JP2006282602A - New piperidine derivative having melanocortin-4 receptor agonist action - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new piperidine derivative having melanocortin-4 receptor agonist action or its pharmaceutically acceptable salt, and a medicine for treatment and/prophylaxis of diseases in which the melanocortin-4 receptor participates. <P>SOLUTION: The present invention provides the medicine for treatment and/or prophylaxis of diseases in which the melanocortin-4 receptor participates by a compound represented by a piperidine derivative represented by general formula (I) (wherein each symbol is specifically determined) or its pharmaceutically acceptable salt. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel piperidine derivative. More specifically, the present invention relates to a piperidine derivative having a melanocortin-4 receptor agonistic action and a salt thereof, and uses thereof.

  Metabolic abnormalities such as obesity, impaired glucose tolerance, hyperlipidemia, and hypertension are so-called arteriosclerotic diseases (events) including myocardial infarction and cerebral infarction in the combined condition even if each abnormality is mild It has become clear that it develops frequently. In other words, these metabolic abnormalities have attracted attention as risk factors that have a close relationship with the onset and progression of arteriosclerosis. The pathophysiology of these risk factors is called metabolic syndrome, and it is suggested that the underlying cause of this syndrome is a lack of exercise due to stress and overeating, satiety, and the spread of TV and cars in many countries. .

  Obesity is not only a risk for the onset of events, but also has a detrimental effect on the mind and body. At the general psychopathological level assessed by psychological tests, both obese and non-obese people remain the same. However, it has been suggested that some women belonging to relatively high or intermediate socio-economic groups are associated with obesity and the psychological problems they have. It is thought that the strong prejudice and discrimination directed at obesity in recent years may be the cause of these problems. While adverse events related to obesity have been reported, including about 300,000 deaths from obesity-related diseases in the United States, the number of obese people in developed countries continues to increase. Therefore, development of a drug that regulates food intake, in particular, a preventive / therapeutic agent for obesity is strongly desired, but an effective drug has not been developed yet. In the United States, D-fenfluramine or a combination of Fenfluramine and Phentermine (Fen-Phen therapy) can effectively control eating, and in the past, there have been cases prescribed to about 18 million people per year. Is no longer used. In other words, a pharmacotherapy that sufficiently satisfies the needs as a food intake regulator for obesity has not yet been developed.

  Various causes of infertility are considered, but it has been pointed out that the recent stressful society may be involved in infertility in women and men. Furthermore, with the advancement of women into the society and the late marriage, the declining birth rate has become a problem especially in developed countries.

  That is, it can be meaningful that diseases such as obesity and infertility are social diseases brought about by the modern car society or stress society.

  In the life science field, research on energy metabolism in the body related to obesity has made great strides since the discovery of leptin secreted from fat cells. Leptin is attracting attention as the ultimate anti-obesity drug that can suppress feeding and increase basal metabolism, and is itself expected to be developed as a medicine. However, the body's blood leptin concentration increases in proportion to the body mass index (BMI), and there are many cases in which metabolic syndrome such as obesity falls into a “leptin resistance” state. As a cause of leptin resistance, there is a possibility that the leptin has a brain transfer disorder in a disease state. Therefore, it is unclear whether leptin is effective even if administered from the periphery in a state of leptin resistance. Furthermore, since the leptin receptor is not a GPCR (G-protein coupled receptor), it is expected that it will be difficult to create a low molecular weight ligand for the leptin receptor having central migration.

  It has been reported that the expression of proopiomelanocortin, which is a melanocortin precursor, is induced by leptin in the brain, and the feeding-regulating action of leptin is exerted via the melanocortin-4 type receptor (Non-patent Document 1) ).

  Melanocortin is a peptide hormone produced by processing pro-opiomelanocortin with a protease. It has a variety of anti-inflammatory effects, pigmentation, hormone secretion control, feeding regulation, basic metabolic regulation, memory / learning, sexual behavior, and emotional behavior. It is known to have an effect. These actions are exerted through the melanocortin receptor.

  Melanocortin receptor is a kind of GPCR (G-protein coupled receptor), and it is known that there are 5 types of subtypes (type 1, type 2, type 3, type 4, type 5 receptor). Yes. Among the five subtypes, the type 4 receptor (melanocortin receptor type-4) (hereinafter sometimes abbreviated as “melanocortin-4 type receptor” or “MC4R”) is expressed centrally, and the action of melanocortin Among them, it is a receptor that has been suggested to be involved in regulation of feeding, regulation of basal metabolism, and sexual behavior.

