WO2005047253A1 - Agonistes du récepteur de la mélanocortine - Google Patents

Agonistes du récepteur de la mélanocortine Download PDF

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WO2005047253A1
WO2005047253A1 PCT/KR2004/002930 KR2004002930W WO2005047253A1 WO 2005047253 A1 WO2005047253 A1 WO 2005047253A1 KR 2004002930 W KR2004002930 W KR 2004002930W WO 2005047253 A1 WO2005047253 A1 WO 2005047253A1
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Prior art keywords
amino
cyclohexyl
alkyl
boc
piperidine
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PCT/KR2004/002930
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English (en)
Inventor
Koo Lee
Heui-Sul Park
In-Ae Ahn
Hyun-Ju Yoo
Sung-Pil Choi
Deog-Young Choi
Hyeon-Joo Yim
O-Hwan Kwon
Yutaka Kondoh
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Lg Life Sciences Ltd.
Yamanouchi Pharmaceutical Co., Ltd.
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Publication of WO2005047253A1 publication Critical patent/WO2005047253A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a compound of the following formula 1, pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof effective as an agonist for melanocortin receptor.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are defined as described below.
  • the melanocortin 1 receptor (MC1R) is mainly expressed in melanocytes, monocytes and mast cells and mediates pigmentation of the hair and skin and blocking inflammation.
  • MC2R is expressed in adipocytes and adrenal cells and mediates steroidogenesis in the adrenal gland.
  • MC3R is present in the brain, hyphothalamus, heart, gut and placenta and has been associated with energy homeostasis and inflammation.
  • MC4R is uniquely expressed in the brain and control feeding behavior, energy homeostasis and erectile function.
  • MC4R knock out mice revealed the phenotype of hyperphasia and obesity.
  • MC5R is found in a wide range of tissues and is considered to have a role in the exocrine gland system.
  • melanocortin receptors With the plethora of physiological functions of melanocortin receptors, a large number of compounds have been designed and synthesized in search for potent agonists and antagonists.
  • NDP- ⁇ MSH is a highly potent and nonselective agonist of MC1R, 3R, 4R and 5R and has been reported to attenuate food intake and body weight gain in rat models.
  • a cyclic heptapeptide MT-II is an agonist with a similar non-selective profile and its therapeutic use has proven in clinical trials for the treatment of erectile dysfunction.
  • MC4R agonists for the melanocortin receptors have been disclosed with most of activity in drug discovery aiming at MC4R agonists for the treatment of obesity, sexual dysfunction or inflammation.
  • the Merck research group has disclosed a series of potent and selective MC4R agonists, one of which demonstrated its great effect on augmenting erectile response in mice (J Med. Chem. 2002, 45, 4849).
  • the Chiron research group has disclosed a series of guanidine compounds as agonists that have hyphophasic and anti-obesity effects in the ob/ob mouse model (WO 02/18327).
  • the Bristol-Myers Squibb group has disclosed a highly potent selective MC1R agonist, which showed efficacy in an acute mouse model of inflarnmation (J. Med. Chem. 2003, 46, 1123).
  • the present invention relates to a compound of the following formula 1, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof. in which
  • R 1 represents hydrogen, -(CH 2 ) P -R 6 , -(CH 2 ) p -CO-R 6 , -(CH 2 ) p -SO 2 -R 6 , or -CO-(CH 2 ) p -R 6 , wherein p represents independently 0, 1, 2, or 3,
  • R 6 represents Ci-Cio-alkyl, C 3 -C 8 -cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxyl, each of which is unsubstituted or mono- to polysubstituted by substituents from the group consisting of C ⁇ -C 6 -alkyl, halogen, amino, CrC ⁇ -alkylamino, di(C 1 -C 6 -alkyl)amino, hydroxy, Ci- C 8 -alkoxy, trifluoromethoxy, C !
  • R 2 represents hydrogen, d-Cg-alkyl, or C 3 -C -cycloalkyl
  • R and R together with the atom to which they attached, may form 4- or 8- membered single ring or two rings which may be interrupted by heteroatom from the group consisting of by O, S, and N-(CrC 4 -alkyl),
  • R 3 represents -d-C ⁇ -alkyl, -(CH 2 ) q -C 3 -C 7 -cycloalkyl, -(CH 2 ) q -phenyl, or - (CH 2 ) q -heteroaryl, each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of d-C 6 -alkyl, halogen, amino, CrCe-alkylamino, di(C 1 -C 6 -alkyl)amino, hydroxy, Q-Cs-alkoxy, d-C ⁇ - alkylcarbonyl, arylcarbonyl, d-C 6 -alkoxycarbony
  • R represents phenyl, cyclohexyl, or NR R , wherein
  • R 7 and R 8 independently of one another represent C ⁇ -C 6 -alkyl, -(CH ) q -C - C ⁇ -cycloalkyl, -(CH 2 ) q -phenyl, or -(CH 2 ) q -heteroaryl (wherin q is as defined above), or together with the nitrogen atom to which they attached, may form 4- or 8-membered single ring or two rings which may contain O, S, or N-(C 1 -C 4 -alkyl), and these radicals are unsubstituted or mono- to poly-substituted by substituents from the group consisting of C ⁇ -C 6 -alkyl, halogen, amino, CrC ⁇ -alkylamino, di(C !
  • R 5 represents -(CH 2 ) 0 -R 9 , -(CH 2 ) 0 -COR 9 , or wherein o represents independently 0, 1, 2, or 3, R 9 andR 10 independently of one another represent hydrogen, amino, hydroxy, Ci-C ⁇ -alkyl, d-C ⁇ -alkoxy, C 3 -C -cycloalkyl, phenyl, heterocycle, or heteroaryl, and these radicals except for hydrogen are unsubstituted or substituted by one to three substituents from the group consisting of C ⁇ -C 6 - alkyl, halogen, amino, C ⁇ -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, hydroxy, C ⁇ -C 8 -alkoxy, trifluoromethoxy, d-C 6 -alkylcarbonyl, arylcarbonyl, CrC 6 - alkoxycarbonyl, carbamoyl, d-C ⁇
  • R 9 andR 10 together with the nitrogen atom to which they attached, may form 4- or 8-membered single ring or two rings which may contain O, S, or N- (C ⁇ -C 4 -alkyl).
  • alkyl means straight-chain or branched hydrocarbon radical when used alone or in combination with hetroatoms such "alkyloxy.”
  • cycloalkyl represents unsaturated aliphatic ring including cyclohexyl.
  • aryl represents aromatic group including phenyl, naphthyl, etc.
  • heteroaryl includes 1 to 2 heteroatom(s) from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and represents aromatic 3- to 6- membered ring which can be fused with benzo or C 3 -C 8 -cycloalkyl.
  • monocyclic heteroaryl are, but are not limited to, thiazole, oxazole, thiophene, furane, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and similar group to them.
  • Examples of acyclic heteroaryl are, but are not limited to, indole, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine, furopyridine, and similar group to them.
  • heterocycle includes 1 to 2 heteroatom(s) from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and represents saturated 3- to 6- membered ring which can be fused with benzo or C 3 -C 8 -cycloalkyl. Its examples are, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and similar group to them.
