WO2005047253A1 - Melanocortin receptor agonists - Google Patents

Melanocortin receptor agonists 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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amino
cyclohexyl
alkyl
boc
piperidine
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PCT/KR2004/002930
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French (fr)
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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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    • 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
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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

Abstract

The present invention relates a compound of formula 1, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof effective as agonist of melanocortin receptor, and an agonistic composition of melanocortin receptor comprising the same as active ingredient.

Description

MELANOCORTIN RECEPTOR AGONISTS
TECHNICAL FIELD
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.
Figure imgf000002_0001
in which R1, R2, R3, R4, and R5 are defined as described below.
BACKGROUND ART
Five receptor subtypes have been cloned and characterized in the melanocortin family. These G-protein coupled receptors (GPCR) stimulate the cAMP signal transduction pathway in many different tissues, mediating a wide range of physiological functions. 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.
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.
Early examples are synthetic peptides and peptide analogues that have been identified based on endogenous agonists such as α-MSH. These peptide agonists have been used to characterize the function of these receptors. NDP-αMSH 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. HP-228, a peptide analogue with similar affinity for all four receptors, was in clinical trials for the treatment of pain and inflammation associated with surgery.
Several small molecule 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. For example, 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). On the other hand, 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).
In view of the unresolved deficiencies of the various pharmaceutical compounds as discussed above, there is continuing need for in the arts for small molecule MCR agonists and pharmacological compositions that have improved pharmacological profiles. It is therefore an object of the present invention to provide novel compounds that are useful for the treatment of obesity, diabetes, sexual dysfunction and inflammation.
DISCLOSURE OF THE INVENTION
The present invention relates to a compound of the following formula 1, and pharmaceutically acceptable salt, hydrate, solvate, and isomer thereof.
Figure imgf000004_0001
in which
R1 represents hydrogen, -(CH2)P-R6, -(CH2)p-CO-R6, -(CH2)p-SO2-R6, or -CO-(CH2)p-R6, wherein p represents independently 0, 1, 2, or 3,
R6 represents Ci-Cio-alkyl, C3-C8-cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxyl, each of which is unsubstituted or mono- to polysubstituted by substituents from the group consisting of Cι-C6-alkyl, halogen, amino, CrCό-alkylamino, di(C1-C6-alkyl)amino, hydroxy, Ci- C8-alkoxy, trifluoromethoxy, C!-C6-alkylcarbonyl, arylcarbonyl, Cι-C6- alkoxycarbonyl, carbamoyl, Cr -alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo,
hydrogen atom in -(CH )P- group can be replaced by R as defined above,
R2 represents hydrogen, d-Cg-alkyl, or C3-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-(CrC4-alkyl), R3 represents -d-Cβ-alkyl, -(CH2)q-C3-C7-cycloalkyl, -(CH2)q-phenyl, or - (CH2)q-heteroaryl, each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of d-C6-alkyl, halogen, amino, CrCe-alkylamino, di(C1-C6-alkyl)amino, hydroxy, Q-Cs-alkoxy, d-Cό- alkylcarbonyl, arylcarbonyl, d-C6-alkoxycarbonyl, carbamoyl, Ci-Cβ- alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo, wherein q represents independently 0, 1, 2, or 3,
R represents phenyl, cyclohexyl, or NR R , wherein
R7 and R8 independently of one another represent Cι-C6-alkyl, -(CH )q-C - Cγ-cycloalkyl, -(CH2)q-phenyl, or -(CH2)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-(C1-C4-alkyl), and these radicals are unsubstituted or mono- to poly-substituted by substituents from the group consisting of Cι-C6-alkyl, halogen, amino, CrCδ-alkylamino, di(C!-C6-alkyl)amino, hydroxy, Q-Cs-alkoxy, trifluoromethoxy, d-C6- alkylcarbonyl, arylcarbonyl, d-Cδ-alkoxycarbonyl, carbamoyl, d-Cό- alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo
R5 represents -(CH2)0-R9, -(CH2)0-COR9, or
Figure imgf000005_0001
wherein o represents independently 0, 1, 2, or 3, R9 andR10 independently of one another represent hydrogen, amino, hydroxy, Ci-Cβ-alkyl, d-Cό-alkoxy, C3-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 Cι-C6- alkyl, halogen, amino, Cι-C6-alkylamino, di(C1-C6-alkyl)amino, hydroxy, Cι-C8-alkoxy, trifluoromethoxy, d-C6-alkylcarbonyl, arylcarbonyl, CrC6- alkoxycarbonyl, carbamoyl, d-Cδ-alkylsulfonyl, arylsulfonyl, C3-C6- cycloalkyl C2-C8-alkanoyl, d-Ce-alkylsulfamoyl, carboxy, cyano, and oxo, or
R9 andR10 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- (Cι-C4-alkyl).
In the radical definitions of the compound of formula (1) according to the present invention, the term "alkyl" means straight-chain or branched hydrocarbon radical when used alone or in combination with hetroatoms such "alkyloxy."
The term "cycloalkyl" represents unsaturated aliphatic ring including cyclohexyl.
The term "aryl" represents aromatic group including phenyl, naphthyl, etc.
The term "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 C3-C8-cycloalkyl. Examples of 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.
The term "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 C3-C8-cycloalkyl. Its examples are, but are not limited to, piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and similar group to them.
Preferred compounds among the compounds of formula (1) above are those wherein i) R1 represents hydrogen, -(CH2)P-R6, -(CH2)p-CO-R6, or -(CH2)p-SO2-R6, wherein p is as defined above, preferably, R1 represents hydrogen, or -(CH )P-R6, wherein p is as defined above, ii) R1 represents -CO-(CH2)p-R6, wherein p is as defined above, iii) R2 represents hydrogen, or d-C6-alkyl, iv) R3 represents -(CH2)q-C3-C -cycloalkyl, -(CH2)q-phenyl, or -(CH )q- heteroaryl, each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of halogen, cyano, carboxy, hydroxy, -C4-alkyl, Cι-C8- alkoxy, amino, Cι-C4-alkylamino, and di(C1-C4-alkyl)amino, wherin q is as defined above, preferably, R represents -CH2-cyclohexyl or CH2-phenyl, each of which is unsubstituted or mono- to tri-substituted by substituents from the group consisting of halogen, cyano, hydroxy, C1-C4-alkoxy, trifluoromethoxy, and Cι-C -alkyl, v) R4 represents phenyl, cyclohexyl, C1-C4-alkylamino, di(C1-C4-alkyl)amino, pyrrolidinyl, piperidinyl, or azepinyl, wherein d-C4-alkyl, pyrrolidinyl, piperidinyl or azepinyl is unsubstituted or mono- to tri-substituted by substituents from the group consisting of halogen, hydroxy, C1-C4-alkyl, d-C4-alkoxy, amino, C1-C4-alkylamino, and di(C1-C4-alkyl)amino, vi) R5 represents Cι-C6-alkyl, -(CH2)0-heteroaryl, -(CH2)0-heterocycle, -CO2R9, - C(O)N(R9)(R10), -(CH2)0-ORπ, -(CH2)0-NHRπ, or -(CH2)0-N(Rπ)(R12), wherein heteroary is unsubstituted or mono- to tri-substituted by substituents from the group consisting of hydroxy, d-C4-alkyl, C1-C -alkoxy, amino, C1-C4-alkylamino, di(d-C4- alkyl)amino, and oxo, wherin R9 and R10 are as defined above, R11 and R12 independently of one another represent Cι-C6-alkyl, C3-C6-cycloalkyl, C2-C8-alkanoyl, d-Cδ-alkylsulfonyl, Cι-C6-alkylsulfamoyl, or arylsulfonyl, and o is as defined above, preferably,
R5 represents -(CH2)0-1-heteroaryl, -(CH2)0-ι -heterocycle, -C(O)N(R9)(R10), - (CH2)0-ORn, -(CH2)0-1-NHRπ, or -(CH2)0-1-N(Rπ)(R12), wherein R9, R10, R andR are defined above.
Representative compounds of formula 1 according to the present invention include the compounds listed in the following Table 1.
