and one or more of positions 1 to 6 are optionally a heteroatom selected from N for position 1, the position to which R 6 is bound if such position does not comprise C, and any double bond position and otherwise S, O or NH for positions 2 to 6, provided that not more than two positions are S or O, and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present
  • R 6 is hydroxyl, (CH 2 ) y -CH 3 , (CH 2 ) y -NH 2 , NH 2 , NH-(CH 2 ) y -CH 3 or N(-(CH 2 ) y -CH 3 ) 2 ;
  • t is an index value from 0 to 6;
  • y is in each instance independently an index value from 0 to 5; and
  • z is an index value from 1 to 6; provided that, any NH or NH 2 in the foregoing may be substituted by N-Prg or NH- Prg, respectively, where each Prg is independently an amine protecting group.
  • the ring structure may include only one double bond, or may include more than one double bond, and in particular, the use of the circle does not imply that all possible double bonds are present.
  • each Prg may independently be acetyl, adamantyloxy, benzoyl, benzyl, benzyloxy, t-butoxycarbonyl, mesitylene-2-sulfonyl, 4-methoxy-2,3- 6-trimethyl-benzenesulfonyl, 2,2,4,6,7-pentamethyldihydrobenzofurane-5-sulfonyl, 2,2,5 s 7,8-pentamethylchromane-6-sulfonyl, or tosyl.
  • W is ; where R 4 is NH,
  • R 5 comprises a diamine, CH 2 , provided that R 5 comprises a diamine, N(-CH 2 ) Z where N(CH 2 ) 2 together with R 5 forms a ring,
  • R 4 comprises a diamine
  • R 4 comprises a diamine
  • R 4 comprises a diamine, where none, one or more of positions 1 to 5 are a heteroatom selected from N for position 1 and S, O or NH for positions 2 to 5, provided that only one N is present if R 4 comprises an N 5 no N is present if R 4 comprises a diamine and otherwise R 5 comprises a diamine,
  • positions 1 to 5 are a heteroatom selected from N for position 1 and for the position to which R 6 is bound if such position does not comprise C, and otherwise S, O or NH, provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • At least one bond between adjacent ring atoms is a double bond, and none or one or more of positions 1 to 5 are a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH for positions 2 to 5, provided that not more than one position is S or O, and further provided that only one N is present if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 comprises a diamine,
  • positions 1 to 5 are optionally a heteroatom selected from N for position 1, the position to which R 6 is bound if such position does not comprise C, and any double bond position and otherwise S, O or NH for positions 2 to 5, provided that not more than one position is S or O, and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine, where at least one bond between adjacent ring atoms is a double bond, the oxo is bound to a ring carbon, and one or more of the remaining of positions 1 to 5 are optionally a heteroatom selected from N for position 1 and any double bond position and otherwise S 5 O or NH for positions 2 to 5, provided that not more than one ring position is S or O, and further provided that only one N is present if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise
  • positions 1 to 5 are optionally a heteroatom selected from N for position 1, the position to which R 6 is bound if such position does not comprise C 5 and any double bond position and otherwise S 5 O or NH for positions 2 to 5, provided that not more than one position is S or O 5 and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N 5 no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • positions 1 to 6 are a heteroatom selected from N for position 1 and S 5 O or NH for positions 2 to 6, provided that R 5 together with R 6 comprises only one N if R 4 comprises an N 5 no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • positions 1 to 6 are a heteroatom selected from N for position 1 and the position to which R 6 is bound if such position does not comprise C, and otherwise S, O or NH, provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • positions 1 to 6 are a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH or N- (CH 2 ) y -CH 3 for positions 2 to 6, provided that not more than two positions are S or O, and further provided that R 5 together with R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • positions 1 to 6 are optionally a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH for positions 2 to 6, provided that not more than two positions are S or O, and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present if R 4 comprises a diamine and otherwise R 5 including R 6 comprises a diamine,
  • the oxo is bound to a ring carbon, and one or more of the remaining of positions 1 to 6 are optionally a heteroatom selected from N for position 1 and any double bond position and otherwise S, O or NH for positions 2 to 6, provided that not more than two positions are S or O, and further provided that only one N is present if R 4 comprises an N 5 no N is present if R 4 comprises a diamine and otherwise R 5 comprises a diamine, or where at least one bond between adjacent ring atoms is a double bond, the oxo is bound to a ring carbon, and one or more of positions 1 to 6 are optionally a heteroatom selected from N for position 1, the position to which R 6 is bound if such position does not comprise C, and any double bond position and otherwise S, O or NH for positions 2 to 6, provided that not more than two positions are S or O, and further provided that R 5 including R 6 comprises only one N if R 4 comprises an N, no N is present
  • R 6 is hydroxyl, (CH 2 ) y -CH 3 , (CH 2 ) y -NH 2 , NH 2 , NH-(CH 2 ) y -CH 3 or N(-(CH 2 ) y -CH 3 ) 2 ;
  • R 7 is a C 4 to C 10 aliphatic comprising an optionally substituted cycloalkane or aryl ring;
  • y is in each instance independently an index value from 0 to 5; and
  • z is an index value from 1 to 6; wherein any NH or NH 2 in the foregoing may be substituted by N-Prg or NH-Prg, respectively, where each Prg is independently an amine protecting group.
  • the ring structure may include only one double bond, or may include more than one double bond, and in particular, the use of the circle does not imply that all possible double bonds are present.
  • each Prg may independently be acetyl, adamantyloxy, benzoyl, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, mesitylene-2-sulfonyl, 4- methoxy-2,3-6-trimethyl-benzenesulfonyl, 2,2,4,6,7-pentamethyldihydrobenzofurane- 5-sulfonyl, 2,2,5,7 5 8-pentamethylchromane-6-sulfonyl, 9-fiuorenylmethoxycarbonyl or tosyl.
  • one of R 2a and R 2b is and the remaining of R 2a and IT and both R la and i R n i 1 b are hydrogen,
  • the invention further provides a compound having the formula of structure II
  • R la , R lb , R 2a , and R 2b are independently a Ci to C 6 aliphatic linear or branched chain and the remaining of R la , R lb , R 2a , and R 2b are hydrogen, provided that at least one of R la and R lb and at least one of R 2a and R 2b are hydrogen; or one of R la , R lb , R 2a , and R 2b are
  • R 5a is NH 2 , NH-(CH 2 ) r CH 3 , or N(-(CH 2 ) y -CH 3 ) 2 ;
  • y is in each instance independently an index value from 0 to 5;
  • R 9 is hydrogen or N(R 1Oa )R 10b ;
  • R 1Oa and R 10b are independently hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butanoyl, pentanoyl, heptanoyl, cyclopropyl, cyclopropyhnethyl, cyclobutyl, cyclobutyhnethyl, cyclohexyl or cyclohexylmethyl;
  • Q and J are the same and represent an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl; and z is an index value from 1 to 6;
  • carbon atoms marked with an asterisk can have any stereochemical configuration.
  • a pharmaceutical composition comprising a compound of structure I or structure II and a pharmaceutically acceptable carrier.
  • the use of such pharmaceutical composition is further provided, such as use for affecting melanocortin receptor ranction in a human or non-human mammal by administering the pharmaceutical composition.
  • the pharmaceutical composition for making a medicament for treating a condition responsive to changes in melanocortin receptor function in a human or non- human mammal.
  • the condition may be selected from the group consisting of male sexual dysfunction, female sexual dysfunction, an eating disorder, above optimal body weight, obesity, below-optimal body weight and cachexia.
  • the present invention further provides compounds that are agonists of a melanocortin receptor, including one or more of MCl-R, MC3-R, MC4-R, or MC5-R.
  • the compounds alternatively are antagonists of a melanocortin receptor, including one or more of MCl-R, MC3-R, MC4-R, or MC5-R.
  • the compounds alternatively are inverse agonists of a melanocortin receptor, including one or more of MCl-R, MC3- R, MC4-R, or MC5-R.
  • the compounds alternatively are antagonists of an inverse agonist of a melanocortin receptor, including one or more of MCl-R, MC3-R, MC4- R, or MC5-R.
  • the invention further includes methods for altering a disorder or condition associated with the activity of a melanocortin receptor, comprising administering to a patient a pharmaceutically effective amount a compound of this invention.
  • the disorder or condition is an eating disorder such as cachexia.
  • the disorder or condition is obesity and associated impairment of energy homeostasis.
  • the disorder or condition is sexual dysfunction such as erectile dysfunction or female sexual dysfunction.
  • One object of the present invention is to provide conformationally constrained and optically pure isomers of tetra-substituted piperazine, wherein the pendant group substituents are amino acid moieties, amino acid side chain moieties or derivatives thereof, such that the resulting ring compound biologically mimics a relevant reverse turn peptide structure.
  • Another object of the present invention is to provide methods for the synthesis of optically pure tetra-substituted piperazine compounds.
  • Another object of the present invention is to provide a method for synthesis of tetra- substituted piperazine compounds of the invention.