  • R 1 represents hydrogen, -(CH 2 ) P -R 6 , -(CH 2 ) p -CO-R 6 , or -(CH 2 ) p -SO 2 -R 6 , wherein p is as defined above, preferably, R 1 represents hydrogen, or -(CH ) P -R 6 , wherein p is as defined above, ii) R 1 represents -CO-(CH 2 ) p -R 6 , wherein p is as defined above, iii) R 2 represents hydrogen, or d-C 6 -alkyl, iv) R 3 represents -(CH 2 ) q -C 3 -C -cycloalkyl, -(CH 2 ) q -phenyl, or -(CH ) q - heteroaryl, each of which is unsubstituted or mono- to tri-substituted by substituents from
  • R 5 represents -(CH 2 ) 0-1 -heteroaryl, -(CH 2 ) 0- ⁇ -heterocycle, -C(O)N(R 9 )(R 10 ), - (CH 2 ) 0 -OR n , -(CH 2 ) 0-1 -NHR ⁇ , or -(CH 2 ) 0-1 -N(R ⁇ )(R 12 ), wherein R 9 , R 10 , R andR are defined above.
  • Representative compounds of formula 1 according to the present invention include the compounds listed in the following Table 1.
  • the compound according to the present invention also can form pharmaceutically acceptable salts.
  • These pharmaceutically acceptable salts include acid forming non-toxic acid addition salt containing pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; organic carboxylic acid such as tartaric, formic, citric, acetic, trichloroacetic, trifluoroacetic, gluconic, benzoic, lactic, fumaric, maleic, and the like; acid-addition salts formed by sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-tolunesulfonic acid or naphthalenesulfonic acid, and the like; preferably, acid-addition salts formed by sulfuric acid, methansulfonic acid or hydrohalic acid, and the like.
  • the compound according to the present invention can have asymmetric carbon center, and so can be present as R or S isomeric forms, racemates, diasteromeric mixtures, and individual diasteromers.
  • the present invention encompasses all these isomeric forms and mixtures.
  • Compounds of formula (3) can be prepared by coupling a protected amino acid of formula (1) (wherein P represents protecting group, such as BOC, Cbz, Fmoc, etc.) with a piperidine derivative of formula (2) according to general amide coupling conditions, as illustrated in Scheme 1.
  • P represents protecting group, such as BOC, Cbz, Fmoc, etc.
  • Protected amino acid derivatives (1) are either commercially available or may be prepared by literature methods (Williams, R. M., Synthesis of Optically Active a- Amino Acids, Pergamon Press: Oxford, 1989).
  • piperidine derivatives (2) can be prepared from commercially available compounds described in literature (WO 00/14930).
  • Compounds of formula (14) can be prepared through reductive animation of compounds of formula (3) prepared in Scheme 1 and protected amino aldehydes of formula (13), as shown in Scheme 4.
  • a reducing agent for reductive animation NaHB(OAc) 3 or NaBH 3 CN may be used, and DCE, DMF, methanol, DCM, etc. may be used as solvent, but the reaction reagent and solvent are not limited to these.
  • Protected amino aldehydes (13) can be prepared by known methods such as reductive reaction of thioesters or oxidation of amino alcohols from commercially available amino acid, but not limited to them.
  • 4,4-Disubstituted piperidine derivatives (21) can be prepared from acid derivatives that known in literature (WO 00/14930) and converted to the oxazoline- substituted compounds of formula (23). Coupling piperidine derivatives (21) with amino alcohols gives the intermediate of formula (22). The compound (22) can be converted to compounds (23) by cyclization using phosgene and then deprotection. Scheme 6
  • Piperidine substituted piperidine derivatives can be prepared as illustrated in Scheme 7.
  • Piperidinecarboxylic acids of formula (24) can be prepared from commercially available 4-amino-piperidine carboxylic acids or 4-piperidinone and converted to compounds of formula (25) through amide coupling. Cyclization of the compounds of formula (25) carried out through reductive amination using dialdehyde, or alkylation reaction using dihaloalkanes, gives the 4- piperidine substituted piperidine derivatives (26).
  • Compounds (28) can be prepared by the same manner as in the preparation of compounds of formula (23) from compounds of formula (24), and converted into compound of formula (29) through cyclization.
  • Deprotection reaction can be carried out in the presence of strong acid such as hydrochloric acid, trifluoroacetic acid, etc., in the presence of amine base such as triethylamine, diisopropylethylamine, etc., or by hydrogenation.
  • strong acid such as hydrochloric acid, trifluoroacetic acid, etc.
  • amine base such as triethylamine, diisopropylethylamine, etc.
  • Suitable coupling agents usable in coupling reaction are, but are not limited to, carbodiimides such as dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC), l,l'-dicarbonyldiimidazole (CDI), etc.
  • DCC dicyclohexylcarbodiimide
  • EDC l-(3-dimethylaminopropyl)-3- ethylcarbodiimide
  • CDI l,l'-dicarbonyldiimidazole
  • BOP-C1 bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride
  • DPP A diphenylphosphorylazide
  • HATU O-(7-Azabenzotriazol- 1 -yl)-N,N,N' ,N' -tetramethyl- uronium hexafluorophosphate
  • HBTU O-Benzotriazol-l-yl-N,N,N',N'-tetramethyl- uronium hexafluorophosphate
  • products can be separated and purified by customary work-up methods, for example, chromatography, recrystallization, etc.
  • the compounds of the present invention have potent agonistic effect against melanocortin receptors, and so the present invention provides a melanocortin receptor agonistic composition comprising the compound of formula 1 as active ingredients together with pharmaceutically acceptable carrier.
  • the composition according to the present invention has potent effect for the prevention and treatment of, but not limited to, diabetes, erectile dysfunction, obesity, and inflammation.
  • a preferable daily dose would be within the range of 0.01 ⁇ 10 mg/ kg body weight as unitary dosage or separated dosage.
  • a dosage level specific to individual patients can be varied, depending upon specific compound to be used, weight, sex, health condition, diet, administration time and method of drug, excretion rate, drug mixing, and severity of disease condition.
  • any route depending on purpose can administer the compounds according to the present invention. Injection, and oral and nasal administration are preferred, but administration may be made through dermal, intraperitoneal, retroperitoneal, and rectal route.
  • Injectable preparation for example, aqueous or oily suspension for sterile injection, can be prepared according to known method by using proper dispersants, wetting agents, or suspending agents.
  • Solvents usable for this purpose are water, ringer's solution, and isotonic NaCl solution, and sterilized fixed oil is conventionally used as solvent or suspending media, too. Any non-irritable fixed oil including mono-, di-glyceride can be used for this purpose, and aliphatic acid such as oleic acid can be used for injectable preparation.
  • Solid dosage forms for oral administrations are capsules, tablets, pills, powders and granules, and in particular, capsules and tablets are useful. Capsules and tablets are preferable to be prepared as enteric coating.
  • Solid dosage forms can be prepared by mixing compound (1) according to the present invention with one or more inert diluents such as sucrose, lactose, starch, etc., and carriers, for example, lubricants like magnesium stearate, disintegrants, binding agents, etc.
  • inert diluents such as sucrose, lactose, starch, etc.
  • carriers for example, lubricants like magnesium stearate, disintegrants, binding agents, etc.