Table 1
Figure imgf000009_0001
Table 1 (continued)
Figure imgf000010_0001
Table 1 (continued)
Figure imgf000011_0001
Table 1 (continued)
Figure imgf000012_0001
Table 1 (continued)
Figure imgf000013_0001
Table 1 (continued)
Figure imgf000014_0001
Table 1 (continued)
Figure imgf000015_0001
Table 1 (continued)
Figure imgf000016_0001
Table 1 (continued)
Figure imgf000017_0001
Table 1 (continued)
Figure imgf000018_0001
Table 1 (continued)
Figure imgf000019_0001
Table 1 (continued)
Figure imgf000020_0001
Table 1 (continued)
Figure imgf000021_0001
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 of formula 1 according to the present invention can be converted to its salts by customary method.
Also, 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.
The compound according to the present invention can be prepared according to the procedures in the following Reaction Schemes 1 - 7. In the following Schemes, compounds (3), (6), (10), (11), (12), (14), (18), (20) and (31) represent representative compounds of formula 1.
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. 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). Similarly, piperidine derivatives (2) can be prepared from commercially available compounds described in literature (WO 00/14930). Scheme 1
R4 i) amide coupling r_>5 ii) deprotection
Figure imgf000023_0001
Figure imgf000023_0002
Compounds of formula (6) (R1 = Ac, Ms, etc.) can be prepared by coupling amino acid derivatives (5) with piperidine derivatives (2) as illustrated in Scheme 2. Alkyl, acyl, or sulfonyl substituted amino acid derivatives (4) can be converted to amino acid derivatives (5) by hydrolysis in the presence of base.
Scheme 2
Figure imgf000023_0003
(4) (5) (6)
Compounds formula (10), (11), and (12) [R2 = H, R1 = C(O)-containing group] can be prepared by coupling protected amino acid derivatives (7), (8), or (9) with compounds formula (3) prepared in the Reaction Scheme 1, as shown in Scheme 3. Cy in compound (8) represents pyrrolidine, azetidine, aziridine, piperidine, etc.. Protected amino acid derivatives (7), (8) and (9) are commercially available or can be prepared by protection reaction from available amino acids.
Scheme 3
Figure imgf000024_0001
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. As a reducing agent for reductive animation, NaHB(OAc)3 or NaBH3CN 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.
Scheme 4
Figure imgf000024_0002
Compounds of formula (18), (19) and (20) can be prepared as shown in the following Scheme 5. Nitrobenzenesulfonyl protected intermediates of formula (15) can be converted to the compounds of formula (17) by alkylation or reductive amination {Tetrahedron Lett., 1995, 36, 6373-6374). In protected compounds of formula (16), Q represents aminoalkyl or alkylated aminoalkyl, and X represents halogen. Compounds of formula (19) can be prepared through reductive amination of compounds of formula (17) and then converted into the compounds of formula (20) by alkylation.
Scheme 5
Figure imgf000025_0001
(15) i) P-Q-X (16) ii) desul fonyl t ion
Figure imgf000025_0002
reduct ive aminat ion
Figure imgf000025_0003
(19) (20)
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
Figure imgf000026_0001
4- 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.
Scheme 7
Figure imgf000026_0002
Compounds of formula (31) can be prepared as illustrated in Scheme 8. Amide coupling of compounds of formula (3) with 4-cyclohexyl-4- piperidinecarboxylicacid can give compounds of formula (30) which can be converted to compounds of formula (31) through amide coupling and deprotection.
Scheme 8
Figure imgf000027_0001
It is preferable to carry out each step of the above methods in conventional solvents which do not have significant deleterious effect to the reaction, and particularly preferable to use one or more kinds selected from the group consisting of, but not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, and chloroform.
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. Specific reaction conditions are described in T. W. Green & G. M. Wuts Protective Groups in Organic Synthesis, Chapter 7, pp 309-405.
Known 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. which are used in a mixture with 1-hydroxybenzotriazole (HOBT) or l-hydroxy-7-azabenzotriazole (HOAT); bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (BOP-C1), diphenylphosphorylazide (DPP A), O-(7-Azabenzotriazol- 1 -yl)-N,N,N' ,N' -tetramethyl- uronium hexafluorophosphate (HATU), O-Benzotriazol-l-yl-N,N,N',N'-tetramethyl- uronium hexafluorophosphate (HBTU), etc.
General separation of mixtures is conducted by column chromatography, and in case of final compound, separation can be done by recrystallization or normal or reverse HPLC (Waters, Delta Pack, 300x50 mm I.D., C18 5 βm, 100A). When recrystallization or HPLC is used for purification, the compound can be obtained in the form of trifluoroacetic acid salt. Hydrochloric acid salt can be obtained by using ion exchange resin.
After the above reactions according to the present invention are completed, 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. In particular, 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.
When the compounds according to the present invention are administered for clinical purpose, a preferable daily dose would be within the range of 0.01 ~ 10 mg/ kg body weight as unitary dosage or separated dosage. However, 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.
Abbreviations used in the above Description, and the following Preparations and Examples are as follows:
Ac acetyl
BOC tert-butoxycarbonyl
Bn benzyl
Bu butyl
CBZ(Cbz) benzyloxycarbonyl c-Hep cycloheptyl c-Hex cyclohexyl c-Pen cyclopentyl
DCC dicyclohexylcarbodiimide
DCE dichloroethane
DCM dichloromethane
Die decahydroisoquioline-3 -carboxylic acid
DIPEA diisopropylethyamine
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl
Fmoc 9-fluorenylmethoxycarbonyl
Hex hexane
HOBt 1 -hydroxybenzotriazole
HPLC high performance liquid chromatography i-Bu isobutyl iPr isopropyl
Imz imidazole
LAH lithiumaluminium hydride Ms methansulfonyl
Ph phenyl
Phe phenylalanine
Pid piperidine
Pro proline
Pyd pyrrolidine
TEA triethylamine
Tez tetrazole
TFA trifluoroacetic acid
THF tetrahydrofuran
Tic 1 ,2,3 ,4-tetrahydroisoquinoline-3 -carboxylic acid
TPAP tetrapropylamonium peruthenate
Trz triazole
The following Preparations further illustrate preparation of intermediates needed for synthesis of the compound according to the present invention.
Intermediate 1: 4-CyclohexyI-4-(t-butylcarbamoyl)piperidine
Step A: l-BOC-4-Cyclohexyl-4-(t-butylcarbamoyl)piperidine To a solution of 4-cyclohexyl-4-piperidine carboxylic acid (311 mg, 1 mmol) in DMF (3 mL) were added DIPEA (0.348 mL, 2 mmol), EDC (600 mg, 1.3 mmol), HOBT (230 mg, 1.5 mmol), and t-butyl amine (0.137 mL, 1.3 mmol). After the reaction mixture was stirred at rt for 6 h, DMF was distilled off in vacuo, and the residue was diluted with a saturated aqueous NaHCO3 solution. The organic material was extracted with EtOAc and washed with an aqueous NaHCO3 solution and IN HCI. The extracts were dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/n-Hex = 1/1) to give the title compound (350 mg, 94 %). MS [M+H] = 367 (M+l).
Step B: 4-Cyclohexyl-4-(t-butylcarbamoyl)piperidine l-BOC-4-Cyclohexyl-4-(t-butylcarbamoyl)piperidine, prepared in Step A, (300 mg, 0.818 mmol) was dissolved in DCM (2 mL), and then TFA (2 mL) was added dropwise. The reaction mixture was stirred at rt for 30 min. and concentrated in vacuo to give the title compound (235 mg, 90%) as a TFA salt. MS [M+H] = 267 (M+l).
Intermediates 2 - 8: The following Intermediates listed in Table 2 were prepared from 4-cyclohexyl- 4-piperidinecarboxylic acid and amine derivatives using the same procedure described in Intermediate 1.
Table 2
Figure imgf000032_0001
Figure imgf000032_0002
Intermediate 9: 4-Cyclohexyl-4-[(4,4-dimethyl)oxazolin-2-yl]piperidine
Step A: l-BOC-4-Cyclohexyl-4-piperidine carboxyl chloride To a solution of 4-cyclohexyl-4-piperidine carboxylic acid (3.11 g, 10 mmol) in DCM (30 mL) was added oxalyl chloride (1.40 g, 11 mmol) and the reaction mixture was stirred at rt for 3 h. After the solvent was distilled off in vacuo, the residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/4) to give the title compound (3.06 g, 94 %). MS [M+H] = 307 (M+l).