  Findings related to food intake regulation include α-Melanocyte stimulating hormone (hereinafter sometimes referred to as “αMSH”), a physiological melanocortin receptor agonist, and melanotan, a synthetic cyclic peptide that acts well on type 4 and type 3 receptors. 2 (MT-II) has been reported to be able to suppress animal feeding (Non-patent Document 2). Furthermore, HS014, which is an antagonist selective for the melanocortin-4 type receptor, has been reported to enhance feeding (Non-patent Document 3). These findings suggest that the melanocortin-4 receptor is closely involved in animal feeding behavior.

  As for knowledge related to metabolic regulation, there is a report that αMSH increases the gene expression of Thyrotropin releasing hormone (Non-patent Document 4), and a report that MC4R knockout mice have impaired diet-induced heat production (Non-patent Document 5). is there.

  Therefore, it is suggested that the melanocortin-4 type receptor is involved not only in energy input (feeding regulation) but also in energy output (basal metabolic rate regulation).

  It is reported that MT-II promotes erection of male animals via the center (Non-patent document 6) and induces sexual behavior of female animals (Non-patent document 7) as knowledge related to sexual behavior. .

  Furthermore, the melanocortin receptor is a kind of GPCR to which a large number of pharmaceuticals bind so far, and it can be expected that the molecular weight of the active substance is reduced. That is, the melanocortin receptor acting substance has a concept capable of canceling “leptin resistance”, and at the same time, it can be expected to have a low molecular weight that can be administered orally.

  Based on the above, active substances on the melanocortin-4 type receptor can regulate feeding behavior and sexual behavior, and prevention and treatment of obesity, sexual dysfunction, sexual dysfunction and infertility including sexual intercourse It can be strongly expected to have an effect on the disease obtained.

On the other hand, spiropiperidine derivatives (Patent Documents 1 to 3) and specific piperidine derivatives (Patent Documents 4 to 8) suggesting an action on a melanocortin receptor are disclosed.
PCT International Publication No. WO99 / 64002 PCT International Publication No. WO01 / 70337 PCT International Publication No. WO01 / 91752 PCT International Publication WO00 / 74679 PCT International Publication No. WO01 / 70708 PCT International Publication No. WO02 / 15909 PCT International Publication No. WO03 / 007949 PCT International Publication No. WO03 / 093234 Cheung CC et al, Endocrinology 138 p4489-4492 (1997) Michelle M et al, Peptides 22 p129-134. (2001) Kask A et al, BBRC 245, p90-93 (1998) Harris M et al, JCI 107, p111-120 (2001) Butler AA et al, Science 4 p605-611 (2001) Wessells-H et al, Ann.NYAcad.Sci. 994 p90-95 (2003) Pfaus JG et al, PNAS 101 p10201-10204 (2004)

  The present invention relates to a novel piperidine derivative or salt thereof having a melanocortin-4 receptor (MC4R) action, and further having an agonist action, and a prophylactic / therapeutic agent for obesity and sexual function based on the MC4R agonist action. The present invention provides a useful drug as a remedy for dysfunction or infertility.

  As a result of diligent research to solve the above problems, the present inventors synthesized a specific piperidine derivative or a salt thereof for the first time, and based on the structural characteristics of the present invention, the present invention has an excellent MC4R agonistic action. In addition, the present inventors have found that it is excellent in pharmacokinetics and is clinically useful as a preventive / therapeutic agent for the above-mentioned diseases, and the present inventors have completed the present invention.

  Since the compound represented by the formula (I) of the present invention strongly acts as an agonist on the melanocortin-4 receptor (MC4R), various diseases (for example, obesity, sexual dysfunction, and sexual intercourse dysfunction) It is useful as an agent for preventing, treating and improving infertility.

  In addition, the compound of the present invention is useful for providing a drug having low drug interaction and weak drug-metabolizing enzyme inhibition in the liver.

  In addition, the compound of the present invention is excellent in metabolic stability, and is useful for providing a medicament excellent in sustained drug efficacy.

  The present invention relates to the following piperidine derivatives or pharmaceutically acceptable salts thereof, and uses thereof.