  • Step A l-BOC-4-Cyclohexyl-4-(t-butylcarbamoyl)piperidine
  • DIPEA 0.348 mL, 2 mmol
  • EDC 600 mg, 1.3 mmol
  • HOBT 230 mg, 1.5 mmol
  • t-butyl amine 0.1137 mL, 1.3 mmol
  • Step B 1 -BOC-4-Cyclohexyl-4- [(2-hydroxy- 1 , 1 -dimethyl)ethylcarbamoyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-piperidine carboxyl chloride and 2-amino-2-methyl-l-propanol using the same procedure as Step
  • Step C l-BOC-4-Cyclohexyl-4-[(4,4-dimethyl)oxazolin-2-yl]piperidine
  • DIPEA 0.348 mL, 2 mmol
  • DMAP 25 mg, 0.2 mmol
  • phosgene 2.5M solution in toluene, 2 mL
  • Step D 4-Cyclohexyl-4-[(4,4-dimethyl)oxazolin-2-yl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(4,4-dimethyl)- oxazolin-2-yl]piperidine prepared in Step C according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 265 (M+l).
  • Step A 1 -BOC-4-Cyclohexyl-4-[(4,4-dimethyl)thiooxazolin-2-yl]piperidine
  • Step B 4-Cyclohexyl-4-[(4,4-dimethyl)thiooxazolin-2-yl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(4,4- dimethyl)thiooxazolin-2-yl]piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 281 (M+l).
  • Step A l-BOC-4-Cyclohexyl-4-[(l-hydroxy)isobutyl]piperidine l-BOC-4-cyclohexyl-4-piperidine aldehyde prepared in Intermediate 15 (295 mg, 1 mmol) was placed in a two-neck round-bottomed flask and 5 mL of THF was added dropwise. The reaction mixture was cooled at 0 ° C and isopropylmagnesium chloride (2.5M solution in hexane, 1 mL) was added dropwise. After 30 min., the reaction mixture was warmed to rt and stirred for additional 3 h.
  • Step B 4-Cyclohexyl-4-[(l-hydroxy)isobutyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(l- hydroxy)isobutyl]piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 240 (M+l).
  • Intermediate 17 4-Cyclohexyl-4-(isobutyryl)piperidine
  • Step A l-BOC-4-Cyclohexyl-4-(isobutyryl) ⁇ iperidine l-BOC-4-Cyclohexyl-4-[(l-hydroxy)isobutyl]piperidine prepared in Step A of Intermediate 16 (200 mg, 0.59 mmol) was placed in a two-neck round bottomed flask and oxalyl chloride (0.052 mL, 0.590 mmol) was added dropwise. The reaction mixture was cooled to -78 °C, and DMSO (0.042 mL) was added dropwise keeping the temperature below -50 °C.
  • Step B 4-Cyclohexyl-4-(isobutyryl)piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4- (isobutryl)piperidine prepared in Step A of Intermediate 17 according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 238 (M+l).
  • Step A 1 -BOC-4-Cyclohexyl-4- ⁇ N-[(2-hydroxy- 1 , 1 -dimethyl)ethyl]imino ⁇ piperidine
  • a solution of l-BOC-4-cyclohexyl-4-piperidine aldehyde, prepared in Intermediate 15, (590 mg, 2 mmol) and 2-hydroxy-l,l-dimethylethylamine (178 mg, 2 mmol) in toluene (10 mL) was added acetic acid (0.05 mL).
  • the reaction mixture was refluxed using Dean Stark apparatus at 90 ° C for 8 h to remove water formed.
  • the reaction mixture was concentrated in vacuo and the residue was dissolved in acetic acid.
  • Step B l-BOC-4-Cyclohexyl-4-[(4,4-dimethyloxazolidin-2-one-3-yl)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4- ⁇ N-[(2-hydroxy- l,l-dimethyl)ethyl]imino ⁇ piperidine prepared in Step A according to the same procedure as Step C of Intermediate 9.
  • MS [M+H] 395 (M+l).
  • Step C 4-Cyclohexyl-4-[(4,4-dimethyloxazolidin-2-one-3-yl)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(4,4- dimethyloxazolidin-2-one-3-yl)methyl]piperidine prepared in Step B according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 295 (M+l).
  • Step A l-BOC-4-Cyclohexyl-4-[(N-methoxy)iminyl]piperidine l-BOC-4-Cyclohexyl-4-piperidine aldehyde, prepared in Intermediate 15, (295 mg, 1 mmol) and methoxyamine (94 mg, 2 mmol) were dissolved in toluene (10 mL), and acetic acid (1-2 drops) was added dropwide to the solution. The reaction mixture was refluxed using Dean Stark apparatus at 90 °C for 8 h. The reaction mixture was quenched with a saturated aqueous NH 4 C1 solution and the organic layer was extracted with EtOAc.
  • Step B 4-Cyclohexyl-4-[(N-methoxy)iminyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(N- methoxy)iminyl]piperidine prepared in the above Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 225 (M+l).
  • Step A l-BOC-4-Cyclohexyl-[(methanesulfonyloxy)methyl]piperidine
  • TEA 2.8 mL, 20 mmol
  • methansulfonyl chloride 3.11 mL, 20 mmol
  • EtOAc a saturated aqueous NH 4 C1 solution
  • the extracts were dried over MgSO 4 , filtered, and concentrated in vacuo.
  • MS [M+H] 323 (M+l).
  • Step B 4-Cyclohexyl-4-[(methanesulfonyloxy)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4- [(methanesulfonyloxy)methyl]piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 276 (M+l).
  • Step A l-BOC-4-Cyclohexyl-4-(azidomethyl)piperidine
  • l-BOC-4-cyclohexyl-4-[(methanesulfonyl)methyl]piperidine prepared in Intermediate 21 (1.88 g, 5 mmol) in DMF (20 mL) was added sodium azide, and the reaction mixture was warmed to 90 °C for 4 h.
  • DMF was distilled off in vacuo, the residue was diluted with water, and the organic material was extracted with EtOAc. The extracts were dried over MgSO 4 , filtered, and concentrated in vacuo.
  • MS [M+H] 323 (M+l)
  • Step B l-BOC-4-Cyclohexyl-4-(aminomethyl)piperidine
  • Pd/C 200 mg
  • Step A l-BOC-4-Cyclohexyl-4-[(cyclohexylamino)methyl]piperidine
  • a solution of l-BOC-4-cyclohexyl-4-(aminomethyl)piperidine prepared in Intermediate 25 (296 mg, 1 mmol) and cyclohexanone (98.3 mg, 1.0 mmol) in DCE (5 mL) was added NaBH(OAc) 3 (678 mg, 3.2 mmol) slowly.
  • a saturated aqueous NaHCO 3 solution was added, and the organic layer was extracted with DCM.
  • the extracts were dried over MgSO , filtered, and concentrated in vacuo.
  • MS [M+H] 379 (M+l)
  • Step B l-BOC-4-Cyclohexyl-4- ⁇ [(cyclohexylmethyl)amino]methyl ⁇ piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-
  • Step C 4-Cyclohexyl-4- ⁇ [(cyclohexyhnethyl)amino]methyl ⁇ piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4- ⁇ [(cyclohexylmethyl)amino]methyl ⁇ piperidine prepared in Step B according to the same procedure as Step B.
  • MS [M+H] 293 (M+l)
  • Step A l-BOC-4-Cyclohexyl-4-[(l,2,4-triazol-l-yl)methyl]piperidine
  • l-BOC-4-cyclohexyl-4-[(methanesulfonyloxy)methyl] piperidine 375 mg, 1 mmol
  • Na-l,2,4-triazole 273 mg, 3 mmol
  • the reaction mixture was quenched wirh a saturated aqueous NH 4 C1 solution, and the organic material was extracted with EtOAc.