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
A of Intermediate 1. MS [M+H] = 383 (M+l). Step C: l-BOC-4-Cyclohexyl-4-[(4,4-dimethyl)oxazolin-2-yl]piperidine To a solution of l-BOC-4-cyclohexyl-4-[(2-hydroxy-l,l-dimethyl)ethyl- carbamoyljpiperidine, prepared in Step B, (3.82 mg, 1 mmol) in DCM (5 mL) were added DIPEA (0.348 mL, 2 mmol), DMAP (25 mg, 0.2 mmol), and phosgene (2.5M solution in toluene, 2 mL). After being stirred at rt for 2 h, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex = 2/1) to give the title compound (328 mg, 90%). MS [M+H] = 365 (M+l).
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).
Intermediate 10: 4-Cyclohexyl-4-(oxazolin-2-yl)piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4-piperidine carboxyl chloride according to the same procedure as Intermediate 9. MS [M+H] = 237 (M+l).
Intermediate 11 : 4-CycIohexyl-4-[(4,4-dimethyl)thiooxazolin-2-yl]piperidine
Step A: 1 -BOC-4-Cyclohexyl-4-[(4,4-dimethyl)thiooxazolin-2-yl]piperidine To a solution of l-BOC-4-Cyclohexyl-4-[(4,4-dimethyl)oxazolin-2- yl]piperidine, prepared in Step C of Intermediate 9, (382 mg, 1 mmol) in toluene (30 mL) was added Laewsson's reagent (330 mg, 3 mmol). After the reaction mixture was stirred at 120 °C for 2 h, the precipitate was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent: DCM/MeOH = 19/1) to give the title compound (304 mg, 80%). MS [M+H] = 381 (M+l).
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).
Intermediate 12: 4-CycIohexyl-4-(thiooxazolin-2-yl)piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4-[(2- hydroxyethyl)carbamoyl]piperidine according to the same procedure as Intermediate 11. MS [M+H] = 253 (M+l). Intermediate 13: Methyl 4-cycIohexyI-4-piperidinecarboxylate
Step A: Methyl l-BOC-4-cyclohexyl-4-piperidinecarboxylate To a solution of l-BOC-4-cyclohexyl-4-piperidinecarboxylic acid (311 mg, 1 mmol) in DMF (5 mL) was added K2CO3 (414 mg, 3 mmol) and methyl iodide (0.183 mL, 1.2 mmol). After the reaction was stirred at room temperature for 3 h, the reaction mixture was concentrated in vacuo, and the residue was diluted with an aqueous IN HCI solution. The organic material was extracted with EtOAc and the organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/10) to give the title compound (109 mg, 95%). MS [M+H] = 326 (M+l).
Step B: Methyl 4-cyclohexyl-4-piperidinecarboxylate The title compound was obtained from l-BOC-4-cyclohexyl-4-piperidine carboxylate prepared in Step A according to the same procedure as Step B of Intermediate 1. MS [M+H] = 226 (M+l).
Intermediate 14: l-BOC-4-Cyclohexyl-4-piperidinemethanol To a solution of methyl l-BOC-4-cyclohexyl-4-piperidine carboxylate (3.25 g, 10 mmol), prepared in Step A of Intermediate 13, in THF (30 mL) was added LAH (759 mg, 20 mmol) at 0 "C , and then the reaction mixture was warmed to rt. After the reaction was stirred at rt for 2 h, the reaction mixture was cooled at 0°C and was quenched by slow adding of water. When no further gas evolution occurred, the organic layer was extracted with EtOAc, and the organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/1) to give the title compound. MS [M+H] = 298 (M+l).
Intermediate 15: l-BOC-4-Cyclohexyl-4-piperidineaIdehyde l-BOC-4-Cyclohexyl-4-piperidinemethanol prepared in Intermediate 14 was dissolved in DCM (10 mL). After the reaction temperature was cooled to 0°C, 4- methylmorpholine-N-oxide (351 mg, 3 mmol) and TPAP (25 mg) were added dropwise, and the reaction mixture was stirred at rt for 3 h. The precipitate was filtered through Florisil and Celite, and the filtrate was dried over MgSO4 and concentrated in vacuo to give the title compound. MS [M+H] = 296 (M+l).
Intermediate 16: 4-Cyclohexyl-4-[(l-hydroxy)isobutyl]piperidine
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. The reaction was quenched with a saturated aqueous NH4C1 solution, and the organic material was extracted with EtOAc. The combined organic solution was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/2) to give the title compound. MS [M+H] = 340 (M+l).
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)ρiperidine 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. After the reaction mixture was stirred for 30 min., TEA (0.248 mL, 2 mmol) was added dropwise to the solution and, the reaction mixture was warmed to rt. The reaction was diluted with a saturated aqueous NH4C1 solution and the organic layer was extracted with DCM, The extracts were dried over MgSO4, filtrated, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/2) to give the title compound (177 mg, 89%). MS [M+H] = 338 (M+l).
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).
Intermediate 18 : 4-Cyclohexyl-4- [(4,4-dimethyIoxazolidin-2-one-3-yI) methyl] - piperidine
Step A: 1 -BOC-4-Cyclohexyl-4- {N-[(2-hydroxy- 1 , 1 -dimethyl)ethyl]imino}piperidine To 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. PtO2 was added to the solution and the rection mixture was stirred under hydrogen for 12 hr. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound. MS [M+H] = 367 (M+l). 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).
Intermediate 19: 4-Cyclohexyl-4-[(oxazolidin-2-one-3-yl)methyl]piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4-piperidine aldehyde prepared in Intermediate 15 according to the same procedure as Intermediate 18. MS [M+H] = 267 (M+l).
Intermediate 20: 4-Cyclohexyl-4-[(N-methoxy)iminyl]piperidine
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 NH4C1 solution and the organic layer was extracted with EtOAc. The combined organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 9/1) to give the title compound. MS [M+H] = 325 (M+l).
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).
Intermediate 21 : 4-Cyclohexyl-4-[(methanesulfonyloxy)methyl]piperidine
Step A: l-BOC-4-Cyclohexyl-[(methanesulfonyloxy)methyl]piperidine To a solution of l-BOC-4-cyclohexyl-4-piperidine methanol prepared in Intermediate 14 (2.97 g, 10 mmol) in DCM (60 mL) was added TEA (2.8 mL, 20 mmol) and methansulfonyl chloride (3.11 mL, 20 mmol). After lh, a saturated aqueous NH4C1 solution was added, and the organic material was extracted with DCM followed by EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/9) to give the title compound (1.55 g, 95%). 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).
Intermediate 22: 1,2,3-Triazole-l-carboxyl chloride 1,2,3-Triazole (207 mg, 3 mmol) and DMAP (366 mg, 3 mmol) were dissolved in DCM (10 mL), and phosgene (25% solution in toluene, 3 mL) was added dropwise to the solution. After the reaction mixture was stirred at rt for 30 min., the precipitate was filtered, and the filtrate was concentrated in vacuo to give the title compound. MS [M+H] = 132 (M+l).
Intermediate 23: 1,2,4-Triazole-l-carboxyl chloride The title compound was obtained from 1,2,4-Triazole according to the same procedure as Intermediate 22. MS [M+H] = 132 (M+l) Intermediate 24: 1,3-Imidazole-l-carboxyl chloride The title compound was obtained from 1,3-Imidazole according to the same procedure as Intermediate 22. MS [M+H] = 131 (M+l)
Intermediate 25: l-BOC-4-Cyclohexyl-4-(aminomethyI)piperidine
Step A: l-BOC-4-Cyclohexyl-4-(azidomethyl)piperidine To a solution of 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. After 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 MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/15) to give the title compound (1. 55 g, 96%). MS [M+H] = 323 (M+l)
Step B: l-BOC-4-Cyclohexyl-4-(aminomethyl)piperidine To a solution of l-BOC-4-cyclohexyl-4-(azidomethyl)piperidine prepared in Step A (1.0 g, 3.10 mmol) in methanol was added Pd/C (200 mg), and the reaction mixture was stirred under H2 for 12 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound. MS [M+H] = 297 (M+l)
Intermediate 26 : 4-Cy clohexyl-4-{ [(cyclohexylmethyl)amino] methyl}piperidine
Step A: l-BOC-4-Cyclohexyl-4-[(cyclohexylamino)methyl]piperidine To 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. After the reaction mixture was stirred at rt for 4 h, a saturated aqueous NaHCO3 solution was added, and the organic layer was extracted with DCM. The extracts were dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: MeOH/EtOAc/n-Hex = 1/4/4) to give the title compound. 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-
[(cyclohexylamino)methyl]piperidine prepared in Step A and formalin according to the same procedure as Step A of Intermediate 1. MS [M+H] = 393 (M+l)
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)
Intermediates 27 - 37: The following intermediates listed in the following Table 3 were prepared from 1 -BOC-4-cyclohexyl-4-piperidinemethanol, 1 -BOC-4-cyclohexyl-4-(amino-methyl)- piperidine and l-BOC-4-cyclohexyl-4-[(cyclohexylamino)methyl]piperidine using the same procedure described in Intermediate 21.