  • piperazine rings may be employed with four descriptors, wherein each descriptor is a pendant group attached to a given ring atom, and where one descriptor includes a diamine group. At least two, and optionally all three, of the remaining pendant groups comprise a ring structure, wherein the ring in each of the descriptors or pendant groups is carbocyclic, and where at least two of such rings are aromatic.
  • the inventors have further found that the chirality of the ring, and stereo structure generally, is fixed in a desired structure, thereby more closely mimicking the desired pharmacophores, and with the descriptors positioned in the most relevant chemical space.
  • the invention further also relates to enantiomerically pure tetra-substituted piperazines, preferably made by the synthetic schemes disclosed herein or variants thereof.
  • a classical piperazine ring is a conformationally dynamic six-membered ring structure. It can exist in a variety of conformational states, commonly referred to as chair, boat, twisted chair or twisted boat conformations. Because of this dynamism in structural states, the location of descriptors on the ring plays an important role in stabilizing the ring in a single conformational state; if the appropriate conformational state is selected, this is conducive to making a molecule more selective for its receptor.
  • a 1,3 axial placement of two bulky descriptors generally causes unfavorable steric interactions between these two groups, and thus make a chair conformation energetically less stable. Consequently, the chair conformation is less preferred, resulting in a twisted chair or boat conformation.
  • the twisted chair or boat conformation results in a specific stereochemical alignment of the descriptors, which is specifically relevant to interaction with the desired receptor.
  • a conformation resulting from 1,3 axial placement of two descriptors may result in a structure more selective for a given receptor sub-type.
  • the invention describes tetra-substituted piperazine compounds in which one substituted group includes a diamine which are specific for G-protein coupled receptor systems, such systems including, but not limited to, melanotropin or melanocortin receptors (MCl-R, MC3-R, MC4-R and MC5-R).
  • G-protein coupled receptor systems such systems including, but not limited to, melanotropin or melanocortin receptors (MCl-R, MC3-R, MC4-R and MC5-R).
  • amino acid and “amino acids” used in this invention, and the terms as used in the specification and claims, include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviations. See generally Synthetic Peptides: A User's Guide. GA Grant, editor, W.H. Freeman & Co., New York, 1992, the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino .
  • amino acid side chain moiety used in this invention includes any side chain of any amino acid, as the term "amino acid' is defined herein, including any derivative of an amino acid side chain moiety, as the term “derivative” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non- protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid disclosed herein is included within the definition of an amino acid side chain moiety.
  • derivatives of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties.
  • derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, and saturated or unsaturated alkyl, aryl or aralkyl moieties.
  • the term "homolog” includes, without limitation, (a) a D-amino acid residue or side chain substituted for an L-amino acid residue side chain, (b) a post-translationally modified residue or side chain substituted for the residue or side chain, (c) a non-peptide or other modified amino acid residue or side chain based on another such residue or side chain, such as phenylglycine, homophenylalanine, ring-substituted halogenated, and alkylated or arylated phenylalanines for a phenylalanine residue, diamino propionic acid, diamino butyric acid, ornithine, lysine and homoarginine for an arginine residue, and the like, and (d) any amino acid residue or side chain, coded or otherwise, or a construct or structure that mimics an amino acid residue or side chain, and which has at least a similarly charged side chain (neutral, positive or negative),
  • alkene includes unsaturated hydrocarbons that contain one or more double carbon-carbon bonds. Examples of such alkene groups include ethylene, propene, and the like.
  • alkenyF includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one double bond; examples thereof include ethenyl, 2- propenyl, and the like.
  • alkyl groups specified herein include those alkyl radicals in either a straight or branched configuration.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
  • alkynyF includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one triple bond; examples thereof include ethynyl, propynyl, butynyl, and the like.
  • aryl includes a monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, amino, monosubstituted amino, dis ⁇ bstituted amino, hydroxy, carboxy, or alkoxy-carbonyl.
  • substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, amino, monosubstituted amino, dis ⁇ bstituted amino, hydroxy, carboxy, or alkoxy-carbonyl.
  • Examples of an aryl group include phenyl, biphenyl, naphthyl, 1-naphthyl, and 2-naphthyl, derivatives thereof, and the like.
  • aralkyl includes a radical -R a R b where R a is an alkylene (a bivalent alkyl) group and R b is an aryl group as defined above.
  • R a is an alkylene (a bivalent alkyl) group
  • R b is an aryl group as defined above.
  • aralkyl groups include benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
  • aliphatic includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.
  • acyV includes a group RCO-, where R is an organic group.
  • R is an organic group.
  • An example is the acetyl group CH 3 CO-.
  • omega amino derivative' ' ' includes an aliphatic moiety with a terminal amino group.
  • omega amino derivatives include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine.
  • heteroaryF includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
  • 5- or 6-membered heteroaryl are monocyclic heteroaromatic rings; examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazme, pyrimidine, pyrazine, and the like.
  • Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine and thienopyridine.
  • amide includes compounds that have a trivalent nitrogen attached to a carbonyl group (-CO-NH 2 ), such as methylamide, ethylamide, propylamide, and the like.
  • An “imide” includes compounds containing an imido group (-CO-NH-CO-).
  • An “amine” includes compounds that contain an amino group (-NH 2 ).
  • a “nitrile” includes compounds that are carboxylic acid derivatives and contain a (-CN) group bound to an organic group.
  • amino acid side chain moiety is "hydrogen bonding" when the side chain includes hydrogen bond donors and/or hydrogen bond acceptors.
  • an "amine capping group” includes any terminal group attached through a terminal amine, including but not limited to any omega amino derivative, acyl group or terminal aryl or aralkyl, including groups such as a C 1 to C 6 linear or branched chain such as methyl, dimethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or hexyl, groups such as allyl, cyclopropane methyl, hexanoyl, heptanoyl, acetyl, propionoyl, butanoyl, phenylacetyl, cyclohexylacetyl, naphthylacetyl, cinnamoyl, phenyl, benzyl, benzoyl, 12-Ado, 7'-amino heptanoyl, 6-Ahx, Amc or 8-Aoc, or a molecule such as polyethylene glycol with
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and one or more pharmaceutically acceptable carriers and/or other excipients, and optionally one or more other pharmaceutically active ingredients and agents.
  • a "tetra-substituted piperazine”, as used herein, is a piperazine compound or derivative thereof wherein a group other than solely H, and preferably including an amino acid residue or an amino acid side chain moiety, is attached to each ring N member, and further wherein groups other than solely H, O, S or a halogen, preferably including an amino acid side chain moiety, are attached to two ring C members.
  • “Sexual dysfunction” means any condition that inhibits or impairs normal sexual function, including coitus. The term is not limited to physiological conditions, and includes psychogenic conditions or perceived impairment without a formal diagnosis of pathology or disorder.
  • Sexual dysfunction includes erectile dysfunction in a male mammal and female sexual dysfunction in a female mammal.
  • “Erectile dysfunction” is a disorder involving the failure of a male mammal to achieve functional erection, ejaculation, or both. Erectile dysfunction is accordingly synonymous with impotence, and may include the inability to attain or sustain an erection of sufficient rigidity for coitus.
  • Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm, which symptoms may occur separately or in any combination.
  • An increase in erectile dysfunction is often associated with age or may be caused by a physical disease or as a side-effect of drug treatment.
  • Female sexual dysfunction is a disorder including sexual arousal disorder.
  • the term "sexual arousal disorder” includes a persistent or recurrent failure to attain or maintain the lubrication-swelling response of sexual excitement until completion of sexual activity.
  • Sexual dysfunction in females may also include inhibited orgasm and dyspareunia, which is painful or difficult coitus.
  • Female sexual dysfunction includes, but is not limited to, a number of categories of diseases, conditions and disorders including hypoactive sexual desire disorder, sexual anhedonia, sexual arousal disorder, dyspareunia and vaginismus.
  • Hypoactive sexual desire disorder includes a disorder in which sexual fantasies and desire for sexual activity are persistently or recurrently diminished or absent, causing marked distress or interpersonal difficulties.
  • Hypoactive sexual desire disorder can be caused by boredom or unhappiness in a long-standing relationship, depression, stress, dependence on alcohol or psychoactive drugs, side effects from prescription drugs, or hormonal deficiencies.
  • Sexual anhedonia includes decreased or absent pleasure in sexual activity.
  • sexual anhedonia can be caused by depression, drugs, or interpersonal factors.
  • Sexual arousal disorder can be caused by reduced estrogen, illness, or treatment with diuretics, antihistamines, antidepressants or antihypertensive agents.