  • Step B 4-Cyclohexyl-4-[(l,2,4-triazol-l-yl)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(l,2,4-triazol- l-yl)methyl]piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 249 (M+l)
  • Step B 4-Cyclohexyl-4-[(l,2,3-triazol-l-yl)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(l,2,3-triazol- l-yl)methyl]piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 249 (M+l)
  • Step B l-BOC-4-Cyclohexyl-4- ⁇ [(l-methyl)tetrazol-5-yl]methyl ⁇ piperidine
  • Step C 4-Cyclohexyl-4- ⁇ [(l-methyl)tetrazol-5-yl]methyl ⁇ piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4- ⁇ [(l- methyl)tetrazol-5-yl]methyl ⁇ piperidine prepared in Step B according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 250 (M+l)
  • Step A 1 -BOC-4-Cyclohexyl-4-[(2-pyrrolidinon- 1 -yl)methyl]piperidine NaH (60% in mineral oil, 60 mg, 1.5 mmol) was placed in a 50-mL two-neck round-bottomed flask, filled in nitrogen, and THF (5 mL) was added. The reaction solution was cooled at 0°C in an ice- water bath, and a solution of 2-pyrrolidinone (102 mg, 1.2 mmol) in THF (1 mL) was slowly added.
  • Step B 4-Cyclohexyl-4-[(2-pyrrolidinon-l-yl)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(2- pyrrolidinon-l-yl)methyl]piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 265 (M+l)
  • Step A l-BOC-4-Cyclohexyl-4-[(dimethylamino)methyl] ⁇ iperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-(aminomethyl)- piperidine and formaline according to the same procedure as Intermediate 26.
  • MS [M+H] 325 (M+l)
  • Step B 4-Cyclohexyl-4-[(dimethylamino)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(dimethyl- amino)methyl)piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 225 (M+l)
  • Step A 1 -BOC-4-Cyclohexyl-4- ⁇ [methyl(cyclohexyl)amino]methyl ⁇ piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4- ⁇ [(cyclohexyl)- aminojmethyl ⁇ piperidine and formaline according to the same procedure as
  • Step B 4-Cyclohexyl-4-[(methyl(cyclohexyl)amino)methyl]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4- ⁇ [methyl-
  • Step A l-BOC-4-Cyclohexyl-4-[(benzyloxycarbonyl)amino]piperidine
  • l-BOC-4-cyclohexyl-4-piperidinecarboxylic acid 3.0 g, 10 mmol
  • TEA 2.8 ml, 20 mmol
  • DPPA diphenyl phosphoryl azide
  • Step B l-BOC-4-Cyclohexyl-4-aminopiperidine
  • l-BOC-4-cyclohexyl-4-[benzyloxycarbonyl]amino]piperidine prepared in Step A
  • Pd/C 200 mg
  • the reaction mixture was stirred under H 2 at rt for 12 hr.
  • the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give the title compound.
  • MS [M+H] 283 (M+l)
  • Step A l-BOC-4-Cyclohexyl-4-(dimethylamino)piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-aminopiperidine prepared in Step B of Intermediate 45 and formaline according to the same procedure as Intermediate 26.
  • MS [M+H] 311 (M+l)
  • Step B 4-Cyclohexyl-4-(dimethylamino)piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-(dimethyl- amino)piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 211 (M+l)
  • Step A l-BOC-4-Cyclohexyl-4-[(isopropyl)amino]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-aminopiperidine and acetone according to the same procedure as Step A in Intermediate 26.
  • MS [M+H] 325 (M+l)
  • Step B l-BOC-4-Cyclohexyl-4-[isopropyl(methyl)amino]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[(isopropyl)- aminojpiperidine and formaline according to the same procedure as step A in
  • Step C 4-Cyclohexyl-4-[isopropyl(methyl)amino]piperidine
  • the title compound was obtained from l-BOC-4-cyclohexyl-4-[isopropyl- (methyl)amino]piperidine according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 239 (M+l)
  • Step A (2R)-N-Methanesulfonyl-(4-chlorophenyl)alanine methyl ester
  • TEA 280 mL, 2.00 mmol
  • methansulfonyl chloride 0 ° C .
  • Step B (2R)-N-Methanesulfonyl-(4-chlorophenyl)alanine
  • a solution of (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methyl ester, prepared in Step A, (590 mg, 2 mmol) in H 2 O/MeOH (5 ml, 1/1) was added LiOH (70.0 mg, 2.00 mmol). After the reaction mixture was stirred at rt for 3 h, the reaction solution was concentrated in vacuo and diluted with a aqueous IN HCI. The organic material was extracted with EtOAc, and the extracs were concentrated in vacuo to give the title compound (179 mg, 94.3 %).
  • MS [M+H] 278 (M+l)
  • Step B (2R)-N-Boc-Prolinecarboxyaldehyde
  • (2R)-N-Boc-Proline thioester prepared in Step A, (15.0 g, 6.5 mmol) in acetone was added triethylsilane (5.39 g, 46.3 mmol) and Pd/C (100 mg) at 0°C.
  • the reaction mixture was warmed to rt and stirred for 30 min.
  • the reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo.
  • MS [M+H] 200 (M+l)
  • Intermediate 53 (2R)-N-Methyl-prolinecarboxyaldehyde
  • Step A (2R)-N-Methyl-proline methyl ester
  • (2R)-Proline methylester (1.20 g, 10.0 mmol) and formalin (37 % in H 2 O, 1.12 mL, 15.0 mmol) in DMF (30 mL)
  • NaBH(OAc) 3 (4.20 g, 20.0 mmol)
  • the reaction mixture was concentrated in vacuo, and the residue was diluted with NaHCO 3 (30 mL).
  • the organic material was extracted with EtOAc, and the extracts were dried over MgSO 4 , filtered, and concentrated in vacuo.
  • MS [M+H] 144 (M+l)
  • Step B (2R)-N-Methyl-prolinecarboxyaldehyde
  • the title compound was obtained from (2R)-N-Methyl-proline methyl ester prepared in Step A according to the same procedure as Step B of hitermediate 49 and hitermediate 52.
  • MS [M+H] 114 (M+l)
  • Step B Methyl l-BOC-2-aziridinecarboxylate.
  • Pd/C 300 mg
  • the reaction mixture was filtered through Celite, the filtrate was concentrated in vacuo.
  • MS [M+H] 202 (M+l)
  • Step C l-BOC-2-Aziridinecarboxylic acid
  • the title compound was obtained from Methyl l-BOC-2-aziridinecarboxylate prepared in Step B according to the same procedure as Step B of Intermediate 49.
  • MS [M+H] 188 (M+l)
  • Step A l-BOC-4-(Cbz-Amino)-4-(dimethylcarbamoyl)piperidine
  • the title compound was obtained from l-BOC-4-(Cbz)aminopiperidine carboxylic acid and dimethylamine according to the same procedure as Step A of Intermediate 1.
  • MS [M+H] 406 (M+l)
  • Step B l-BOC-4-Amino-4-(dimethylcarbamoyl)piperidine
  • the title compound was obtained from l-BOC-4-(Cbz)amino-4-(dimethyl- carbamoyl)piperidine prepared in Step A according to the same procedure as Step B of Intermediate 45.