Table 3
Figure imgf000040_0001
Figure imgf000040_0002
Table 3 (continued)
Figure imgf000041_0001
Intermediate 38: 4-Cyclohexyl-4~[(l,2,4-triazol-l-yl)methyl]piperidine
Step A: l-BOC-4-Cyclohexyl-4-[(l,2,4-triazol-l-yl)methyl]piperidine To a solution of l-BOC-4-cyclohexyl-4-[(methanesulfonyloxy)methyl] piperidine (375 mg, 1 mmol) in DMF (10 mL ) was added Na-l,2,4-triazole (273 mg, 3 mmol), and the solution was stirred at 90-100°C for 12 h. After DMF was distilled off in vacuo, the reaction mixture was quenched wirh a saturated aqueous NH4C1 solution, and the organic material was extracted with EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: acetone/DCM = 3/1) to give the title compound (313 mg, 90%). MS [M+H] = 349 (M+l)
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)
Intermediate 39: 4-Cyclohexyl-4-[(l,2,3-triazol-l-yl)methyl]piperidine Step A: l-BOC-4-Cyclohexyl-4-[(l,2,3-triazol-l-yl)methyl]piρeridine To a solution of l-BOC-4-cyclohexyl-4-[(methanesulfonyloxy)methyl]- piperidine (375 mg, 1 mmol) and 1,2,3-triazol (205 mg, 3 mmol) in DMF (10 mL) was added sodium isopentoxide (220 mg, 2 mmol), and the reaction mixture was stirred at 90 -100°C for 12 h. After DMF was distilled off in vacuo, a saturated aqueous NH4C1 solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: acetone/DCM = 3/1) to give the title compound (292 mg, 84%). MS [M+H] = 349 (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)
Intermediate 40 : 4-Cyclohexyl-4-[(tetrazol-l-yl)methyl]piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4- [(methanesulfonyloxy)methyl]piperidine and tetrazole according to the same procedure as Intermediate 39. MS [M+H] = 250 (M+l)
Intermediate 41 : 4-Cyclohexyl-4-{[(l-methyl)tetrazol-5-yl]methyl}piperidine
Step A: l-BOC-4-Cyclohexyl-4-(cyanomethyl)piperidine l-BOC-4-Cyclohexyl-4-[(methanesulfonyloxy)methyl]piperidine (375 mg, 1 mmol) and sodium cyanide (153 mg, 3 mmol) were dissolved in DMF (5 mL), and the mixture was stirred 100°C for 24 h. The reaction mixture was quenched with an aqueous IN HCI solution, and the organic material was extracted with EtOAc. The extracts were washed with saturated aqueous NaHCO solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/3) to give the title compound. MS [M+H] = 306 (M+l)
Step B: l-BOC-4-Cyclohexyl-4-{[(l-methyl)tetrazol-5-yl]methyl}piperidine To a solution of l-BOC-4-Cyclohexyl-4-(cyanomethyl)piperidin,e prepared in Step A, (250 mg, 0.82 mmol) in DMF (5 mL) were added sodium azide (195 mg, 3 mmol) and NH4C1 (132 mg, 3 mmol), and the mixture was stirred at 90°C for 24 h. The reaction mixture was diluted with water, and the organic material was extracted with EtOAc. The extracts were washed with a IN HCI solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: aceton/DCM = 3/1) to give the title compound. MS [M+H] = 350 (M+l)
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)
Intermediate 42 : 4-CycIohexyl-4-[(2-pyrrolidinon-l-yl)methyI]piperidine
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. After the reaction mixture was stirred at 0°C for 30 min., a solution of l-BOC-4-cyclohexyl-4-[(methanesulfonyloxy)- methyl]}piperidine (375 mg, 1 mmol) in THF (1 mL) was slowly added. After 30 minuets, the reaction mixture was warmed to rt, and stirred for additional 5 h. The reaction mixture was quenched with a saturated aqueous NH4C1 solution, and the organic material was extracted with EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (255 mg, 70 %). MS [M+H] = 365 (M+l)
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)
Intermediate 43 : 4-Cyclohexyl-4-[(dimethylamino)methyl]piperidine
Step A: l-BOC-4-Cyclohexyl-4-[(dimethylamino)methyl]ρiperidine 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)
Intermediate 44: 4-Cyclohexyl-4-{[methyl(cyclohexyl)amino]methyl}piperidine
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
Intermediate 26. MS [M+H] = 393 (M+l)
Step B: 4-Cyclohexyl-4-[(methyl(cyclohexyl)amino)methyl]piperidine The title compound was obtained from l-BOC-4-cyclohexyl-4-{[methyl-
(cyclohexyl)amino]methyl}piperidine prepared in Step A according to the same procedure as Step B of Intermediate 1. MS [M+H] = 293 (M+l)
Intermediate 45: l-BOC-4-Cyclohexyl-4~aminopiperidine
Step A: l-BOC-4-Cyclohexyl-4-[(benzyloxycarbonyl)amino]piperidine To a solution of l-BOC-4-cyclohexyl-4-piperidinecarboxylic acid (3.1 g, 10 mmol) and TEA (2.8 ml, 20 mmol) in THF (30 mL) was added DPPA (diphenyl phosphoryl azide) (2.6 g, 12 mmol), and the reaction mixture was stirred at 70 °C for 24 h. After THF was distilled off in vacuo, Toluene (10 mL) and benzyl alcohol (1.5 mL) were added dropwide, and the reaction mixture was stirred at 100°C . After 24h, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc/n-Hex = 1/5) to give the title compound. MS [M+H] = 417 (M+l)
Step B: l-BOC-4-Cyclohexyl-4-aminopiperidine To a solution of l-BOC-4-cyclohexyl-4-[benzyloxycarbonyl]amino]piperidine, prepared in Step A, (2.1 g, 5 mmol) in MeOH (30 mL) was added Pd/C (200 mg). The reaction mixture was stirred under H2 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)
Intermediate 46: 4-Cyclohexyl-4-(dimethylamino)piperidine
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)
Intermediate 47: 4-Cyclohexyl-4-(acetylamino)piperidine
The title compound was obtained from l-BOC-4-cyclohexyl-4-aminopiρeridine and acetic acid according to the same procedure as Intermediate 1. MS [M+H] = 225 (M+l) Intermediate 48: 4-Cyclohexyl-4-[isopropyl(methyl)amino]piperidine
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
Intermediate 26. MS [M+H] = 339 (M+l)
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)
Intermediate 49: (2R)-N-Methanesulfonyl-(4-chlorophenyl)alanine
Step A: (2R)-N-Methanesulfonyl-(4-chlorophenyl)alanine methyl ester To a solution of (2R)-(4-chlorophenyl)alanine methyl ester (213mg, 1.00 mmol) in DCM (5 mL) was added TEA (280 mL, 2.00 mmol) and methansulfonyl chloride at 0°C . After 30 minutes, DCM was distilled off in vacuo, and the residue was diluted with EtOAc, and then washed with IN HCI. The organic solution was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chromatography (eluent: MeOH/CHCl3 = 1/25) to give the title compound (280 mg, 96.1 %). MS [M+H] = 292 (M+l)
Step B: (2R)-N-Methanesulfonyl-(4-chlorophenyl)alanine To a solution of (2R)-N-methanesulfonyl-(4-chlorophenyl)alanine methyl ester, prepared in Step A, (590 mg, 2 mmol) in H2O/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)
Intermediate 50: (2R)-N-Acetyl -(4-chlorophenyl)aIanine The title compound was obtained from (2R)-(4-chlorophenyl) alanine methylester and acetic anhydride according to the same procedure as Intermediate 49. MS [M+H] = 240 (M+l)
Intermediate 51: (2R)-N-Dimethylcarbamoyl -(4-chlorophenyϊ)alanine The title compound was obtained from (2R)-(4-chlorophenyl)alanine methyl ester and chlorodimethylcarbamate according to the same procedure as Intermediate 49. MS [M+H] = 269 (M+l)
Intermediate 52: (2R)-N-Boc-Prolinecarboxyaldehyde
Step A: (2R)-N-Boc-Prolinethioester To a solution of DCC (2.55 g, 12.4 mmol), DMAP (100 mg), and EtSH (0.71 g, 11.1 mmol) DCM (30 mL) was added a solution of (2R)-N-Boc-proline (3.00 g, 9.52 mmol) in DCM (30 mL). After the reaction mixture was stirred at rt for 30 min., the precipitate was filtered off through Celite. The filtrate was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (2.34 g, 95.2%). MS [M+H] = 260 (M+l)
Step B: (2R)-N-Boc-Prolinecarboxyaldehyde To a solution of (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. When the bubbling was not generated any more, 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. The residue was purified by column chromatography (eluent: EtO Ac/Hex = 1/2) to give the title compound (1.43 g, 93.2%). MS [M+H] = 200 (M+l) Intermediate 53: (2R)-N-Methyl-prolinecarboxyaldehyde
Step A: (2R)-N-Methyl-proline methyl ester To a solution of (2R)-Proline methylester (1.20 g, 10.0 mmol) and formalin (37 % in H2O, 1.12 mL, 15.0 mmol) in DMF (30 mL) was added NaBH(OAc)3 (4.20 g, 20.0 mmol). After being stirred for 12h, the reaction mixture was concentrated in vacuo, and the residue was diluted with NaHCO3 (30 mL). The organic material was extracted with EtOAc, and the extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtO Ac/Hex = 4/1) to give the title compound. 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)
Intermediates 54 - 62: The following intermediates listed in the following Table 4 were obtained from amino acid methyl ester using the same procedure described in Intermediate 26, or Intermediate 49 and Intermediate 52.