  • Dyspareunia and vaginismus are sexual pain disorders characterized by pain resulting from penetration and may be caused, for example, by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
  • a melanocortin receptor "agonist” is meant an endogenous or drug substance or compound, including a compound of this invention, which can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.
  • a melanocortin receptor "antagonist” is meant a drug or a compound, including a compound of this invention, which opposes the melanocortin receptor-associated responses normally induced by a melanocortin receptor agonist agent.
  • binding affinity is meant the ability of a compound or drug to bind to its biological target.
  • the compounds disclosed herein can be used for both medical applications and animal husbandry or veterinary applications. Typically, the product is used in humans, but may also be used in other mammals.
  • the term "patient” is intended to denote a mammalian individual, and is so used throughout the specification and in the claims. The primary applications of this invention involve human patients, but this invention may be applied to laboratory, farm, zoo, wildlife, pet, sport or other animals.
  • Melanocortin receptor-specific compounds of this invention that are MCl-R specific can be used as chemoprevention agents against sun-induced, such as by UV radiation, neoplastic activity in human skin.
  • MCl-R agonist compounds of this invention may be employed to stimulate epidermal melanocytes to produce melanin as well as to convert pheomelanin to eumelanin.
  • Eumelanin which is dark brown or black pigmentation, is considered more photo-protective than pheomelanin, which is yellow or red pigmentation.
  • the process of melanogenesis is believed to involve stimulation of MCl-R in epidermal melanocytes, thereby mediating the stimulation of tyrosinase enzymes within these pigment cells, inducing the conversion of tyrosine to dopa and then through dopaquinone to eumelanin.
  • Sun tanning due to direct sun exposure is proposed to result from the same pathway by local production of melanotropic peptide from a POMC gene in the epidermis.
  • stimulation of eumelanin production and conversion of pheomelanin to eumelanin may be a desirable chemoprevention modality in blocking sun- or UV-induced neoplastic activity in skin.
  • a potent, high- affinity and highly selective MCl-R agonist compound of this invention can accordingly be used as a therapeutic chemoprevention agent for combating harmful sun or UV exposure that induces neoplastic activity in skin melanocytes.
  • compounds of this invention including but not limited to compounds that are MC4-R agonists, partial agonists or functionally inactive may be used as a therapeutic agent to modify energy metabolism and feeding behavior, including treatment of pathologic obesity and related conditions.
  • compounds of this invention may be employed with persons who are above optimal body weight, as an aid in weight loss.
  • Compounds of this invention, including but not limited to MC4-R antagonists may be used as a therapeutic agent in eating disorders, such as treatment of anorexia and cachexia, which is malnutrition and wasting due to illness.
  • compounds of this invention may be employed with persons who have below optimal body weight, and in particular with patients desiring to gain additional muscle mass.
  • compounds of this invention can be used as therapeutic agents for treatment of sexual dysfunction, including treatment of both male erectile dysfunction and female sexual dysfunction.
  • compounds of this invention may be used as therapeutic agents for treatment of inflammation, including specifically MCl-R, MC3-R and MC5-R agonists.
  • compounds of this invention that are MC5-R specific can be used as agents to decrease sebum production, and thus may be efficacious in the treatment of acne and related diseases.
  • the compounds for this application may be conveniently formulated for local administration, as through a gel, lotion, cream or other topical formulation.
  • compounds of this invention may be employed in the treatment of drug or alcohol dependence, depression, anxiety and related conditions and indications.
  • the compounds may be formulated by any means, such as those known in the art, including but not limited to tablets, capsules, caplets, suspensions, powders, lyophilized forms and aerosols/aerosolizable formulations and may be mixed and formulated with buffers, binders, stabilizers, anti-oxidants and other agents known in the art.
  • the compounds may be administered by any systemic or partially systemic means such as those known in the art, including but not limited to intravenous injection, subcutaneous injection, administration through mucous membranes, oral administration, dermal administration, skin patches, aerosols and the like.
  • the invention further provides a pharmaceutical composition that includes a compound of this invention and a pharmaceutically acceptable carrier.
  • the compound of this invention may thus be formulated or compounded into pharmaceutical compositions that include at least one compound of this invention together with one or more pharmaceutically acceptable carriers, including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
  • pharmaceutically acceptable carriers including excipients, such as diluents, carriers and the like, and additives, such as stabilizing agents, preservatives, solubilizing agents, buffers and the like, as may be desired.
  • Formulation excipients may include polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • water containing at least one or more buffering constituents is suitable, and stabilizing agents, preservatives and solubilizing agents may also be employed.
  • stabilizing agents, preservatives and solubilizing agents may also be employed.
  • solid administration formulations any of a variety of thickening, filler, bulking and carrier additives may be employed, such as starches, sugars, fatty acids and the like.
  • topical administration formulations any of a variety of creams, ointments, gels, lotions and the like may be employed.
  • non-active ingredients will constitute the greater part, by weight or volume, of the preparation.
  • any of a variety of measured-release, slow-release or time-release formulations and additives may be employed, such that the dosage may be formulated so as to effect delivery of a compound of this invention over a period of time.
  • the compounds of this invention may be in the form of any pharmaceutically acceptable salt.
  • Acid addition salts of the compounds of this invention are prepared in a suitable solvent from the compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic.
  • the acetate salt form is especially useful.
  • suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts.
  • the compounds and pharmaceutical compositions of this invention may be administered by injection, which injection may be intravenous, subcutaneous, intramuscular, intraperitoneal or by any other means known in the art.
  • any route of administration by which the compounds of this invention are introduced across an epidermal layer of cells may be employed.
  • Administration means may include administration through mucous membranes, buccal administration, oral administration, dermal administration, inhalation administration, nasal administration and the like.
  • the dosage for treatment is administration, by any of the foregoing means or any other means, of an amount sufficient to bring about the desired therapeutic effect.
  • One advantageous route of administration is nasal administration, such as by means of a liquid spray, gel or powder.
  • an aqueous solution is employed, preferably administered by means of a metered delivery device.
  • compounds and pharmaceutical compositions of this invention include an aqueous solution, such as a solution including saline, citrate or other common excipients or preservatives, formulated for intranasal administration.
  • compounds and pharmaceutical compositions of this invention include a dry or powder formulation, formulated for intranasal administration.
  • a preparation for nasal administration can take a variety of forms, such as for administration in nasal drops, nasal spray, gel, ointment, cream, powder or suspension.
  • dispensers and delivery vehicles are known in the art, including single-dose ampoules, metered dose devices, atomizers, nebulizers, pumps, nasal pads, nasal sponges, nasal capsules, and the like.
  • the pharmaceutical composition may be in a solid, semi-solid, or liquid form.
  • the compound and other components may be mixed together by blending, tumble mixing, freeze-drying, solvent evaporation, co-grinding, spray-drying, and/or other techniques known in the art.
  • a semi-solid pharmaceutical composition suitable for intranasal administration may take the form of an aqueous or oil-based gel or ointment.
  • the compound and other components can be mixed with microspheres of starch, gelatin, collagen, dextran, polylactide, polyglycolide or other similar materials that form hydrophilic gels.
  • the microspheres can be internally loaded or coated with compound, which upon administration forms a gel that adheres to the nasal mucosa.
  • the formulation is liquid, it being understood that this includes, for example, an aqueous solution, an aqueous suspension, an oil solution, an oil suspension, or an emulsion, depending on the physicochemical properties of the compound and other components.
  • excipients necessary or desirable for formulation, stability, and/or bioavailability may be included in the pharmaceutical composition.
  • exemplary excipients include sugars (such as glucose, sorbitol, mannitol, or sucrose), uptake enhancers (such as chitosan), thickening agents and stability enhancers (such as celluloses, polyvinyl pyrrolidone, starch, and the like), buffers, preservatives, and/or acids and bases to adjust the pH.
  • an absorption promoting component is included in the pharmaceutical composition.