  (1) The following general formula (I)

{Wherein R ¹ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;
R ² is
Hydrogen atom,
An alkyl group having 1 to 8 carbon atoms,
(CR ^a R ^b ) _n C _3-8 cycloalkyl group,
(CR ^a R ^b ) _n aryl group,
^(CR a ^R _{b) n} heteroaryl,
(CR ^a R ^b ) _n heterocycle group,
_{^{(CR a R b) n -N}} (R 1c) C (O) R 2c,
_{^{(CR a R b) n -N}} (R 1c) S (O) m R 2c,
_{^{(CR a R b) n -N}} (R 1c) (R 2c),
(CR ^a R ^b ) _n -C (O) OR ^1c ,
_{^{(CR a R b) n -C}} (O) N (R 1c) (R 2c),
(CR ^a R ^b ) _n -OR ^1c
[Cycloalkyl group (3) in the above ^{R 2,} an aryl group (4), heteroaryl groups (5), heterocyclic group (6), 1-4 selected from ^{R d} or oxo optionally Each of the substituents may be the same or different, when the number of the substituents is 2 or more.
n is 0, 1, 2 or 3;
m is 0, 1 or 2;
R ^a , R ^b , R ^1c and R ^2c may be the same or different and each is a hydrogen atom,
An alkyl group having 1 to 8 carbon atoms,
An aryl group,
An arylalkyl group (an alkyl group having 1 to 4 carbon atoms),
A hydroxy group,
Indicates that it is a hydroxyalkyl group having 1 to 4 carbon atoms,
Furthermore, R ^a and R ^b may together form a C _3-8 cycloalkyl group. ]
R ¹ and R ² may be taken together to form a heterocycle group (the heterocycle group is substituted with 1 to 4 groups selected from R ^{d and} oxo). In addition, when there are two or more substituents, each of the substituents may be the same or different.
R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or a hydroxy group,
R ² and R ³ may be taken together to form a cycloalkyl group or heterocycle group having 3 to 10 carbon atoms (the cycloalkyl group or heterocycle group is selected from R ^d or oxo). 1 to 4 selected groups may be substituted, and when further substituted with two or more of the substituents, each of the substituents may be the same or different.
R ² , R ³ and R ⁴ may be taken together to form an aryl group or heteroaryl group (the aryl group or heteroaryl group is selected from R ^{d and} oxo 1 -4 groups may be substituted, and when the number of substituents is 2 or more, each of the substituents may be the same or different).
[R ^d of R ^{1 to} R ⁴ is
A halogen atom,
A cyano group,
An alkyl group having 1 to 8 carbon atoms,
A cycloalkyl group having 3 to 8 carbon atoms,
An aryl group,
An arylalkyl group (an alkyl group having 1 to 4 carbon atoms),
A heteroaryl group,
Heterocycle groups,
-OR ^1d ,
_-NH-SO ^{2 R 1d,}
-N (R ^1d ) (R ^2d ),
-NH-C (O) R ^1d ,
-C (O) OR ^1d ,
-C ( ^R1d ) ( ^R2d ) -N ( ^R3d ) ( ^R4d ),
-C (O) R ^1d ,
^{_{-SO 2 -N (R 1d) (}} R 2d),
-S (O) _m -R ^1d ,
-CF _3,
-OCF ₃
The cycloalkyl group, aryl group, arylalkyl group, heteroaryl group and heterocycle group in R ^d may be substituted with a halogen atom, a cyano group, or an alkyl group having 1 to 8 carbon atoms, and the substitution is further performed. When two or more groups are present, each of the substituents may be the same or different,
m is 0, 1 or 2;
R ^1d , R ^2d , R ^3d and R ^4d may be the same or different,
Hydrogen atom,
An alkyl group having 1 to 8 carbon atoms,
An aryl group,
An arylalkyl group (an alkyl group having 1 to 4 carbon atoms),
Indicating a heteroaryl group,
The aryl group, arylalkyl group and heteroaryl group of R ^1d , R ^2d , R ^3d and R ^4d may be substituted with an alkyl group having 1 to 8 carbon atoms, a halogen atom or a cyano group. When is 2 or more, each of the substituents may be the same or different. ]
R ⁵ is
Hydrogen atom,
An alkyl group having 1 to 8 carbon atoms,
(CHR ^e ) _p C _3-8 cycloalkyl group,
(CHR ^e ) _p aryl group,
^(CHR _{e) p} heteroaryl group,
A (CHR ^e ) _p O (CHR ^e ) _p aryl group,
[The cycloalkyl group, aryl group and heteroaryl group in R ⁵ may be substituted with 1 to 4 R ^f , and when R ^f is 2 or more, each R ^f is the same, or May be different,
p is 0, 1 or 2;
^Re is
Hydrogen atom,
An alkyl group having 1 to 8 carbon atoms,
An aryl group,
An arylalkyl group (an alkyl group having 1 to 4 carbon atoms),
A cycloalkyl group,
R ^f has the same ^meaning as R ^d . ]
W ¹ is
Hydrogen atom,
An alkyl group having 1 to 8 carbon atoms,
_{(CH 2)} q _{C 3-8} cycloalkyl group,
(CH ₂ ) _qaryl group,
(CH ₂ ) _qheteroaryl group,
(CH ₂ ) _q heterocycle group,
W ² is
Hydrogen atom,
An alkyl group having 1 to 8 carbon atoms,
_{(CH 2)} q _{C 3-8} cycloalkyl group,
(CH ₂ ) _qaryl group,
(CH ₂ ) _qheteroaryl group,
_{(CH 2) q} heterocyclic group,
(CH ₂ ) _q cyano group,
_{(CH 2) q -C (O} ) N (R 1g) (R 2g),
_{(CH 2) q -C (O} ) OR 1g,
_{(CH 2) q -N (R} 1g) C (O) R 2g,
_{(CH 2) q -N (R} 1g) C (O) OR 2g,
_{(CH 2) q -N (R} 1g) C (O) N (R 2g) (R 3g),
_{(CH 2) q -N (R} 1g) S (O) N (R 2g) (R 3g),
_{(CH 2) q -S (O} ) m R 1g,
_{(CH 2) q -SO 2 N} (R 1g) (R 2g),
_{(CH 2) q -OC (O} ) R 1g,
_{(CH 2) q -OC (O} ) OR 1g,
_{(CH 2) q -OC (O} ) N (R 1g) (R 2g),
_{(CH 2) q -N (R} 1g) (R 2g),
_{(CH 2) q -N (R} 1g) S (O) m R 2g,
_{(CH 2) q -C (O} ) N (R 1g) (CH 2) q N (R 2g) (R 3g),
_{(CH 2) q -C (O} ) N (R 1g) (CH 2) q N (R 2g) S (O) m R 3g,
In _{(CH 2) q -N (R} 1g) C (O) (CH 2) q N (R 2g) it is (R ^{3 g)} [the ^{W 1, W 2,}
q is 0, 1, 2 or 3;
m is 0, 1 or 2;
R ^1g , R ^2g and R ^3g may be the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. ] Is shown. } Or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. (2) The piperidine derivative according to the above (1), wherein R ¹ is a hydrogen atom or —CH ₃ , or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. (3) The piperidine derivative according to the above (2), wherein R ⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (4) The following general formula (II)