  • MS [M+H] 272 (M+l)
  • Step C l-BOC-4-(Piperidin-l-yl)-4-(dimethylcarbamoyl)piperidine
  • l-BOC-4-amino-4-(dimethylcarbamoyl)piperidine prepared in Step B, (1.35 g, 5 mmol) in DMF (15 mL) was added glutaraldehyde (25% in water, 6 mL) and NaBH(OAc) 3 (2.1 g, 10 mmol). After being stirred at rt for 4h, the reaction mixture was concentrated in vacuo, and the residue was diluted with saturated a aqueous NaHCO 3 solution.
  • Step D 4-(Piperidin-l-yl)-4-(dimethylcarbamoyl)piperidine
  • the title compound was obtained from l-BOC-4-(piperidin-l-yl)-4- (dimethylcarbamoyl)piperidine prepared in Step C according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 240 (M+l)
  • Step A l-BOC-4-(Cbz)Amino-4- ⁇ [(2-hydroxy-l,l-dimethyl)ethyl]carbamoyl ⁇ piperidine
  • the title compound was obtained from l-BOC-4-(Cbz)amino-4-piperidine carboxylic acid and 2-amino-2-methyl-l-propanol according to the same procedure as Step A of Intermediate 1.
  • MS [M+H] 450 (M+l)
  • Step B 1 -BOC-4-(Cbz)Amino-4-[4,4-(dimethyl)oxazolin-2-yl]piperidine
  • the title compound was obtained from l-BOC-4-(Cbz)amino-4- ⁇ [(2-hydroxy- l,l-dimethyl)ethyl]carbamoyl ⁇ piperidine prepared in Step A according to the same procedure as Step C of Intermediate 9.
  • MS [M+H] 432 (M+l)
  • Step C l-BOC-4-Amino-4-[4,4-(dimethyl)oxazolin-2-yl]piperidine
  • the title compound was obtained from l-BOC-4-(Cbz)amino-4-[4,4-
  • Step D l-BOC-4-(Piperidin-l-yl)-4-[4,4-(dimethyl)oxazolin-2-yl]piperidine
  • the title compound was obtained from l-BOC-4-amino-4-[4,4-
  • Step E 4-(Piperidin-l-yl)-4-[4,4-(dimethyl)oxazolin-2-yl]piperidine
  • the title compound was obtained from l-BOC-4-(piperidin-l-y ⁇ )-4-[4,4-
  • Step A Methyl l-BOC-4-(piperidin-l-yl)-4-piperidinecarboxylate
  • the title compound was obtained from methyl l-BOC-4-amino-4-piperidine carboxylate according to the same procedure as Step C of Intermediate 67.
  • MS [M+H] 327 (M+l)
  • Step A l-BOC-4-(pyrrolidin-l-yl)-4-(dimethylcarbamoyl)piperidine
  • TEA 0.560 mL, 4 mmol
  • dibromobutane 473 mg, 1.1 mmol
  • Step B 4-(Pyrrolidin-l-yl)-4-(dimethylcarbamoyl)piperidine
  • the title compound was obtained from l-BOC-4-(pyrrolidin-l-yl)-4-(dimethyl- carbamoyl)piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1.
  • MS [M+H] 226 (M+l)
  • Step A 2-Phthalimino-l-[methyl(BOC)amino]ethane
  • THF 3 mL
  • 2-Phthalimino-l-BOC-aminoethane prepared in Step A of Intermediate 98 (291 mg, 1 mmol) at 0°C.
  • methyl iodide 74.5 ⁇ L, 1.2 mmol
  • THF 1 mL
  • Step B 2-Phthalimino-l-(methyl)aminoethane
  • the title compound was obtained from 2- ⁇ hthalimino-l-methyl(N-BOC)- aminoethane prepared in Step A according to the same procedure as Step B of Intermediate 98.
  • MS [M+H] 205 (M+l)
  • Step B (3S)-l-(2-Nitrobenzene)sulfonyl-3-aminopyrrolidine
  • the title compound was obtained from (3S)-l-(2-nitrobenzene)sulfonyl-3- (BOC)aminopyrrolidine prepared in Step A according to the same procedure as Step B of hitermediate 98.
  • MS [M+H] 272 (M+l)
  • Step B (2R)-2-Amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- 1 -yl]-3-(4- chlorophenyl)propionamide TFA
  • (2R)-2-(BOC)amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step A, (1.00 g, 1.93 mmol) in DCM (7 mL) was added TFA (7 mL).
  • Step A (2R)-2- ⁇ [(2R)-l-(BOC)pyrrolidin-2-yl]carbonyl ⁇ amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin- 1 -yl]-3-(4-chlorophenyl)propionamide
  • Step B (2R)-2- ⁇ [(2R)-Pyrrolidin-2-yl]carbonyl ⁇ amino-N-[4-cyclohexyl-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide TFA
  • (2R)-2- ⁇ [(2R)-l-(BOC)pyrrolidin-2-yl]carbonyl ⁇ amino-N-[4- cyclohexyl-4-(t-butylcarbamoyl)piperidin- 1 -yl] -3 -(4-chlorophenyl)propionamide prepared in Step A, (50.0 mg, 0.081 mmol) in DCM ( 2 mL) was added TFA (2 mL), and the reaction mixture was stirred at rt for 1 h. The reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound
  • Step A (2R)-2- ⁇ [(2R)- 1 -(BOC)Pyrrolidin-2-yl]methyl ⁇ amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • (2R)-2-amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- l-yl]-3-(4-chlorophenyl)propionamide prepared in Example 1 (TFA salt, 100 mg, 0.191 mmol), and (2R)-N-BOC-proline carboxyaldehyde (37.9 mg, 0.191 mmol) in DCE (5 mL) was added NaBH(OAc) 3 (80.0 mg, 0.380 mmol).
  • Example 4 (2R)-2- ⁇ [(2R)-1 -(Methyl)pyrrolidin-2-yl] methyl ⁇ ⁇ amino-N- [4-cyclo- hexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2- ⁇ [(2R)-l-(BOC) ⁇ yrrolidin-2- yl]methyl ⁇ amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide and formaline according to the same procedure as Example 3.
  • MS [M+H] 545 (M+l).
  • Example 5 (2R)-2-(Dimethyl)amino-N-[4-cyclohexyI-4-(t-butylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide TEA
  • the title compound was obtained from (2R)-2-amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide (TFA salt) prepared in Example 1 and formaline according to the same procedure as Example 3.
  • MS [M+H] 476 (M+l).
  • Step A (2R)-2-[ 1 -(BOC)Azetidin-3-yl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin- 1 -yl] -3 -(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide (TFA salt) prepared in Example 1 and formaline according to the same procedure as Step A of Example 3.
  • MS [M+H] 603 (M+l).
  • Step B (2R)-2- ⁇ Fmoc[ 1 -(BOC)azetidin-3-yl] ⁇ amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-[l-(BOC)azetidin-3-yl]amino-N- [4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step A and Fmoc chloride according to the same procedure as Step A of Intermediate 98.
  • MS [M+H] 825 (M+l).
  • Step C (2R)-2-[Fmoc(Azetidin-3-yl)]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin- 1 -yl]-3-(4-chlorophenyl)propionamide TFA.