  • Exemplary absorption promoting components include surfactant acids, such as cholic acid, glycocholic acid, taurocholic acid, and other cholic acid derivatives, chitosan and cyclodextrins.
  • the pharmaceutical composition may further include optional components such as humectants, preservatives and the like.
  • a humectant or moisturizing agent can be employed to decrease water loss from the pharmaceutical composition and optionally moisturize nasal mucosa.
  • Exemplary humectants include hygroscopic materials such as glycerine, propylene glycol, polyethylene glycol, polysaccharides and the like.
  • Preservatives may be employed, to prevent or limit bacteria and other microbial growth.
  • One such preservative that may be employed is benzalkonium chloride, such as 0.05% benzalkonium chloride.
  • preservatives include, for example, benzyl alcohol, methylparaben, propylparaben, butylparaben, chlorobutanol, phenethyl alcohol, phenyl mercuric acetate and the like.
  • the pharmaceutical composition may also include rheology modifying agents, such as for varying the viscosity of the pharmaceutical composition.
  • rheology modify agents include polymers and similar materials, such as sodium carboxymethyl cellulose, algin, carageenans, carbomers, galactomannans, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycols, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl chitin, sodium carboxymethyl dextran, sodium carboxymethyl starch, xanthan gum and combinations of the foregoing.
  • Such agents may also act as bioadhesives, to extend the residence time of a compound of the invention within the nasal mucosa.
  • an aqueous solution of compounds or pharmaceutical compositions of this invention may be appropriately buffered by means of saline, acetate, phosphate, citrate, acetate or other buffering agents, which are at any physiologically acceptable pH, generally from about pH 4 to about pH 8.
  • a combination of buffering agents may also be employed, such as phosphate buffered saline, a saline and acetate buffer, and the like.
  • a 0.9% saline solution may be employed.
  • a 50 mM solution may be employed.
  • compounds and pharmaceutical compositions of this invention are administered directly into the lung.
  • Intrapulmonary administration may be performed by means of a metered dose inhaler, a device allowing self- administration of a metered bolus of a compound and pharmaceutical composition of this invention when actuated by a patient during inspiration. Both dry powder inhalation and nebulized aerosols may be employed.
  • compounds and pharmaceutical compositions of this invention may be in a dried and particulate form.
  • the particles are between about 0.5 and 6.0 ⁇ m, such that the particles have sufficient mass to settle on the lung surface and not be exhaled, but are small enough that they are not deposited on surfaces of the air passages prior to reaching the lung.
  • any of a variety of different techniques may be used to make dry powder microparticles, including but not limited to micro-milling, spray drying and a quick freeze aerosol followed by lyophilization.
  • micro-particles the constructs may be deposited to the deep lung, thereby providing quick and efficient absorption into the bloodstream. Further, with such an approach, penetration enhancers are not required, as is sometimes necessary with transdermal, nasal or oral mucosal delivery routes.
  • Any of a variety of inhalers may be employed, including propellant-based aerosols, nebulizers, single dose dry powder inhalers and multidose dry powder inhalers.
  • metered dose inhalers which are used to deliver medications for the treatment of asthma, chronic obstructive pulmonary disease and the like.
  • Preferred devices include dry powder inhalers, designed to form a cloud or aerosol of fine powder with a particle size that is always less than about 6.0 ⁇ m.
  • Microparticle size may be controlled by means of the method of making.
  • the size of the milling head, speed of the rotor, time of processing and the like control the microparticle size.
  • the nozzle size, flow rate, dryer heat and the like control the microparticle size.
  • the nozzle size, flow rate, concentration of aerosoled solution and the like control the microparticle size.
  • the compounds and pharmaceutical compositions of this invention may be formulated for and administered by means of an injection, such as a deep intramuscular injection, such as in the gluteal or deltoid muscle, of a time release injectable formulation.
  • a compound or pharmaceutical composition of this invention is formulated with a PEG, such as poly(ethylene glycol) 3350, and optionally one or more additional excipients and preservatives, including but not limited to excipients such as salts, polysorbate 80, sodium hydroxide or hydrochloric acid to adjust pH, and the like.
  • a compound or pharmaceutical composition of this invention is formulated with a poly(ortho ester), which may be an auto-catalyzed poly(orfho ester) with any of a variable percentage of lactic acid in the polymeric backbone, and optionally one or more additional excipients.
  • poly (D,L-lactide-co-glycolide) polymer (PLGA polymer) is employed, preferably a PLGA polymer with a hydrophilic end group, such as PLGA RG502H from Boehringer Ingelheim, Inc. (Ingelheim, Germany).
  • Such formulations may be made, for example, by combining a compound of this invention in a suitable solvent, such as methanol, with a solution of PLGA in methylene chloride, and adding thereto a continuous phase solution of polyvinyl alcohol under suitable mixing conditions in a reactor.
  • a suitable solvent such as methanol
  • PLGA polyvinyl alcohol
  • any of a number of injectable and biodegradable polymers, which are preferably also adhesive polymers may be employed in a time release injectable formulation.
  • the teachings of U.S. Patents 4,938,763, 6,432,438, and 6,673,767, and the biodegradable polymers and methods of formulation disclosed therein, are incorporated herein by reference.
  • the formulation may be such that an injection is required on a weekly, monthly or other periodic basis, depending on the concentration and amount of construct, the biodegradation rate of the polymer, and other factors known to those of skill in the art.
  • the actual quantity of compound of this invention administered to a patient will vary between fairly wide ranges depending upon the mode of administration, the formulation used, and the response desired.
  • the dosage for treatment is administration, by any of the foregoing means or any other means known in the art, of an amount sufficient to bring about the desired effect. This may readily be determined by one of ordinary skill in the art through means such as pharmacokinetic studies, plasma half-life studies, dose escalation studies, and the like.
  • a pharmaceutically effective amount includes an amount of a compound or pharmaceutical composition of this invention that is sufficient to induce the desired effect.
  • the compounds of this invention are highly active, with dose responses as low as 0.01 ⁇ g/kg, generally with optimal or peak dose responses between about 0.01 ⁇ g/kg and 25 ⁇ g/kg, depending on the specific compound and the route of administration.
  • the compound can be administered at 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, 100, or 500 ⁇ g/kg body weight, depending on specific compound selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art.
  • Conventional dose response studies and other pharmacological means may be employed to " determine the optimal dose for a desired effect with a given compound, given formulation and given route of administration.
  • Compounds of this invention may be employed for decreasing food intake and/or body weight in combination with any other agent or drug heretofore employed as a diet aid, or for decreasing food intake and/or body weight. Compounds of this invention may further be employed for increasing food intake and/or body weight in combination with any other agent or drug heretofore employed for increasing food intake and/or body weight.
  • Drugs that reduce energy intake include, in part, various pharmacological agents, referred to as anorectic drags, which are used as adjuncts to behavioral therapy in weight reduction programs.
  • Classes of anorectic drags include, but are not limited to, noradrenergic and serotonergic agents.
  • Noradrenergic medications may be described as those medications generally preserving the anorectic effects of amphetamines but with weaker stimulant activity.
  • the noradrenergic drugs, except phenylpropanolamine generally act through a centrally mediated pathway in the hypothalamus that causes anorexia. Phenylpropanolamine, a racemic mixture of norephedrine esters, causes a release of norepinephrine throughout the body and stimulates hypothalamic adrenoreceptors to reduce appetite.
  • Suitable noradrenergic agents include, but are not limited to, diethylpropion such as TENUATETM (1- ⁇ ropanone, 2-(diethylamino)-i -phenyl-, hydrochloride) commercially available from Merrell; mazindol (or 5-(p-chlorophenyl)-2 5 5-dihydro- 3H-imidazo[2,l-a]isoindol-5-ol) such as SANOREXTM commercially available from Novartis or MAZANORTM commercially available from Wyeth Ayerst; phenylpropanolamine (or Benzenemethanol, alpha-(l-aminoethyl)-, hydrochloride); phentermine (or Phenol, 3-[[4,5-duhydro-lH-imidazol-2-yl)ethyl](4- methylphenyl)amino], monohydrochloride) such as ADIPEX-PTM commercially available from Le
  • Suitable serotonergic agents include, but are not limited to, sibutramine such as MERIDIATM capsules (a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine, 1 -(4-chlorophenyl)-N,N-dimethyl-(alpha)-(2- methylpropyl)-, hydrochloride, monohydrate) commercially available from Knoll, fenfluramine such as PondiminTM (Benzeneethanamine, N-ethyl-alpha-methyl-3- (trifluoromethyl)-, hydrochloride) commercially available from Robbins; dexfenfiuramine such as ReduxTM (Benzeneethanamine, N-ethyl-alpha-methyl-3- (trifluoromethyl)-, hydrochloride) commercially available from Interneuron.
  • sibutramine such as MERIDIATM capsules (a racemic mixture of the (+) and (-) enantiomers
  • Fenfluramine and dexfenfiuramine stimulate release of serotonin and inhibit its reuptake.