[In the general formula (II), R ¹ , R ³ and R ⁴ in the general formula (I) are hydrogen atoms, R ⁵ is a (CHR ^e ) _p aryl group, R ^e is a hydrogen atom, p = 1, an aryl group is a phenyl ^{group, R 2, R f, W} 1, W 2 of the general formula (II), ^{respectively, R 2, R f, W} 1, W 2 as defined in formula (I) Indicates that ] The piperidine derivative as described in said (1) represented by these, its pharmacologically acceptable salt, or those hydrates or solvates. (5) The piperidine derivative according to (4), wherein n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (6) R ² is (CR ^a R ^b ) _n C _3-8 cycloalkyl group, (CR ^a R ^b ) _n aryl group, (CR ^a R ^b ) _n heteroaryl group, (CR ^a R ^b ) _n hetero The piperidine derivative according to the above (5), which is a cycle group, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. (7) R ² is
Cyclohexyl, cycloheptyl, cyclopentyl,
Phenyl, naphthyl,
Furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolinyl, oxazolinyl, pyranyl, thiazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazinyl, triazinyl, indolyl, indolinyl, benzoimidazolyl Quinolyl, isoquinolyl, isothiazolyl,
The piperidine derivative according to the above (6) selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, piperidino, piperidyl, piperazinyl, morpholino, morpholinyl, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. . (7) The following general formula (III)