  • the title compound was obtained from (2R)-2- ⁇ Fmoc[l-(BOC)azetidin-3- yl] ⁇ amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- 1 -yl] -3 -(4- chloro ⁇ henyl)propionamide prepared in Step B according to the same procedure as Step B of Example 1.
  • MS [M+H] 725 (M+l).
  • Step D (2R)-2-[Fmoc(l-Methylazetidin-3-yl)]amino-N-[4-cyclohexyl-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-[Fmoc(azetidin-3-yl)]amino-N- [4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide TFA prepared in Step C and formaline according to the same procedure as Step A of Example 3.
  • MS [M+H] 739 (M+l).
  • Step E (2R)-2-[l-(Methyl)azetidin-3-yl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)]- piperidin- 1 -yl ⁇ -3-(4-chlorophenyl)propionamide 2TFA (2R)-2- ⁇ Fmoc[ 1 -(Methyl)azetidin-3-yl] ⁇ amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide, prepared in Step D, (71.1 mg, 1 mmol) was desolved in 50%) piperidine/DMF solution (2 mL), and the mixture was stirred at rt for 30 min. The reaction solution was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (TFA salt, 52 mg,
  • Examples 7 - 186 The following compounds listed in Table 7 were synthesized from piperidine derivatives prepared in Intermediates using the same procedure described in Examples 1-6.
  • Step A (2R)-2-(BOC)Amino-N-(4-cyclohexyl-4-carboxypiperidin- 1 -yl)-3-(4-chloro- phenyl)propionamide
  • the title compound was obtained from (2R)-N-BOC-(4-chlorophenyl)alanine and 4-cyclohexyl-4-carboxypiperidin-l-yl according to the same procedure as Step A of Example 1.
  • MS [M+H] 493 (M+l).
  • Step B (2R)-2-(BOC)Amino-N-(4-cyclohexyl-4-chlorocarbonylpiperidin-l-yl)-3-(4- chlorophenyl)propionamide
  • MS [M+H] 511 (M+l)
  • Step C (2R)-2-(BOC)Amino-N-[4-cyclohexyl-4-(aminoethylcarbamoyl)piperidin-l- yl] -3 -(4-chlorophenyl)propionamide
  • TEA 1.0 mmol
  • N(BOC)-ethylene diamine 90 mg, 1.5 mmol
  • DCM 0.5 mL
  • Step D (2R)-2- Amino-N-[4-cyclohexyl-4-(aminoethylcarbamoyl)piperidin- 1 -yl] -3 -(4- chlorophenyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2-(BOC)amino-N-[4-cyclohexyl- 4-(aminoethylcarbamoyl)piperidin- 1 -yl]-3-(4-chlorophenyl)propionamide prepared in Step C according to the same procedure as Step B of Example 1.
  • MS [M+H] 435 (M+l).
  • Step E (2R)-2-Amino-N-[4-cyclohexyl-4-(aminoethylcarbamoyl)piperidin-l -yl]-3-(4- chlorophenyl)propionamide 2HC1
  • the title compound was obtained from (2R)-2-amino-N-[4-cyclohexyl-4- (aminoethylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide (2TFA salt) prepared in Step D in methanol, and passed through HCl-substituted ion exchange resin.
  • MS [M+H] 435 (M+l).
  • Step A (2R)-2-(BOC)A ⁇ r ⁇ ino-N-[4-cyclohexyl-4-(phthaliminoethylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-(BOC)Amino-N-[4-cyclohexyl- 4-(chlorocarbonyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step B of Example 187 and 2-phthalimino-l-aminoethanol prepared in hitermediate 98 according to the same procedure as Step C of Example 187.
  • MS [M+H] 665 (M+l).
  • Step B (2R)-2-Amino-N-[4-cyclohexyl-4-(phthaliminoethylcarbamoyl)piperidin-l-yl]- 3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-(BOC)amino-N-[4-cyclohexyl-4- (phthaliminoetl ⁇ ylcarbamoyl)-piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step A according to the same procedure as Step B of Example 1.
  • MS [M+H] 565 (M+l).
  • Step C (2R)-2-(Dimethyl)amino-N-[4-cyclohexyl-4-(phthaliminoethylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-amino-N-[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step B according to the same procedure as Example 3.
  • MS [M+H] 593 (M+l).
  • Step D (2R)-2-(Dimethyl)amino-N-[4-cyclohexyl-4-(aminoethylcarbamoyl)piperidin- l-yl]-3-(4-chlorophenyl)propionamide 2TFA
  • (2R)-2-(dimethyl)amino-N-[4-Cyclohexyl-4-(phthaliminoethyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide, prepared in Step C (200 mg, 0.34 mmol) in MeOH (5 mL) was added hydrazine (0.10 mL, 3.64 mmol), and the reaction mixture was stirred at rt for 12 h.
  • Examples 189 - 225 The following compounds listed in Table 8 were synthesized from reaction piperidin-1-yl derivatives prepared in Intermediates using the same procedure descried in Examples 187 and 188.
  • Step A (2R)-2-Amino-N-[4-cyclohexyl-4-(3-oxo-azetidin-l-yl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide 2TFA
  • (2R)-2-(BOC)amino-N-[4-cyclohexyl-4-(3-hydroxyazetidin-l- yl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Example 204, (200 mg, 0.45 mmol) in DCM (5 mL) was added Dess-Martin reagent (3.0 mL, 15 wt% in DCM, 10 mmol).
  • Step B (2R)-2- Amino-N-[4-cyclohexyl-4-(3-oxo-azetidin- 1 -yl)piperidin- 1 -yl] -3 -(4- chlorophenyl)propionamide 2HC1
  • the title compound was obtained from (2R)-2-amino-N-[4-cyclohexyl-4-(3- oxoazetidin-l-yl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA prepared in Step A according to the same procedure as Step E of Example 187.
  • MS [M+H] 446 (M+l).
  • Example 227 (2R)-2-Amino-N-[4-cyclohexyl-4-(4-oxo ⁇ piperidin-l-yI)piperidin-l- yl]-3-(4-chlorophenyl)propionamide 2HC1
  • the title compound was obtained from (2R)-2-amino-N-[4-cyclohexyl-4-(4- hydroxyazetidin-l-yl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2HC1 prepared in Example 207 according to the same procedure as Example 226.
  • MS [M+H] 474 (M+l).
  • Step A (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl-3-(4-chlorophenyl)propionamide
  • (2R)-2-Amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- l-yl]-3-(4-chlorophenyl)propionamide, prepared in Example 1 (519 mg, 1 mmol), in DMF (10 mL) were added TEA (280 mL, 2 mmol) and (2-nitrobenzene)- sulfonylchloride (222 mg, 1.00 mmol).
  • Step B (2R)-2- ⁇ (2-Nitrobenzene)sulfonyl[2-(dimethyl)aminoethyl] ⁇ amino-N-[4-cyclo- hexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide, prepared in Step A (500 mg, 0.79 mmol) in DMF (5 mL) were added K 2 CO 3 (280 mg, 2 mmol) and 2- (dimethylamino)ethyl chloride (HCI salt, 125.9 mg, 1 mmol).