  • Sibutramine inhibits the reuptake of serotonin, norepinephrine and dopamine, but does not stimulate secretion of serotonin.
  • serotonergic agents useful with the practice of the present invention include, but are not limited to, certain auoretic gene 5HTIa inhibitors (brain, serotonin) such as carbidopa and benserazide as disclosed by U.S. Pat. No. 6,207,699 which is incorporated herein by reference; and certain neurokinin 1 receptor antagonist and selective serotonin reuptake inhibitors including fluoxetine, fluvoxamine, paroxtine, sertraline and other useful compounds as disclosed by U.S. Pat No. 6,162,805, which is incorporated herein by reference.
  • Other potential agents that may be employed include, for example, 5HT2c agonists.
  • Other useful compounds for reducing energy intake include, but are not limited to, certain aryl-substituted cyclobutylalkylamines as disclosed by U.S. Pat. No. 6,127,424, which is incorporated herein by reference; certain trifluoromethylthiophenylethylamine derivatives as disclosed by U.S. Pat. No. 4,148,923, which is incorporated herein by reference; certain compounds as disclosed by U.S. Pat. No. 6,207,699, which is incorporated herein by reference; certain kainite or AMPA receptor antagonists as disclosed by U.S. Pat. No. 6,191,117, which is incorporated herein by reference; certain neuropeptide receptor subtype 5 as disclosed by U.S. Pat. No. 6,140,354, which is incorporated herein by reference; and certain alpha-blocking agents as disclosed by U.S. Pat. No. 4,239,763, which is incorporated herein by reference.
  • cholecystokinin and serotonin act to decrease appetite and food intake.
  • Leptin a hormone produced by fat cells, controls food intake and energy expenditure.
  • a decrease in weight is associated with a decrease in circulating levels of leptin, suggesting its role in weight homeostasis.
  • Obese patients with high leptin levels are thought to have peripheral leptin resistance secondary to the down-regulation of leptin receptors.
  • Non-limiting examples of useful compounds affecting feeding behavior include certain leptin- lipolysis stimulated receptors as disclosed by WO 01/21647, which is incorporated herein by reference; certain phosphodiesterase enzyme inhibitors as disclosed by WO 01/35970, which is incorporated herein by reference; certain compounds having nucleotide sequences of the mahogany gene as disclosed by WO 00/05373, which is incorporated herein by reference; and certain sapogenin compounds as disclosed by U.S. Pat. No. 4,680,289, which is incorporated herein by reference.
  • PPAR peroxisome proliferator activated receptor
  • monoamine oxidase inhibitors that decrease energy intake or increase energy expenditure are useful with the practice of the present invention.
  • Suitable, but non-limiting, examples of monoamine oxidase inhibitors include befloxatone, moclobemide, brofaromine, phenoxathine, esuprone, befol, toloxatone, pirlindol, amiflamine, sercloremine, apelinaprine, lazabemide, milacemide, caroxazone and other certain compounds as disclosed by WO 01/12176, which is incorporated herein by reference.
  • Certain compounds that increase lipid metabolism are also useful with the practice of the present invention. Such compounds include, but are not limited to, evodiamine compounds as disclosed by U.S. Pat. No. 6,214,831, which is incorporated herein by reference.
  • Nutrient partitioning agents and digestive inhibitors are another strategy in the treatment of obesity by interfering with the breakdown, digestion or absorption of dietary fat in the gastrointestinal tract.
  • Gastric and pancreatic lipases aid in the digestion of dietary triglycerides by forming them into free fatty acids that are then absorbed in the small intestine. Inhibition of these enzymes leads to inhibition of the digestion of dietary triglycerides.
  • Non-limiting examples include a lipase inhibitor, orlistat, such as XENICALTM capsules ((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl ⁇ 4-oxo-2-oxetanyl]methyl]-dodecyl ester) commercially available from Roche Laboratories and certain benzoxazinone compounds as described by WO 00/40247, which is incorporated herein by reference.
  • orlistat such as XENICALTM capsules ((S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl ⁇ 4-oxo-2-oxetanyl]methyl]-dodecyl ester) commercially available from Roche Laboratories and certain benzoxazinone compounds as described by WO 00/40247, which is incorporated herein by reference.
  • thermogenic medications include xanthines, such as caffeine and theophylline, selective ⁇ -3 -adrenergic agonists, for example certain compounds in U.S. Pat. No. 4,626,549, which is incorporated by reference herein, and ⁇ -2-adrenergic and growth hormones compounds as described in U.S. Pat. Nos. 4,937,267 and 5,120,713, which are incorporated by reference herein.
  • a total dosage of the above-described obesity control agents or medications, when used in combination with a compound of this invention can range from 0.1 to 3,000 mg/day, preferably from about 1 to 1,000 mg/day and more preferably from about 1 to 200 mg/day in single or 2-4 divided doses.
  • the exact dose is determined by the attending clinician and is dependent on such factors as the potency of the compound administered, the age, weight, condition and response of the patient.
  • Agents or drugs employed for increasing food intake and/or body weight include appetite stimulants such as megestrol acetate, adrenocorticoids such as prednisolone and dexamethasone, cyproheptidine, serotonergic drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as fiutamide, nilutamide, and zanoterone.
  • appetite stimulants such as megestrol acetate, adrenocorticoids such as prednisolone and dexamethasone, cyproheptidine, serotonergic drugs such as fenfluramine, neuropeptide Y, and androgen antagonists such as fiutamide, nilutamide, and zanoterone.
  • Selected compounds were tested in assays to determine binding and functional status, and were tested in animal models of feeding behavior as discussed below.
  • the following assays and animal models were employed, with modifications as discussed in the examples.
  • a competitive inhibition binding assay was performed using membrane homogenates prepared from HEK-293 cells that express recombinant hMC4-R, hMC3-R, or hMC5- R, and from B- 16 mouse melanoma cells (containing endogenous MCl-R). In some instances, HEK-293 cells that express recombinant hMCl-R were employed. In the examples that follow, all MC3-R, MC4-R and MC5-R values are for human recombinant receptors.
  • MCl-R values are for B-16 mouse melanoma cells, unless the heading is "hMCl-R", in which case the value is for human recombinant MCl-R.
  • Assays were performed in 96 well GF/B Millipore multiscreen filtration plates (MAFB NOBlO) pre-coated with 0.5% bovine serum albumin (Fraction V).
  • Membrane homogenates were incubated with 0.2nM (for hMC4-R) 0.4 nM (for MC3- R and MC5-R) or 0.1 nM (for mouse Bl 6 MCl-R or hMCl-R) [I 125 ]-NDP- ⁇ -MSH (Perkin Elmer) and increasing concentrations of test compounds in buffer containing 25 mM HEPES buffer (pH 7.5) with 100 mM NaCl, 2 mM CaCl 2 , 2 mM MgCl 2 , 0.3 mM 1,10-phenanthroline, and 0.2% bovine serum albumin.
  • the assay mixture contained 25 mM HEPES buffer (pH 7.5) with 100 mM NaCl, 2 mM CaCl 2 , 2 mM MgCl 2 , 0.3 mM 1,10-phenanthroline, 0.5% bovine serum albumin, membrane homogenates, radioligand [I 125 J-AgRP (83-132) (Perkin Elmer) and increasing concentrations of compounds in a total volume of 200 ⁇ L. Binding was measured at radioligand concentrations of 0.2 nM. After incubating for 1 hour at 37 0 C, the reaction mixture was filtered and washed with assay buffer containing 500 mM NaCl.
  • Ki values for test compounds were determined using Graph-Pad Prism ® curve-fitting software.
  • HEK-293 cells that express MC4-R Confluent HEK-293 cells that express recombinant hMC4-R were detached from culture plates by incubation in enzyme-free cell dissociation buffer. Dispersed cells were suspended in Earle's Balanced Salt Solution containing 10 mM HEPES (pH 7.5), 1 mM MgCl 2 , ImM glutamine, 0.5% albumin and 0.3 mM 3-isobutyl-l-methyl- xanthine (IBMX), a phosphodiesterase inhibitor.
  • HEPES pH 7.5
  • IBMX 3-isobutyl-l-methyl- xanthine
  • the cells were plated in 96-well plates at a density of 0.5 x 10 5 cells per well and pre-incubated for 30 minutes. Cells were exposed for 1 hour at 37 0 C to test compounds dissolved in DMSO (final DMSO concentration of 1%) at a concentration range of 0.05 - 5000 nM in a total assay volume of 200 ⁇ L. NDP- ⁇ -MSH was used as the reference agonist. At the end of the incubation period, cells were disrupted by the addition of 50 ⁇ L of lysis buffer (cAMP EIA kit, Amersham) followed by vigorous pipetting. Levels of cAMP in the lysates were determined using a cAMP EIA kit (Amersham). Data analysis was performed by nonlinear regression analysis with Graph-Pad Prism ® software. The maximum efficacies of the test compounds were compared to that achieved by the reference melanocortin agonist NDP- ⁇ MSH.
  • mice Male C57BL/6 mice were obtained from Jackson labs (Bar Harbor, ME). Animals were individually housed in conventional plexiglass hanging cages and maintained on a controlled 12 hour on/off light cycle. Water and pelleted (Harlan Teklad 2018 18% Protein Rodent Diet) food was provided ad libitum. The mice were dosed IP (by intraperitoneal injection) after a 24 hour fast or IN (by intranasal administration) with vehicle or selected compounds (0.1-3 mg/kg, and in some cases up to 10 mg/kg). All animals were dosed once a day (or up to four consecutive days) at the start of the "lights off' period. The changes in food intake for the 4 hour and 20 hour period after dosing relative to control animals administered vehicle were determined. Body weights were determine 4 hours prior to dosing and 20 hours after dosing, and the change in body weight relative to control animals administered vehicle were determined.
  • the mass values were determined using a Waters MicroMass ZQ device utilizing a positive mode. Mass determinations were compared with calculated values and expressed in the form of mass weight plus one (M+l or M+H). Proton NMR data was obtained using a Bruker 300 MHz spectrometer. The spectra were obtained after dissolving compounds in a deuteriated solvent such as chloroform, DMSO, or methanol as appropriate.