[In general formula (III), R ¹ and R ^{4 in} general formula (I) are hydrogen atoms, and R ² and R ³ together represent a cycloalkyl group having 3 to 10 carbon atoms or hetero Forming a cycle group (abbreviated as “Ar” in the general formula (III)), wherein Ar may be substituted with 1 to 4 groups selected from R ^d or oxo; When the above substituents are substituted, the substituents may be the same or different.) R ⁵ is a (CHR ^e ) _p aryl group, and R ^e is a hydrogen atom, p = 1, an aryl group is a phenyl ^{group, R d, R f, W} 1, W 2 of the general formula (III), respectively, ^R d in the general formula ^(I), R ^f, and W 1, ^{W 2} Indicates that it is synonymous. ] The piperidine derivative as described in said (1) represented by these, its pharmacologically acceptable salt, or those hydrates or solvates. (9) The cycloalkyl group of Ar is cyclohexyl, cycloheptyl, cyclopentyl, adamantyl, and the heterocycle group is pyrrolidinyl, imidazolidinyl, oxazolidinyl, piperidino, piperidyl, piperazinyl, morpholino, morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl The piperidine derivative according to (8) or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, which is selected from quinukiridinyl. (10) The piperidine derivative or the drug thereof according to (4) to (9), wherein the (CH ₂ ) _q C _3-8 cycloalkyl group of W ¹ is selected from cyclohexyl, cycloheptyl, and cyclopentyl. Physiologically acceptable salts thereof, or hydrates or solvates thereof. (11) W ² is (CH ₂ ) _q C _3-8 cycloalkyl group, (CH ₂ ) _q aryl group, (CH ₂ ) _q heteroaryl group, (CH ₂ ) _q heterocycle group, (CH ₂ ) _q ^{-C (O) N (R 1g} ) (R 2g), (CH 2) q -N (R 1g) C (O) R 2g, (CH 2) q -S (O) m R 1g, (CH 2 ^{_{) q -N (R 1g) S}} (O) m R 2g, (CH 2) q -C (O) N (R 1g) (CH 2) q N (R 2g) (R 3g), (CH 2) _{q -C (O) N (R} 1g) (CH 2) q N (R 2g) S (O) m R 3g, (CH 2) q -N (R 1g) C (O) (CH 2) q N The piperidine derivative according to the above (10) which is (R ^2g ) (R ^3g ) or a pharmacologically acceptable salt thereof, or a hydrate or solvent thereof Japanese products. (12) W ² is q = 1, the C _3-8 cycloalkyl group is cyclohexyl, cycloheptyl, cyclopentyl, the aryl group is phenyl, naphthyl, the heteroaryl group is furyl, thienyl , Pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolinyl, oxazolinyl, pyranyl, thiazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazinyl, triazinyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, quinolyl , Isoquinolyl, isothiazolyl and the heterocycle group is from pyrrolidinyl, imidazolidinyl, oxazolidinyl, piperidino, piperidyl, piperazinyl, morpholino, morpholinyl Piperidine derivative or a pharmacologically acceptable salt thereof or a hydrate thereof or a solvate, according to the are those-option (11). (13) The piperidine derivative or the pharmaceutically acceptable salt thereof according to (11), wherein W ² is selected from the following substituents.

Acetylamide, propanamide, butanamide, 2-methylpropanamide, 2,2-dimethylpropanamide. (14) Any piperidine derivative selected from the following compounds, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
N- {1- [4-chloro-N- (1-methylpiperidin-4-yl) -D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide,
N- {1- [N- (1-benzylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide,
N- {1- [N- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- (tert-butyl) -1- (4-chloro-N-{[1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Chloro-N-{[1-ethylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-isopropylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-butylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-isobutylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Fluoro-N-{[1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- (1- {4-chloro-N- [pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- {4-fluoro-N- [pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Chloro-N-{[4-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide
N- [1- (4-Chloro-N-{[4- (methylthio) pyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide ,
N- (1- {4-fluoro-N- [pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- (4-chloro-N-{[4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxamide;
N- (tert-butyl) -1- (4-fluoro-N-{[4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Fluoro-N-{[4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[4-morpholin-4-ylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide. (15) Any piperidine derivative selected from the following compounds, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
N- [1- (4-Chloro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- (tert-butyl) -1- (4-chloro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxy Amide,
N- [1- (4-Chloro-N-{[(2R) -1-ethylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Chloro-N-{[(2R) -1-isopropylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Chloro-N-{[(2R) -1-butylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Chloro-N-{[(2R) -1-isobutylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Fluoro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- (1- {4-chloro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- {4-fluoro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Chloro-N-{[(2R, 4R) -4-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2 -Methylpropanamide,
N- [1- (4-Chloro-N-{[(2R, 4S) -4- (methylthio) pyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- (1- {4-fluoro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- (4-chloro-N-{[(2R, 4S) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4 -Carboxamide,
N- (tert-butyl) -1- (4-fluoro-N-{[(2R, 4S) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4 -Carboxamide,
N- [1- (4-Fluoro-N-{[(2R, 4R) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2 -Methylpropanamide,
N- [1- (4-Chloro-N-{[(2R, 4R) -4-morpholin-4-ylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4- Yl] -2-methylpropanamide.