Figure imgf000049_0001
Figure imgf000049_0002
Intermediate 63: l-BOC-Aziridine-2-carboxylic acid
Step A: Methyl l-benzyl-2-aziridinecarboxylate To a solution of methyl-2,3-dibromopropiolate (92.50 g, 10.0 mmol) and K2CO3 (4.10 g, 3.00 mmol) in acetonitrile (30 mL) was added dropwise benzyl amine (1.20 mL, 11 mmol), and the reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with a saturated aqueous NH4CL solution, and the organic material was extracted with EtOAc (50 mL x 3). The extracts were dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (1.62 g, 85.0%). MS [M+H] = 192 (M+l)
Step B: Methyl l-BOC-2-aziridinecarboxylate. To a solution of methyl l-benzyl-2-aziridinecarboxylate prepared in Step A (1.00 g, 5.23 mmol) and di-t-butyldicarbonate (1.34 g, 5.75 mmol) in MeOH (20 mL) was added Pd/C (300 mg). After being stirred under H2 at rt for 24 h, the reaction mixture was filtered through Celite, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (985 mg, 91.0%). 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)
Intermediate 64: l-BOC-2-Aziridinecarboxyaldehyde The title compound was obtained from l-BOC-aziridine-2-carboxylic acid according to the same procedure as Intermediate 52. MS [M+H] = 172 (M+l)
Intermediate 65: Methyl l-BOC-4-amino-4-piperidinecarboxylate To a solution of l-BOC-4-amino-4-piperidinecarboxylic acid (2.00 g, 8.2 mol) in MeOH (300 mL) and DCM (300 mL) was added diazomethane slowly until the reaction solution became to pale yellow. The reaction mixture was stirred at room temperature for additional 30 min. and concentrated in vacuo to give the title compound. MS [M+H] = 393 (M+l)
Intermediate 66: l-BOC-4-(Cbz)Amino-4-piperidinecarboxylic acid To a solution of methyl l-BOC-4-amino-4-piperidinecarboxylate (1.29 g, 5 mol), prepared in Intermediate 65, in water (10 mL) and dioxane (10 mL) were added Na2CO3 (IN water solution, 10 mL) and CbzCl (1.5 mL, 10 mmol). After the reaction mixture was stirred at room temperature for 6 h, the solvent was distilled off in vacuo, and the residue was diluted with IN HCI. The organic material was extracted with EtOAc, and the extracts were dried over MgSO4) filtered, and concentrated to give the title compound. MS [M+H] = 379 (M+l) Intermediate 67: 4-(Piperidin-l-yl)-4-(dimethylcarbamoyl)piperidine
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 To a solution of 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 NaHCO3 solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/n-Hex = 2/1) to give the title compound (1.51 g, 91.0%). MS [M+H] = 340 (M+l)
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)
Intermediates 68- 76: The following intermediates listed in Table 5 were prepared from l-BOC-4- (Cbz)aminopiperidine using the same procedure described inlntermediate 67. Table 5
Figure imgf000052_0001
Figure imgf000052_0002
Intermediate 77: 4-(Piperidin-l-yl)-4-[4,4-(dimethyl)oxazolin-2-yl]piperidine
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-
(dimethyl)oxazolin-2-yl]piperidine prepared in Step B according to the same procedure as Step B of Intermediate 45. MS [M+H] = 298 (M+l)
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-
(dimethyl)oxazolin-2-yl]piperidine prepared in Step C according to the same procedure as Step C of Intermediate 67. MS [M+H] = 366 (M+l)
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-yι)-4-[4,4-
(dimethyl)oxazolin-2-yl)piperidine prepared in Step D according to the same procedure as Step B of Intermediate 1. MS [M+H] = 266 (M+l)
Intermediate 78: 4-(Piperidin-l-yl)-4-(oxazolin-2-yl)piperidine The title compound was obtained from l-BOC-4-(Cbz)amino-4-piperidine carboxylic acid and aminoethanol according to the same procedure as Intermediate 77. MS [M+H] = 238 (M+l)
Intermediate 79: Methyl 4-(piperidin-l-yl)-4-piperidinecarboxylate
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 B: Methyl 4-(piperidin-l-yl)-4-piperidinecarboxylate The title compound was obtained from Methyl l-BOC-4-(piperidin-l-yl)-4- piperidinecarboxylate prepared in Step A according to the same procedure as Step B of Intermediate 1. MS [M+H] = 227 (M+l)
Intermediate 80: l-BOC-4-(Piperidin-l-yl)-4-(hydroxymethyl)piperidine The title compound was obtained from Methyl l-BOC-4-(piperidin-l-yl)-4- piperidinecarboxylate according to the same procedure as Intermediate 14. MS [M+H] = 299 (M+l)
Intermediate 81 : l-BOC-4-(Piperidin-l-yl)-4-piperidinecarboxyaldehyde The title compound was obtained from l-BOC-4-(piperidin-l-yl)-4- (hydroxymethyl)piperidine according to the same procedure as Intermediate 15. MS [M+H] = 297 (M+l)
Intermediate 82: 4-(Piperidin-l-yI)-4-[(l-hydroxy)isobutyI]piperidine The title compound was obtained from l-BOC-4-(piperidin-l-yl)-4- piperidinecarboxylate and isopropyl magnesium bromide according to the same procedure as Intermediate 16. MS [M+H] = 241 (M+l)
Intermediate 83: 4-(Piperidin-l-yl)-4-(isobutyryl)piperidine The title compound was obtained from 4-(piperidin-l-yl)-4-[(l- hydroxy)isobutyl]piperidine according to the same procedure as Intermediate 17. MS [M+H] = 239 (M+l)
Intermediate 84: 4-(Pyrrolidin-l-yl)-4-(dimethylcarbamoyl)piperidine
Step A: l-BOC-4-(pyrrolidin-l-yl)-4-(dimethylcarbamoyl)piperidine To a solution of l-BOC-4-amino-4-(dimethylcarbamoyl)piperidine (542 mg, 2 mmol) in DMF (10 mL) were added TEA (0.560 mL, 4 mmol) and dibromobutane (473 mg, 1.1 mmol) and the reaction mixture was stirred at 80 - 90°C for 12 h. After DMF was distilled off in vacuo, the residue was diluted with a saturated aqueous NaHCO3 solution, and the organic material was extracted with EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 3/1) to give the title compound (520 mg, 80.0%). MS [M+H] = 326 (M+l)
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)
Intermediates 85 - 97: The following Intermediates listed in Table 6 were obtained from l-BOC-4- (Cbz)amino-4-piperidinecarboxylic acid using the same procedure described in Inteπnediate 67 or 84. Table 6
Figure imgf000055_0001
Figure imgf000055_0002
Table 6 (continued)
Figure imgf000056_0001
Intermediate 98: Phthaliminoethyl amine
Step A: 2-Phthalimino-l-BOC-aminoethane To a solution of commercially available N-BOC-ethylenediamine (1.6 g, 10 mmol) and TEA (2.8 mL, 20 mmol) in DCM (30 mL) was added phthalic anhydride (1.63 g, 11 mmol). After being stirred at rt for 4 h, the reaction mixture was quenched with a aqueous IN HCI solution, and the organic material was was extracted with EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (1.60 g, 84.0%). MS [M+H] = 291 (M+l)
Step B: Phthaliminoethyl amine To a solution of 2-phthalimino-l-BOC-aminoethane prepared in Step A (1.0 g, 3.43 mmol) in DCM (5 mL) was added TFA (5 mL) at rt for 30 min. The reaction mixture was concentrated to give the title compound. MS [M+H] = 191 (M+l)
Intermediate 99: 2-Phthalimino-l-(methyl)aminoethane
Step A: 2-Phthalimino-l-[methyl(BOC)amino]ethane To a solution of NaH (80 mg, 60% in mineral oil, 2 mmol) in THF (3 mL) was added 2-Phthalimino-l-BOC-aminoethane prepared in Step A of Intermediate 98 (291 mg, 1 mmol) at 0°C. After 30 min, methyl iodide (74.5 μL, 1.2 mmol) in THF (1 mL) was added slowly at 0 °C and the reaction mixture was stirred at rt 12 h. The reaction mixture was quenched a saturated aqueous NH4C1 solution and diluted with EtOAc, and the organic layer was extracted with EtOAc. The extracts were dried over MgSO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/5) to give the title compound (198 mg, 64%). MS [M+H] = 305 (M+l)