  • Step C (2R)-2-[2-(dimethyl)aminoethyl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
  • (2R)-2- ⁇ (2-nitrobenzene)sulfoiiyl[2-(dimethyl)aminoethyl] ⁇ - amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)- propionamide prepared in Step B, (500 mg, 0.71 mmol) in DMF (3 mL) were added K 2 CO 3 (300 mg, 2 mmol) and thiobenzene (210 mL, 0.429 mmol).
  • Example 229 (2R)-2- [2-(Methyl)aminoethyl] amino-N- [4-cyclohexyl-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chIorophenyl)propionamide
  • 2TFA Step A: (2R)-2- ⁇ (2-Nitrobenzene)sulfonyl[2-(BOC)aminoethyl] ⁇ amino-N- [4-cyclo- hexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-[(2-nitrobenzene)sulfonyl]- amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)]piperidin-l-yl]-3-(4- chlorophenyl
  • Step B (2R)-2- ⁇ (2-Nitrobenzene)sulfonyl[2-(N-methyl-N-BOC-amino)ethyl] ⁇ amino- N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2- ⁇ (2-nifrobenzene)sulfonyl[2- (BOC)aminoethyl] ⁇ amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide prepared in Step A and iodomethane according to the same procedure as Step B of Example 228.
  • MS [M+H] 740 (M+l).
  • Step C (2R)-2- ⁇ 2-[Methyl(BOC)amino]ethyl] ⁇ amino-N-[4-cyclohexyl-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2- ⁇ (2-nitrobenzene)sulfonyl[2-(N- methyl-N-BOC-amino)ethyl] ⁇ amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l- yl]-3-(4-chlorophenyl)propionamide prepared in Step B according to the same procedure as Step C of Example 228.
  • MS [M+H] 606 (M+l).
  • Step D (2R)-2-[2-(Methyl)aminoethyl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2- ⁇ 2-[Methyl(BOC)amino]- ethyl ⁇ amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide prepared in Step C according to the same procedure as Step B of Example 1.
  • MS [M+H] 506 (M+l).
  • Example 230 (2R)-2-(2-Aminoethyl)amino-N- [4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA Step A: (2R)-2-[2-(BOC)Aminoethyl]amino-N- ⁇ [4-cyclohexyl-4-(t-butylcarbamoyl)]- piperidin- 1 -yl ⁇ -3 -(4-chlorophenyl)propionamide The title compound was obtained from (2R)-2- ⁇ (2-nitrobenzene)sulfonyl[2- (BOC)aminoethyl] ⁇ ammo-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide prepared
  • Step B (2R)-2-(2-Aminoethyl)amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)]piperidin- 1 -yl] -3 -(4-chlorophenyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2-[2-(BOC)aminoethyl]amino-N- [4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step A according to the same procedure as Step B of Example 1.
  • MS [M+H] 463 (M+l).
  • Example 231 (2R)-2-[2-(Acetylamino)ethyl]amino-N-[4-cyclohexyI-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide TFA
  • Step A (2R)-2- ⁇ Methyl[2-(BOC)aminoethyl] ⁇ amino-N-[4-cyclohexyl-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-[2-(BOC)aminoethyl]amino-N- [4-cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step A of Example 230 according to the same procedure as Step A of Example 3.
  • Step B (2R)-2- ⁇ Methyl[2-[methyl(BOC)amino]ethyl] ⁇ -N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin- 1 -yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2- ⁇ Methyl[2-(BOC)aminoethyl] ⁇ - amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)]piperidin-l-yl]-3-(4- chlorophenyl)propionamide prepared in Step A according to the same procedure as Step A of Intermediate 42.
  • MS [M+H] 591 (M+l).
  • Step C (2R)-2- ⁇ Methyl[2-(methyl)aminoethyl] ⁇ -N-[4-cyclohexyl-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2- ⁇ Methyl[2-[methyl(BOC)- amino] ethyl] ⁇ -N- [4-cyclohexyl-4-(t-butylcarbamoyl)]piperidin- 1 -yl] -3 -(4- chloropheny ⁇ )propionamide prepared in Step B according to the same procedure as Step B of Example 1.
  • MS [M+H] 491 (M+l).
  • Example 233 (2R)-2- ⁇ Methyl[2-(amino)ethyl] ⁇ amino-N-[4-cycIohexyl-4-(t- butylcarbamoyl)]piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2- ⁇ Methyl[2-(BOC)amino- ethyl] ⁇ amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- 1 -yl]-3-(4- chlorophenyl)propionamide prepared in Step A of Example 232 according to the same procedure as Step B of Example 1.
  • MS [M+H] 477 (M+l).
  • Step A (2R)-2- ⁇ Methyl[(2-nitrobenzene)sufonyl] ⁇ amino-N-[4-cyclohexyl-4-(t-butyl- carbamoyl)piperidine- 1 -yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-[(2-nitrobenzene)sulfonyl]- amino-N- [4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- 1 -yl] -3 -(4- chlorophenyl)propionamide prepared in Step A of Example 228 according to the same procedure as Step B of Preparation 228.
  • Step B (2R)-2-(Methyl)amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidine-l-yl]-3- (4-chlorophenyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2- ⁇ Methyl[(2-nitrobenzene)- sufonyl] ⁇ amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidine-l-yl]-3-(4- chlorophenyl)propionamide prepared in Step A according to the same procedure as Step C of Preparation 228.
  • MS [M+H] 434 (M+l).
  • Examples 235 - 269 The compounds listed in the following Table 9 were synthesized from piperidine derivatives prepared in Intermediates using the same procedure described in Example 228 -234.
  • Step A (2R)-2-[2-(Dimethyl)aminoethyl]amino-N-[4-cyclohexyl-4-(phthaliminoethyl- carbamoyl)piperidin- 1 -yl]-3 -(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-amino-N-[4-cyclohexyl-4- (phthaliminoethylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide prepared in Step B of Example 188 according to the same procedure as Example 228.
  • MS [M+H] 636 (M+l).
  • Step B (2R)-2-[2-(Dimethyl)aminoethyl]amino-N-[4-cyclohexyl-4-(aminoethyl- carbamoyl)piperidin-l-yl]-3-(4-chloro ⁇ henyl)propionamide 2TFA
  • the title compound was obtained from (2R)-2-[2-(dimethyl)aminoethyl]amino- N- ⁇ [4-cyclohexyl-4-(phthaliminoethylcarbamoyl)]piperidin-l-yl ⁇ -3-(4-chlorophenyl) prepared in Step A according to the same procedures as Steps D and E of Example 188.
  • MS [M+H] 506 (M+l).
  • Examples 271 - 280 The compounds listed in the following Table 10 were synthesized from r piperidine derivatives prepared in Intermediates using the same procedure described in Example 187 and 270.
  • Example 281 (2R)-2-(Carboxymethyl)amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide
  • the title compound was obtained from (2R)-2-[(methoxycarbonyl)- methyl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)pi ⁇ eridin-l-yl]-3-(4-chlorophenyl)- propionamide prepared in Example 259 according to the same procedure as Step B of Preparation 49.
  • MS [M+H] 506 (M+l).
  • A. Binding Assay The membrane fraction binding assay was used to identify competitive inhibitors of 125 I - NDP- MSH binding to cloned human MCRs expressed in HEK cells.
  • Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in ⁇ 150 mm culture dishes in DMEM (GIBCO-BRL) supplemented with 10% FBS, 200 ug/ml Geneticin (GIBCO-BRL), and antibiotics (penicillin and streptomycin) (GIBCO- BRL) in an atmosphere of 6 % CO 2 at 37 ° C. When the cells were fully grown, the cells were washed once with 10 ml of Ca 4- * " , Mg* "1" free DPBS.