  • One general strategy includes developing a linear intermediate using chiral building blocks such as amino acid derivatives.
  • the linear intermediate can be cyclized using a Mitsunobo reaction strategy or by spontaneous cyclization through reactive groups such as a reaction between an amine and an ester or between an amine and an aldehyde function.
  • the driving force for intramolecular reaction versus intermolecular reaction is the thermodynamically favored reaction forming a six-membered ring structure.
  • the methodology incorporates conditions that do not involve inversion or racemization of chiral centers.
  • the desired chiral product is easily purified by methods known in the art, such as flash chromatography on a silica gel column.
  • the group containing the Q ring can be made by use of an aldehyde derivative of a D- amino acid.
  • an aldehyde derivative of a D- amino acid By use of an ⁇ -amino aldehyde the resulting group has, in its most basic form, the general structure:
  • Compound 1-10 was treated with catalytic amounts of Pd on carbon in ethanol under hydrogen (1 arm.) overnight at room temperature. After filtration through a Celite pad, the solvent was removed. The crude product was dried under vacuum and it was used for next step reaction without further purification.
  • each R 1 is the same, such that the compound of structure I is symmetric with respect to R 1 , where R 1 is of the formula
  • a is an index value from 0 to 2;
  • h is an index value from 0 to 4;
  • R 9 is H orN(R 10a )(R 10b );
  • R 1Oa and R 10b are each independently hydrogen, acetyl, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isobutyl, benzyl, benzoyl, hexanoyl, propionyl, butanoyl, pentanoyl, heptanoyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclohexyl, cyclohexylmethyl, or polyethylene glycol;
  • Q is an aromatic carbocyclic ring selected from the group consisting of phenyl, substituted phenyl, naphthyl and substituted naphthyl;
  • R 2x and R 2y is a C 1 to C 6 aliphatic linear or branched chain
  • R 2x and R 2y is hydrogen; and c is an index value from 0 to 4.
  • Pg 1 is a first protecting group
  • the compound of formula IV can be a compound of formula V:
  • Pg 2 is a second protecting group orthogonal to Pg 1 ; and selectively removing the second protecting groups Pg 2 .
  • the amino acid residue comprising at least one aromatic carbocyclic ring is a D-amino acid.
  • the D-amino acid may be a protected D-2-naphthylalanine.
  • the D-amino acid may be a protected D-phenylalanine, optionally wherein the phenyl ring includes one, two or three ring substituents, and when more than one is present, the ring substituents are the same or different and independently hydroxyl, halogen, alkyl, -O-alkyl, aryl or -0-aryl groups.
  • Representative amino acid residues comprising at least one aromatic carbocyclic ring include D-amino acids such as NaI 1, NaI 2, (N-BzI)NaI 2, (N-PhEt)NaI 2, pF-Phe, Phe(4-Br), Phe(4-CF 3 ), Phe(4-Cl), Phe(3-Cl), Phe(2-Cl), Phe(2,4-diCl), Phe(3,4-diCl), Phe(5-Cl), Phe(2-Cl, 4-CF 3 ), Phe(2-Cl, 4-Me), Phe(3,4-diF), Phe(2-F, 4-Cl), Phe(2,4- diF), Phe(4-I), Phe(4-Me), Phe(2,4-diMe), Phe(4-OMe), Phe(3,4-di-OMe), Phe(2-Me, 4-Cl), Phe(4-NC), Phe(4-NO
  • the amino acid residue comprising at least one aromatic carbocyclic ring may be a protected amino acid residue, such as where the protecting group is Pg 2 .
  • the amino acid residue including at least one aromatic carbocyclic ring may be a D-beta-amino acid.
  • reacting the precursor of formula IV with at least two equivalent proportions of an amino acid residue comprising at least one aromatic carbocyclic ring can include reacting the precursor of formula IV with at least two equivalent proportions of the amino acid residue in a solution of N,N-dimethylformamide comprising (l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride) and 1- hydroxy-7-azabenzotriazole.
  • the precursor of formula IV can be reacted with approximately four equivalent proportions of each of the amino acid residue, (l-emyl-3-[3-dimemylaminopropyl]carbodiimide hydrochloride) and 1- hydroxy-7-azabenzotriazole in a solution of N,N-dimethylformamide.
  • the compound of formula V can be made by a method comprising the steps of: reacting Fmoc-Lys(Trt)-OH with H-D-Leu-OMe HCl in an inert solvent containing 2-( 1 H-benzotriazole- 1 -yl)- 1,1,3,3 -tetramethyluronium tetrafluoroborate and N-methyl-rnorpholine to yield a crude product of formula VII: cyclizing the product of formula VII by heating the product of formula VTI in dry N,N-dimethylformamide and recovering the product of formula VLH:
  • the reduction reaction can include lithium aluminum hydride.
  • Introducing Cbz protecting groups can include a reaction in tetrahydrofuran with benzyl chloroformate.
  • each Q ring may be substituted with one or more ring substituents selected from the group consisting of hydroxyl, halogen, sulfonamide, alkyl, -O-alkyl, aryl, -O-aryl and combinations thereof.
  • Ki (nM) NDP- ⁇ -MSH) MCl-R MC3-R MC4-R MC5-R
  • Ki (nM) NDP- ⁇ -MSH) hMCl-R MC3-R MC4-R MC5-R 22 36 81 30
  • Ki (nM) NDP- ⁇ -MSH) MCl-R MC3-R MC4-R MC5-R
  • Ki (nM) NDP- ⁇ -MSH) hMCl-R MC3-R MC4-R MC5-R 215 321 9 253
  • Example 13 fRV2-Ainino-l- ⁇ (2R5S)-4-[(RV2-amino-3-( ' 2.4-dichlorophenynpropionyl]-5-r3-f2- aminoethylairu ⁇ o)propyl]-2-methylpiperazki-l-yl ⁇ -3-( ' 2.4-dichlorophenyl)propan-l- one
  • Example 17 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-3 5 4-di-Cl-Phe-OH were used.
  • Example 18 fRV2-Amino-l- ⁇ (2S.5RV4-[fRV2-amino-3-r2.4-dimethylphenyl s >propionyl1-2-r4-r2- aminoethylamino>butyl]-5-methylpiperazin-l-yl ⁇ -3-r2.4-dimetliylphenyl)propan-l- one
  • Example 18 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-AIa-OMe and Boc-D-3,4-di-methyl-Phe-OH were used.
  • Example 19 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-trifluromethyl-Phe-
  • Example 21 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3-trifluromethyl-Phe-
  • Example 22 l- ⁇ (2R.5SV5-r4-g-Aminoethylainino ⁇ butyll-4-[3-r3,4-dichlorophenyl ' ) ⁇ )ropionyl1-2- isobutylpiperazin- 1 -yl ⁇ -3-(3.4-dichlorophenyl)propan- 1 -one
  • Example 22 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-Cl-propionic acid were used.
  • Example 23 The compound of Example 23 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-Cl-propionic acid were used. The 3,4-di-Cl-propionic acid was converted to the corresponding aldehyde for a reductive alkylation reaction.
  • Example 24 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-(R)-3-Amino-4 ⁇ (2,4- dichlorophenyl)butyric acid were used.
  • Example 25 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-(R)-3-Amino-3-(2,4- dichlorophenyl)propionic acid were used.
  • Example 26 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-2-methyl-4-chloro-Phe-
  • Example 28 f RV2-Ammo- 1 - ⁇ ( 2S.5R)-4-[Y R)-2-amino-3 -(3.4-difluorophenyl) ⁇ ropionyll -2-[4-r2- aminoethylamino)b ⁇ ityl]-5-isobutylpiperazin-l-yl ⁇ -3-(3,4-difluorophenyl)propan-l- one
  • Example 28 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3,4-di-F-Phe-OH were used.
  • Example 29 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-homo-Phe-OH were used.
  • Example 30 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-tBu-Phe-OH were used.
  • Example 31 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and 3,4-di-methyl-propionic acid were used.
  • Example 32 The compound of Example 32 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of 2-amino- 1,3,4- thiadiazole.
  • Example 33 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-3,4-di-methyl-Phe-OH were used.
  • Example 34 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-2-rnethyl-4-chloro-Phe-
  • Example 35 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-methoxy-Phe-OH were used.
  • Example 36 rR)-2-Ammo-l-(r2R.5SV4-frRV2-ammo-3-biphenyl-4-yl-propionylV5-r4-r2-amino- ethylamino)butyl]-2-isobutylpiperazin- 1 -yl ⁇ -3 -biphenyl-4-yl-propan- 1 -one
  • the compound of Example 36 was made by the methods of Scheme 1 described above, in which Fmoc-Lys(Trt)-OH, D-Leu-OMe and Boc-D-4-phenyl-Phe-OH were used.
  • Example 37 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of 1,2,4-triazole.
  • Example 39 was made by the methods of the Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used.
  • the method C in Scheme 5 was used for incorporation of 2- aminothiazole.
  • Example 40 The compound of Example 40 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of 2-amino-5- methylthiazole.
  • Example 41 The compound of Example 41 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of 2-amino-4- methylthiazole.
  • Example 42 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used.
  • Method C in Scheme 5 was used for incorporation of 2-amino-5-methyl-
  • the compound of Example 43 was derived from the compound of Example 37, in which the free amino groups were acetylated by the reaction of acetic anhydride with the compound of Example 37 in the presence of pyridine.
  • Example 44 The compound of Example 44 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of 5-amino-3- methylisoxazole.
  • Example 45 The compound of Example 45 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of 3-amino-5- methylisoxazole.
  • Example 46 rRV2-Amino-l-((2R.5S)-4-rfR)-2-amino-3-naphthalen-2-yl-propionylV2-isobutyl-5- [3 -fpyrimidin-4-ylamino)propyl]piperazin- 1 -yl) -S-naphthalen- ⁇ -yl-propan- 1 -one
  • the compound of Example 46 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of aminopyrazine.
  • Example 48 rRV2-Amino-l- ⁇ (2R.5SV4-(rRV2-amino-3-na ⁇ h1halen-2-yl-propionylV2-isobutyl-5- [3-(pyrimidia-2-ylamino)propyl] ⁇ iperazin- 1 -yl) -S-naphthalen ⁇ -yl-propan- 1 -one
  • the compound of Example 83 was made by the methods of Schemes 2 and 3 described above, in which Fmoc-Glu(OtBu)-OH, D-Leu-OMe and Boc-D-2-Nal-OH were used. Method C in Scheme 5 was used for incorporation of 2-aminopyrimidine.
  • Example 50 was made by the methods of Scheme 4 described above, in which Boc-L-2,4-di-Cl-Phe-OH was used as QCOOH.