Step B: 2-Phthalimino-l-(methyl)aminoethane The title compound was obtained from 2-ρhthalimino-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)
Intermediate 100: (3S)-l-(2-Nitrobenzene)sulfonyl-3-aminopyrrolidine
Step A: (3S)-l-(2-Nitrobenzene)sulfonyl-3-BOC-aminopyrrolidine To a solution of 3-BOC-aminopyrrolidine (372 mg, 2 mmol) in DCM (10 mL), were added TEA (0.56 mL, 4 mmol) and (2-nitrobenzene)sulfonyl chloride (487.4 mg, 2.2 mmol), and the reaction mixture was stirred at rt for 12 h. The reaction mixture was quenched with a saturated aqueous NH C1 solution, the organic material was extracted with EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/7) to give the title compound (697 mg, 94%). MS [M+H] = 372 (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)
The present invention is illustrated by the following examples. However, the scopes of the invention are not limited to these examples. Examples
Example 1 : (2R)-2-Amino-N-[4-Cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3- (4-chlorophenyl)propionamide TFA
Step A: (2R)-2-(BOC-Amino)-N-[4-Cyclohexyl-4-(t-butylcarbamoyl)piperidin-l-yl]-3- (4-chlorophenyl)propionamide To a solution of 4-cyclohexyl-4-(t-butylcarbamoyl)piperidine (HCI salt, 917 mg, 3.30 mmol) in DMF (30 mL) were added DIPEA (1.15 mL, 6.70 mmol), EDC (845 mg, 4.30 mmol), HOBT (668 mg, 5.00 mmol), and (2R)-N-BOC-(4-chlorophenyI)alanine, and the reaction mixture was stirred at rt for 12 h. After DMF was distilled off under reduced pressure, the residue was poured into EtOAc, and subsequently washed with a saturated aqueous NaHCO3 solution and an aqueous IN HCI solution. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column cliromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (1.58 g, 93.9%). MS [M+H] = 520 (M+l)
Step B : (2R)-2-Amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- 1 -yl]-3-(4- chlorophenyl)propionamide TFA To a solution of (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). After being 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, 979 mg, 95.1%). MS [M+H] = 420 (M+l)
Example 2 : (2R)-2-{ [(2R)-Pyrrolidin-2-yl] carbonyl} amino-N- [4-cyclohexyI-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide TFA
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 To a solution of (2R)-2-amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)piperidin- l-yl]-3-(4-chlorophenyl)propionamide, prepared in Example 1, (TFA salt, 100 mg, 0.188 mmol) in DMF (3 mL) were added DIPEA (66.1 mL, 0.381 mmol), EDC (48.7 mg, 0.252 mmol), HOBT (43.6 mg, 0.322 mmol), and (2R)-N-BOC-proline (40.9 mg, 0.190 mmol), and the reaction mixture was stirred at rt for 12 h. After DMF was distilled off in vacuo, the residue was poured into EtOAc, and subsequently washed with a saturated aqueous NaHCO3 solution and an aqueous IN HCI solution. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column cliromatography (eluent: EtOAc/Hex = 2/1) to give the title compound (107 g, 90.8%). MS [M+H] = 617 (M+l)
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 To a solution of (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 (TFA salt, 50.0 mg, 98.2%). MS [M+H] = 516 (M+l)
Example 3 : (2R)-2-{[(2R)-Pyrrolidin-2-yl]methyl}amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
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 To a solution of (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). After being stirred at rt for 4 h, the reaction mixture was quenched with a saturated aqueous NaHCO3. The organic material was extracted with DCM followed by EtOAc, and the extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: DCM/MeOH = 9/1) to give the title compound (109 mg, 95.0%). MS [M+H] = 603 (M+l) Step B: (2R)-2-{[(2R)-Pyrrolidin-2-yl]methyl}amino-N-[4-cyclohexyl-4-(t-butyl- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA The title compound was obtained from (2R)-2-{[(2R)-l-(BOC)pyrrolidin-2- yl]methyl} amino-N-[4-Cyclohexyl-4-(t-butylcarbamoyl)piperidin- 1 -yl] -3 -(4- chlorophenyl)propionamide prepared in Example 1 according to the same procedure as Step B of Example 1. MS [M+H] = 503 (M+l).
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)ρyrrolidin-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).
Example 6: (2R)-2- [1 -(Methyl)azetidin-3-yl] amino-N- [4-cyclohexyl-4-(t-butyI- carbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
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- chloroρhenyl)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, 73.5%). MS [M+H] = 517 (M+l).
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.
Figure imgf000062_0001
Table 7
Figure imgf000063_0001
Table 7 (continued)
Figure imgf000064_0001
Table 7 (continued)
Figure imgf000065_0001
Table 7 (continued)
Figure imgf000066_0001
Table 7 (continued)
Figure imgf000067_0001
Table 7 (continued)
Figure imgf000068_0001
Table 7 (continued)
Figure imgf000069_0001
Figure imgf000069_0002
Table 7 (continued)
Figure imgf000070_0001
Table 7 (continued)
Figure imgf000071_0001
Table 7 (continued)
Figure imgf000072_0001
Figure imgf000072_0002
Table 7 (continued)
Figure imgf000073_0001
Figure imgf000073_0002
Example 187: (2R)-2-Amino-N-[4-cyclohexyl-4-(aminoethyIcarbamoyl)piperidin-l- yl]-3-(4-chlorophenyl)propionamide 2HC1
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 To a solution of (2R)-2-(BOC)Amino-N-(4-cyclohexyl-4-carboxypiperidin-l- yl)-3-(4-chlorophenyl)propionamide, prepared in Step A, (1.0 g, 2.03 mmol) in DCM (10 mL) were added oxaly chloride (0.26 mL, 3.10 mmol) and catalytic amounts of DMF, and the reaction mixture was stirred at 0 °C for 30 min. The reaction solution was removed in vacuo, and the residue was purified by column chromatography (eluent: EtOAc/Hex = 1/1) to give the title compound (705 mg, 68%). MS [M+H] = 511 (M+l)
Step C: (2R)-2-(BOC)Amino-N-[4-cyclohexyl-4-(aminoethylcarbamoyl)piperidin-l- yl] -3 -(4-chlorophenyl)propionamide To a solution of (2R)-2-(BOC)Amino-N-(4-cyclohexyl-4-chlorocarbonyl- piperidin-l-yl)-3-(4-chlorophenyl)propionamide, prepared in Step B, (511 mg, 1.0 mmol) in DCM (5 mL) were added TEA (0.28 mL, 2.0 mmol) and a solution of N(BOC)-ethylene diamine (90 mg, 1.5 mmol) in DCM (0.5 mL), and the reaction mixture was stirred at rt for 2 h. The reaction solution was concentrated in vacuo, the residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (578 mg, 91%). * MS [M+H] = 635 (M+l)
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). Example 188: (2R)-2-(Dimethylamino)-N-[4-cycIohexyl-4-(aminoethylcarbamoyI)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2HC1
Step A: (2R)-2-(BOC)Aιrιino-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- (phthaliminoetlιylcarbamoyl)-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 To a solution of (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. The reaction mixture was concentrated in vacuo, and the residue was purified by HPLC to give the title compound (TFA salt, 111 mg, 57.0%). MS [M+H] = 463 (M+l) Step E: (2R)-2-(Dimethyl)amino-N-[4-cyclohexyl-4-(aminoethylcarbamoyl)piperidin- 1 - yl]-3-(4-chlorophenyl)propionamide 2HC1 The title compound was obtained from (2R)-2-(Dimethyl)amino-N-[4- cyclohexyl-4-(aminoethylcarbamoyl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide 2TFA prepared in Step D according to the same procedure as Step E of Example 187. MS [M+H] = 463 (M+l).