  • the cells were incubated with 8 ml of Ca ⁇ , Mg ⁇ free DPBS for 15 - 30 min at 37 ° C until the cells were easily detached by triturating with pipette.
  • the cells were harvested into 50 ml of conical tubes, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the cells were resuspended in 8 ml of Ca " " " , Mg "1"1" free DPBS, and spun at 1500 rpm for 5 min.
  • pellets were resuspended in 3 ml of membrane preparation buffer (50 mM Tris, pH 7.2 ⁇ 7.4, 4 ug/ml Leupeptin ; 10 uM Phosphoramidon ; 40 ug/ml Bacifracin ; 5 ug/ml Aprotinin ; 10 mM Pefabloc).
  • the pellets were homogenized with dounce homogenizer (Bellco with type "B" glass pestle) using 10 - 12 strokes.
  • the homogenate was centrifuged (Beckman XL-100K Ultracentrifuge, Rotor 45 Ti, 50 ml centrifuge tube) at 40,000 rpm (100,000 X g) for 30 min at 4 ° C.
  • the pellets were resuspended in 20 ml of membrane preparation buffer, and protein was determined by BCA assay kit (PIERCE). Aliquots were placed in tubes and stored at - 80 ° C.
  • the reaction mixture was filtered with 96 well GF/C filter plate (Unifilter GF/CTM, Packard) presoaked with 0.1 % polyethleneimine for 30 min.
  • the filter plate was washed 3 times with 200 ul of washing buffer (50 mM Tris pH 7.2; 20 mM NaCl) under vacuum at 8 "Hg.
  • the filter was dried for 15 min at room temperature, and the bottom was sealed.
  • 40 ul of Packard MicroscintTM-20 was added to each well. The top was sealed, and the radioactivity was quantitated in a Packard Topcount Microplate Scintillation Counter.
  • the IC 50 was defined as the concentration of test compound that results in the half maximal inhibition of 125 I - NDP-MSH binding to cloned human MCRs.
  • the ICso values obtained in the competition assay were converted to affinity constants (Ki values).
  • cAMP Accumulation Assay The membrane fraction cAMP assay was used to identify MC4R agonist compounds.
  • Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in ⁇ 150 mm culture dishes in DMEM (GIBCO-BRL) supplemented with 10% FBS, 200 ug/ml Geneticin (GIBCO-BRL), and antibiotics (penicillin and streptomycin) (GIBCO- BRL) in an atmosphere of 6 % CO 2 at 37 ° C. When the cells were fully grown, the cells were washed once with 10 ml of Ca "1 ⁇ , Mg "1""1" free DPBS.
  • the cells were incubated with 8 ml of Ca ++ , Mg ++ free DPBS for 15 - 30 min at 37 ° C until the cells were easily detached by triturating with pipette.
  • the cells were harvested into 50 ml of conical tubes, and spun at 1500 rpm for 5 min. The supernatant was discarded, and the cells were resuspended in 8 ml of Ca "1-1" , Mg "1""1" free DPBS, and spun at 1500 rpm for 5 min.
  • the supernatant was discarded, and the pellets were resuspended in 3 ml of membrane preparation buffer (lOmM Tris pH 7.4; 0.32M sucrose; 4ug/ml leupeptin; lOuM phosphoramidon; 40ug/ml bacitracin; 5ug/ml aprotinin).
  • the pellets were homogenized with dounce homogenizer (Bellco with type "B" glass pestle) using 20 strokes. The homogenate was centrifuged at 1300Xg at 4°C for 10 min. The supematants were collected, and the pellets were resuspended in membrane preparation buffer, and homogenization and centrifugation were repeated.
  • cAMP was measured using cAMP ( 3 H) assay Kit (Amersham, cat. No. TRK 432).
  • the amount of cAMP produced by the treatment with test compound was compared to that produced in the response to NDP-MSH which was defined as 100 % agonist.
  • the EC 50 was defined as the concentration of test compound that results in half maximal activity of its own.
  • the compounds according to the present invention showed agonistic efficacy and binding affinity to each MCR.
  • the compounds according to the present invention showed excellent agonistic efficacy and binding affinity to the MCR4. i.e., 0.005 ⁇ M - 10 ⁇ M of EC 50 value and 0.01 ⁇ M - 50 ⁇ M of IC50 value.
  • the compounds of examples 1, 2 and 3 showed 0.005 ⁇ M - 0.5 ⁇ M of EC50 value, and 0.1 ⁇ M - 0.5 ⁇ M of IC 50 value, against MCR4.
  • hypophasic effects of melanocortinergic ligands are determined by using the food-deprived mouse model (male ddY mice). The animals are individually housed. One day before treatment, the animals are grouped (7-10 animals/group), based on their basal daily food intakes, and then their food is removed for 20 hr fasting before treatment. In the morning of the test day, each animal receives the administration of vehicle or test substance via oral gavage, and 1 hr after, food is re-supplied. Food intakes after the food-supply are measured for the first 1 hr period.
  • Effects on nocturnal food intake Effects on nocturnal food intake are determined in male ICR mice. The animals are housed individually, and are grouped (7-10 animals/group) based on their basal daily food intakes. Each animal receives the administration of vehicle or test substance via oral gavage 1 hr before starting the dark phase, and food is removed. Food is resupplied lhr after the administration, and food intakes are measured at 1, 2, 4, 8, 24 hr after the food is supplied.
  • DIO mice Effects on food intake and body weight change in diet-induced obese (DIO) mice Effects on food intake and body weight change are determined in male DIO mice.
  • the DIO mice are prepared by feeding C57BL/6 mice on high fat diet for more than 8 weeks.
  • the DIO animals are housed individually, and are grouped (7-10 animals/group) based on their basal body weights. Each animal receives the administration of vehicle or test substance via oral gavage once a day for 14 days. Food intakes and body weigh changes are measured daily.
  • Anti-inflammatory effects in an acute inflammation model Anti-inflammatory effects are determined as the effects on crystal-induced Polymorphonuclear Neutrophil (PMN) recruitment.
  • PMN Crystal-induced Polymorphonuclear Neutrophil
  • E. Erectile effects The erectile effect of the test substance is determined by counting the number of erection of male Sprague Dawley rats. Each animal receives the administration of vehicle or test substance via oral gavage 30 min before the test session, and then is placed in a 2-liter glass beaker. The beakers are located on an observation box designed for the ventral view of the animals. The number of erection is counted by observing the posture of the animals (hip constriction, hip thrust, tiptoe posture) for 1 hr.

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Abstract

L'invention porte sur un composé de formule (I) et sur ses sels, hydrates, solvates ou isomères pharmacocompatibles, agonistes du récepteur de la mélanocortine, ainsi que sur des compositions dont ils forment le principe actif.
PCT/KR2004/002930 2003-11-12 2004-11-12 Agonistes du récepteur de la mélanocortine WO2005047253A1 (fr)

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EP4077307A4 (fr) * 2019-12-18 2024-01-17 Crinetics Pharmaceuticals Inc Antagonistes du récepteur du sous-type 2 de la mélanocortine (mc2r) à pipéridine à double substitution gem et leurs utilisations

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