Abstract

La présente invention concerne des composés répondant à la formule de structure (I) : dans laquelle les groupes -C(R8)(CH2)vCH(R9)(CH2)y-Q et -C(R8)(CH2)vCH(R9)(CH2)y-J sont identiques, et R1a, R1b, R2a, R2b, R8, R9, J, Q, W, X, L2, v et y ont les significations données dans la description. La présente invention concerne également l'utilisation de tels composés dans le traitement d'une condition sensible aux changements de la fonction de récepteur de la mélanocortine chez un être humain ou un mammifère non-humain (par exemple, un dysfonctionnement sexuel chez l'homme, un dysfonctionnement sexuel chez la femme, un trouble de l'alimentation, une surcharge corporelle, l'obésité, une souscharge corporelle ou la cachexie).
PCT/GB2007/003039 2006-08-11 2007-08-10 Composés pipérazine tétrasubstituée contenant une diamine en tant que modulateurs de récepteur de mélanocortine WO2008017852A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US82213506P 2006-08-11 2006-08-11
US60/822,135 2006-08-11
US11/464,053 US7968548B2 (en) 2003-05-01 2006-08-11 Melanocortin receptor-specific piperazine compounds with diamine groups
US11/464,069 US7727990B2 (en) 2003-05-01 2006-08-11 Melanocortin receptor-specific piperazine and keto-piperazine compounds
USPCT/US06/031474 2006-08-11
US11/464,053 2006-08-11
PCT/US2006/031472 WO2007021990A2 (fr) 2005-08-11 2006-08-11 Composes de piperazine specifiques du recepteur de la melanocortine avec groupes diamine
USPCT/US06/031472 2006-08-11
US11/464,069 2006-08-11
PCT/US2006/031474 WO2007021991A2 (fr) 2005-08-11 2006-08-11 Composes de piperazine specifique du recepteur de la melanocortine et composes de ketopiperazine
US88643407P 2007-01-24 2007-01-24
US60/886,434 2007-01-24