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.
Table 8
Figure imgf000077_0001
Figure imgf000077_0002
Table 8 (continued)
Figure imgf000078_0001
Example 226: (2R)-2-Amino-N-[4-cyclohexyI-4-(3-oxo-azetidin-l-yl)piperidin-l- yl]-3-(4-chlorophenyϊ)propionamide 2HC1
Step A: (2R)-2-Amino-N-[4-cyclohexyl-4-(3-oxo-azetidin-l-yl)piperidin-l-yl]-3-(4- chlorophenyl)propionamide 2TFA To a solution of (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). After being stirred at rt for 12 h, the reaction mixture was quenched with a saturated aqueous Na2S2O3 solution, and the precipitate was filtered. The filtrate was dried over MgSO4, concentrated in vacuo, the residue was purified by HPLC to give the title compound (TFA salt, 203 mg, 81.0%). MS [M+H] = 446 (M+l)
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).
Example 228 : (2R)-2- [2-(Dimethyl)aminoethyl] amino-N- [4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
Step A: (2R)-2-[(2-nitrobenzene)sulfonyl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl-3-(4-chlorophenyl)propionamide To a solution of (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). After being st red at rt for 4 h, the reaction mixture was quenched with an aqueous NH4C1 solution, and the organic material was extracted with DCM followed by EtOAc. The extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (570 mg, 90%). MS [M+H] = 633 (M+l)
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 To a solution of (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 K2CO3 (280 mg, 2 mmol) and 2- (dimethylamino)ethyl chloride (HCI salt, 125.9 mg, 1 mmol). After being stirred at rt for 12 h, the reaction mixture was concentrated in vacuo, and the residue was dilueted with a saturated aqueous NH C1 solution. The organic material was extracted with EtOAc, and the extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (511 mg, 92%). MS [M+H] = 703 (M+l)
Step C: (2R)-2-[2-(dimethyl)aminoethyl]amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA To a solution of (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 K2CO3 (300 mg, 2 mmol) and thiobenzene (210 mL, 0.429 mmol). After being stirred at rt for 2 hr, the reaction mixture was concentrated in vacuo, and the residue was diluted with water. The organic material was extracted with EtOAc, the extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (TFA salt, 477 mg, 90%). MS [M+H] = 520 (M+l)
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)propionamide prepared in Step A of Example 228 and N-BOC- aminoethyl bromide according to the same procedure as Step B of Example 228. MS [M+H] = 727 (M+l).
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 in Step A of Example 229 according to the same procedure as Step C of Example 228. MS [M+H] = 563 (M+l).
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 The title compound was obtained from acetylaminoethyl bromide according to the same procedure as Example 228. MS [M+H] = 505 (M+l).
Example 232: (2R)-2-{Methyl[2-(methyl)aminoethyl]amino-N-[4-cyclohexyl-4-(t- butylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
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. MS [M+H] = 577 (M+l). 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- chlorophenyι)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).
Example 234: (2R)-2-(Methyl)amino-N-[4-cyclohexyl-4-(t-butylcarbamoyl)- piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2TFA
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. MS [M+H] = 619 (M+l). 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.
Table 9
Figure imgf000085_0001
Figure imgf000085_0002
Table 9 (continued)
Figure imgf000086_0001
Table 9 (continued)
Figure imgf000087_0001
Figure imgf000087_0002
Example 270: (2R)-2-[2-(Dimethyl)aminoethyI]amino-N-[4-cyclohexyl-4-(amino- ethylcarbamoyl)piperidin-l-yl]-3-(4-chlorophenyl)propionamide 2HC1
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-chloroρhenyl)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.
Table 10
Figure imgf000089_0001
Figure imgf000089_0002
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)piρeridin-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).
Biological Assays
A. Binding Assay The membrane fraction binding assay was used to identify competitive inhibitors of 125I - NDP- MSH binding to cloned human MCRs expressed in HEK cells. Cell lines expressing human melanocortin receptor 4 (MC4R) were grown in Φ150 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 % CO2 at 37 ° C. When the cells were fully grown, the cells were washed once with 10 ml of Ca4-*", 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. The supernatant was discarded, and 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.
Membrane fraction was diluted with membrane binding buffer to make final 600 ug/ml, and 50 ul of membrane fraction containing 30 ug of membrane protein was added onto each well of 96-well assay plate. 25 ul of test compounds or 20 uM unlabelled NDP-MSH (to make the final concentration at 5 uM) diluted with membrane binding buffer was added onto each well of 96-well assay plate. 25 ul of 0.4 nM 125I - NDP-MSH [NEN, Cat. # NEX352 (50 uCi), t1/2 = 60 days] diluted with membrane binding buffer was added onto each well to make the final concentration of 0.1 nM. The resulting mixture was incubated for 2 hours at room temperature. The reaction mixture was filtered with 96 well GF/C filter plate (Unifilter GF/C™, 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 Microscint™-20 was added to each well. The top was sealed, and the radioactivity was quantitated in a Packard Topcount Microplate Scintillation Counter. The IC50 was defined as the concentration of test compound that results in the half maximal inhibition of 125I - NDP-MSH binding to cloned human MCRs. The ICso values obtained in the competition assay were converted to affinity constants (Ki values). B. Functional Assay
1. Luciferase Assay. Cell lines expressing human melanocortin receptor 4 (MC4R) were dissociated from tissue culture dishes by rinsing with Ca""", Mg"1""1" free DPBS, treated with 1 X Trypsin / EDTA solution for 1 min at 37 ° C, and resuspended with DMEM (GIBCO- BRL) supplemented with 10% FBS. The cells were counted and diluted with DMEM supplemented with 10% FBS and 200 ug/ml of Geneticin to 5 X 105 cells/ ml. 90 ul of cell suspension was plated onto each well of 96-well black and clear bottom culture plates (Costar). After the incubation for 24 hours in the atmosphere of 6 % CO2 at 37 °
C, lOul of NDP-MSH and test compounds diluted in DMSO were added to each well. The final DMSO concentration was 1 %. After 4 hours of incubation in the atmosphere of 6 % CO at 37 ° C, 50 ul of Bright-Glo (Promega) was added to each well. Luciferase activity was measured by using L-Max luminometer (Molecular Device). The amount of luciferase activity induced by treatment with NDP-MSH was defined as 100 % to obtain the relative efficacy of test compounds. The EC o.s MSH was defined as the concentration of test compounds that results in half maximal activity of NDP- - MSH. The EC5Q was defined as the concentration of test compound that results in half maximal activity of its own.
2. 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 Φ 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 % CO2 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. All of the supematants were collected and centrifuged at 40,000 rpm (Beckman XL-100K Ultracentrifuge, Rotor 45 Ti, 50 ml centrifuge tube) at 4°C for 15 minutes. The pellets were resuspended in membrane preparation buffer, and protein was determined by BCA assay kit (PIERCE). Aliquots were placed in tubes and stored at - 80 ° C. 20 ul of NDP-MSH or test compounds diluted in DMSO were added onto each well of 96well V-plate. 20 ul of 750ug/ml membrane fraction in MP buffer was added onto each well. After the reaction was performed at room temperature for 15 min, cAMP was measured using cAMP (3H) 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 EC50 was defined as the concentration of test compound that results in half maximal activity of its own.
As can be seen from the above results, the compounds according to the present invention showed agonistic efficacy and binding affinity to each MCR. In particular, the compounds according to the present invention showed excellent agonistic efficacy and binding affinity to the MCR4. i.e., 0.005 μM - 10 μM of EC50 value and 0.01 μM - 50 μM of IC50 value. For example, the compounds of examples 1, 2 and 3 showed 0.005 μM - 0.5 μM of EC50 value, and 0.1 μM - 0.5 μM of IC50 value, against MCR4.
C. In vivo food intake models
1. Hypophasic effects in fasted mice
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.
2. 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.
3. Effects on food intake and body weight change in ob/ob mice Effects on food intake and body weight change are determined in male 8 wks old ob/ob mice. The 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.
4. 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.
D. Anti-inflammatory effects in an acute inflammation model Anti-inflammatory effects are determined as the effects on crystal-induced Polymorphonuclear Neutrophil (PMN) recruitment. Each Balb/c mouse receives the administration of vehicle or test substance via oral gavage. One hour after the vehicle or drug treatment, the animals receive 3 mg of mono-sodium urea crystals in 0.5 ml of PBS (pH 7.4) buffer (time = 0) by the intraperitoneal injection. At 6 hrs after the crystal injection, the animals are euthanized by CO2 exposure, and then their peritoneal cavities are washed with 3 ml of PBS buffer. Aliquots of the lavage fluids are stained with Turk's solution (0.01% crystal violet in 3% acetic acid), and the number of cells are counted by using a hemacytometer and a light microscope. PMNs are counted as many as (1 ~ 10) x 106 per mouse. Data are presented as 106 PMN per mouse.
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.

Claims

A compound of the following formula (1):
Figure imgf000095_0001
in which
R1 represents hydrogen, -(CH2)P-R6, -(CH2)p-CO-R6, -(CH2)p-SO2-R6, or -CO-(CH2)p-R6, wherein p represents independently 0, 1, 2, or 3,
R6 represents Ci-Cio-alkyl, C3-C8-cycloalkyl, heterocycle, aryl, heteroaryl, amino, or hydroxyl, each of which is unsubstituted or mono- to polysubstituted by substituents from the group consisting of d-Ce-alkyl, halogen, amino, d-C6-alkylamino, di(C1-C6-alkyl)amino, hydroxy, Ci- C8-alkoxy, trifluoromethoxy, Ci-Ce-aikylcarbonyl, arylcarbonyl, d-C6- alkoxycarbonyl, carbamoyl, CrCβ-alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo,
hydrogen atom in -(CH2)p- group can be replaced by R6 as defined above,
R2 represents hydrogen, Ci-Cg-alkyl, or C3-C -cycloalkyl,
9 1 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-(d-C4-alkyl),
R3 represents Cι-C8-alkyl, -(CH2)q-C3-C -cycloalkyl, -(CH2)q-phenyl, or - (CH2)q-hetero-aryl, each of which is unsubstituted or mono- to trisubstituted by substituents from the group consisting of d-C6-alkyl, halogen, amino, d-C6-alkylamino, di(C1-C6-alkyl)amino, hydroxy, d-Cs-alkoxy, Cι-C6- alkylcarbonyl, arylcarbonyl, d-C6-alkoxycarbonyl, carbamoyl, Cι-C6- alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo, wherein q represents independently 0, 1, 2, or 3,
R4 represents phenyl, cyclohexyl, or NR7R8, wherein
R and R independently of one another represent Cι-C6-alkyl, -(CH2)q-C3- C -cycloalkyl, -(CH2)q-phenyl, or -(CH2)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-(C1-C4-alkyl), and these radicals are unsubstituted or mono- to poly-substituted by substituents from the group consisting of d-C6-alkyl, halogen, amino, d-C6-alkylamino, di(C1-C6-alkyl)amino, hydroxy, Cι-C8-alkoxy, trifluoromethoxy, Cι-C6- alkylcarbonyl, arylcarbonyl, d-C6-alkoxycarbonyl, carbamoyl, Cι-C6- alkylsulfonyl, arylsulfonyl, carboxy, cyano, and oxo
R5 represents -(CH2)0-R9, -(CH2)0-COR9, or -(CH2)0-C(O)N(R9)(R10), wherein o represents independently 0, 1, 2, or 3,
R9 andR10 independently of one another represent hydrogen, amino, hydroxy, d-C6-alkyl, d-C6-alkoxy, C3-C7-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 Cι-C6- alkyl, halogen, amino, d-C6-alkylamino, di(C1-C6-alkyl)amino, hydroxy, d-Cg-alkoxy, trifluoromethoxy, d-C6-alkylcarbonyl, arylcarbonyl, d-C6- alkoxycarbonyl, carbamoyl, d- -alkylsulfonyl, arylsulfonyl, C3-C6- cycloalkyl C2-C8-alkanoyl, Ci-Cδ-alkylsulfamoyl, carboxy, cyano, and oxo, or
R9 andR10 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- (d- -alkyl), pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
2. The compound according to claim 1 wherein
R1 represents hydrogen, -(CH2)P-R6, -(CH2)p-CO-R6, or -(CH2)p-SO2-R6 (wherein p is as defined in claim 1), and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
3. The compound according to claim 2 wherein
R1 represents hydrogen, or -(CH2)P-R6 (wherein p is as defined in claim 1), and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
4. The compound according to claim 1 wherein R1 represents -CO-(CH2)p-R6 (wherein p is as defined in claim 1), and pharmaceutically acceptable salt, hydrate, solvate or isomer thereof.
5. The compound according to claim 1 wherein R2 represents hydrogen, or Ci-Cβ-alky and pharmaceutically acceptable salt, hydrate, solvate or isomer thereof.
6. The compound according to claim 1 wherein
R3 represents -(CH2)q-C3-C -cycloalkyl, -(CH2)q-phenyl, or -(CH2)q-heteroaryl, each of which is unsubstituted or mono- to trisubstituted by substituents from the group consisting of halogen, cyano, carboxy, hydroxy, C1-C4-alkyl, Cι-C8- alkoxy, amino, Cι-C4-alkylamino, and di(C1-C4-alkyl)amino, wherin q is as defined in claim 1, and, pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
7. The compound according to claim 6 wherein
R represents -CH2-cyclohexyl or CH2-phenyl, each of which is unsubstituted or mono- to trisubstituted by substituents from the group consisting of halogen, cyano, hydroxy, Cι-C4-alkoxy, trifluoromethoxy, and C1-C4-allcyl, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
8. The compound according to claim 1 wherein
R4 represents phenyl, cyclohexyl, C1-C4-alkylamino, di(Cι-C4-alkyl)amino, pyrrolidinyl, piperidinyl, or azepinyl, wherein d-C4-alkyl, pyrrolidinyl, piperidinyl or azepinyl is unsubstituted or mono- to tri-substituted by substituents from the group consisting of halogen, hydroxy, C1-C -alkyl, C1-C4-alkoxy, amino, Cι-C4-alkylamino, and di(C1-C -alkyl)amino, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
9. The compound according to claim 1 wherein
R5 represents Cι-C6-alkyl, -(CH2)0-heteroaryl, -(CH2)0-heterocycle, -CO2R9, - C(O)N(R9)(R10), -(CH2)0-ORπ, -(CH2)0-NHRπ, or -(CH2)0-N(RU)(R12), wherein heteroary is unsubstituted or mono- to tri-substituted by substituents from the group consisting of hydroxy, C1-C4-alkyl, C1-C4-alkoxy, amino, Cj- C4-alkylamino, di(C1-C4-alkyl)amino, and oxo, wherin R9 and R10 are as defined in claim 1, R11 andR12 independently of one another represent d-C6- alkyl, C -C6-cycloalkyl, C2-C8-alkanoyl, d-C6-alkylsulfonyl, d-C6- alkylsulfamoyl, or arylsulfonyl, and o is as defined in claim 1, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
10. The compound according to claim 9 wherein
R5 represents -(CH2)0-1 -heteroaryl, -(CH2)0-ι -heterocycle, -C(O)N(R9)(R10), - (CH2)0-ORπ, -(CH2)0-ι-NHRn, or -(CH2)0-1-N(R11)(R12), wherein R9, R10, 1 1 t o R andR are defined as in claim 9, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
11. An agonistic composition of melanocortin receptor comprising the compound of formula 1, and pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as defined in claim 1 as active ingredients together with pharmaceutically acceptable carrier.
12. The composition according to claim 10 for the prevention and freatment of obesity.
13. The composition according to claim 10 for the prevention and treatment of diabetes.
14. The composition according to claim 10 for the prevention and treatment of inflammation.
15. The composition according to claim 10 for the prevention and treatment of erectile dysfunction.
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