Publications (1)

Publication Number Publication Date
WO2008017852A1 true WO2008017852A1 (fr) 2008-02-14

Family

ID=38565611

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/003039 WO2008017852A1 (fr) 2006-08-11 2007-08-10 Composés pipérazine tétrasubstituée contenant une diamine en tant que modulateurs de récepteur de mélanocortine

Country Status (1)

Country Link
WO (1) WO2008017852A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2009105825A1 (fr) 2008-02-29 2009-09-03 Mimetica Pty Ltd Antagonistes 3-substitués-1,4-diazepan-2-one du récepteur 5 de la mélanocortine
WO2009105824A1 (fr) * 2008-02-29 2009-09-03 Mimetica Pty Ltd Procédés de modulation de l'activité du récepteur mc5 et traitement de pathologies associées audit récepteur
WO2009105823A1 (fr) 2008-02-29 2009-09-03 Mimetica Pty Ltd Antagonistes 3-aminoalkyl-1,4-diazepan-2-one du récepteur 5 de la mélanocortine
WO2010096854A1 (fr) * 2009-02-27 2010-09-02 Mimetica Pty Ltd Procédés de modulation de l'activité des récepteurs mc3 et/ou mc4 et traitement des conditions associées aux dits récepteurs
WO2010096853A1 (fr) * 2009-02-27 2010-09-02 Mimetica Pty Ltd Procédé de modulation de l'activité du récepteur mc1 et traitement des conditions associées au dit récepteur
US8343958B2 (en) 2008-02-29 2013-01-01 Mimetica Pty Ltd 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5-receptor antagonists
US8377925B2 (en) 2008-02-29 2013-02-19 Mimetica Pty Ltd Methods of modulating the activity of the MC5 receptor and treatment of conditions related to this receptor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085925A2 (fr) * 2001-04-25 2002-10-31 The Procter & Gamble Company Ligands recepteurs de melanocortine
US20040224957A1 (en) * 2003-05-01 2004-11-11 Palatin Technologies, Inc. Melanocortin receptor-specific compounds
WO2005102340A1 (fr) * 2003-05-30 2005-11-03 Palatin Technologies, Inc. Composes de piperazine specifiques de la melanocortine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085925A2 (fr) * 2001-04-25 2002-10-31 The Procter & Gamble Company Ligands recepteurs de melanocortine
US20040224957A1 (en) * 2003-05-01 2004-11-11 Palatin Technologies, Inc. Melanocortin receptor-specific compounds
WO2005102340A1 (fr) * 2003-05-30 2005-11-03 Palatin Technologies, Inc. Composes de piperazine specifiques de la melanocortine

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
AU2009219108B2 (en) * 2008-02-29 2013-11-21 Mimetica Pty Ltd 3-substituted-1,4-diazepan-2-one melanocortin-5 receptor antagonists
US8343958B2 (en) 2008-02-29 2013-01-01 Mimetica Pty Ltd 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5-receptor antagonists
WO2009105823A1 (fr) 2008-02-29 2009-09-03 Mimetica Pty Ltd Antagonistes 3-aminoalkyl-1,4-diazepan-2-one du récepteur 5 de la mélanocortine
US9340517B2 (en) 2008-02-29 2016-05-17 Mimetica Pty Ltd Methods of modulating the activity of the MC5 receptor and treatment of conditions related to this receptor
US8440653B2 (en) 2008-02-29 2013-05-14 Mimetica Pty Ltd 3-substituted-1,4-diazepan-2-one melanocortin-5 receptor antagonists
US8008291B2 (en) 2008-02-29 2011-08-30 Mimetica Pty Ltd 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists
WO2009105824A1 (fr) * 2008-02-29 2009-09-03 Mimetica Pty Ltd Procédés de modulation de l'activité du récepteur mc5 et traitement de pathologies associées audit récepteur
US8377925B2 (en) 2008-02-29 2013-02-19 Mimetica Pty Ltd Methods of modulating the activity of the MC5 receptor and treatment of conditions related to this receptor
KR101620114B1 (ko) 2008-02-29 2016-05-12 미메티카 피티와이 리미티드 3-아미노알킬-1,4-디아제판-2-온 멜라노코르틴-5 수용체 길항제
CN102006873B (zh) * 2008-02-29 2013-09-18 麦提卡公司 调整mc5受体活性的方法以及与这种受体相关的病况的治疗
AU2009219106B2 (en) * 2008-02-29 2013-09-26 Marp Therapeutics Pty Ltd 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists
WO2009105825A1 (fr) 2008-02-29 2009-09-03 Mimetica Pty Ltd Antagonistes 3-substitués-1,4-diazepan-2-one du récepteur 5 de la mélanocortine
AU2009219107B2 (en) * 2008-02-29 2013-11-21 Marp Therapeutics Pty Ltd Methods of modulating the activity of the MC5 receptor and treatment of conditions related to this receptor
KR101620115B1 (ko) 2008-02-29 2016-05-12 미메티카 피티와이 리미티드 Ｍｃ5 수용체의 활성을 조절하는 방법 및 이 수용체와 관련된 상태의 치료 방법
WO2010096853A1 (fr) * 2009-02-27 2010-09-02 Mimetica Pty Ltd Procédé de modulation de l'activité du récepteur mc1 et traitement des conditions associées au dit récepteur
WO2010096854A1 (fr) * 2009-02-27 2010-09-02 Mimetica Pty Ltd Procédés de modulation de l'activité des récepteurs mc3 et/ou mc4 et traitement des conditions associées aux dits récepteurs

Similar Documents

Publication Publication Date Title
US7968548B2 (en) Melanocortin receptor-specific piperazine compounds with diamine groups
US7834017B2 (en) Diamine-containing, tetra-substituted piperazine compounds having identical 1- and 4-substituents
US7727991B2 (en) Substituted melanocortin receptor-specific single acyl piperazine compounds
US7727990B2 (en) Melanocortin receptor-specific piperazine and keto-piperazine compounds
US7964601B2 (en) Melanocortin receptor-specific compounds
US7718802B2 (en) Substituted melanocortin receptor-specific piperazine compounds
US7326707B2 (en) Bicyclic melanocortin-specific compounds
US7732451B2 (en) Naphthalene-containing melanocortin receptor-specific small molecule
US7655658B2 (en) Thieno [2,3-D]pyrimidine-2,4-dione melanocortin-specific compounds
WO2008017852A1 (fr) Composés pipérazine tétrasubstituée contenant une diamine en tant que modulateurs de récepteur de mélanocortine
CN103249723B (zh) 作为enac阻断剂的吡嗪衍生物
US7354923B2 (en) Piperazine melanocortin-specific compounds
WO2010065799A2 (fr) Composés spécifiques du récepteur de mélanocortine piperidine substitué amine
WO2007021990A2 (fr) Composes de piperazine specifiques du recepteur de la melanocortine avec groupes diamine
WO2005079574A1 (fr) Composes bicycliques specifiques de la melanocortine
US7709484B1 (en) Substituted melanocortin receptor-specific piperazine compounds
WO2005102340A1 (fr) Composes de piperazine specifiques de la melanocortine
ZA200509683B (en) Melanocortin receptor-specific compounds
WO2008090357A2 (fr) Composés à base de pipérazine spécifiques du récepteur de la mélanocortine
WO2009144432A1 (fr) Agonistes de mc4-r pour le traitement de l'obésité
TW200817341A (en) Diamine-containing, tetra-substituted piperazine compounds having identical 1-and 4-substituents

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07789170

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07789170

Country of ref document: EP

Kind code of ref document: A1