  The present invention also relates to the following therapeutic agents and improving agents. (16) A medicament or pharmaceutical composition comprising the piperidine derivative according to any one of (1) to (15) or a pharmacologically acceptable salt thereof as an active ingredient. (17) A melanocortin-4 receptor agonist comprising the piperidine derivative according to any of (1) to (15) or a pharmacologically acceptable salt thereof as an active ingredient. (18) Melanocortin-containing the active ingredient of the piperidine derivative according to any one of (1) to (15) or a pharmacologically acceptable salt thereof, wherein the melanocortin-4 receptor action is an agonistic action. 4 receptor agonists. (19) A prophylactic or therapeutic agent for obesity or hyperphagia comprising the piperidine derivative according to any one of (1) to (15) or a pharmacologically acceptable salt thereof as an active ingredient. (20) A sexual dysfunction-improving agent comprising the piperidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (15) as an active ingredient. (21) An infertility improving agent comprising the piperidine derivative according to any one of (1) to (15) or a pharmacologically acceptable salt thereof as an active ingredient.

  In the present specification, the “alkyl group having 1 to 8 carbon atoms” may have 1 to 8 carbon atoms and may be linear or branched, for example, methyl, ethyl, normal (hereinafter referred to as n-) propyl. , Isopropyl, butyl, isobutyl, tertiary (hereinafter referred to as t-) butyl, n-pentyl, n-hexyl, or n-octyl.

In the present specification, the “C3-C10 cycloalkyl group” refers to a monocyclic hydrocarbon, a condensed polycyclic hydrocarbon, a bridged hydrocarbon, and includes cyclohexyl, cycloheptyl, cyclopentyl, adamantyl and the like. Can be mentioned. In the present specification, examples of the “C _3-8 (C _3-8 ) cycloalkyl group” include cyclohexyl, cycloheptyl, cyclopentyl and the like.

  In the present specification, an “aryl group” is an ortho-fused bicyclic group such as phenyl, naphthyl, or indenyl having 8 to 10 ring atoms and at least one ring being an aromatic ring. Can be mentioned.

  In the present specification, the “heteroaryl group” has a 5- to 6-membered ring group having 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), or 8 to 10 ring atoms derived therefrom. Examples thereof include ortho-fused bicyclic heteroaryls, particularly benz derivatives, or those derived by fusing propenylene, trimethylene or tetramethylene groups thereto, and stable N-oxides thereof. Specifically, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolinyl, oxazolinyl, pyranyl, thiazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazinyl, triazinyl, indolyl, indolinyl, benzimidazolyl Ryl, benzoxazolyl, quinolyl, isoquinolyl, isothiazolyl.

In the present specification, the “heterocycle group” is a 4- to 6-membered ring group having at least one heteroatom (nitrogen, oxygen or sulfur), specifically, pyrrolidinyl, imidazolidinyl, oxazolidinyl, piperidino, Examples include piperidyl, piperazinyl, morpholino, morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, quinukiridinyl and the like.

  In the present specification, the term “arylalkyl group” means that the aryl part has the same meaning as the “aryl group”, and the alkyl part may be linear or branched having 1 to 4 carbon atoms, such as benzyl, Examples include phenethyl, 3-phenylpropyl and 1-naphthylmethyl.

  In the present specification, examples of the “hydroxyalkyl group having 1 to 4 carbon atoms” include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

  In this specification, “halogen” includes fluorine, chlorine, bromine or iodine.

The receptor denoted as “melanocortin-4 receptor” in the present specification is a type 4 subtype of melanocortin receptor which is a G protein-coupled receptor (GPCR).

  As used herein, “melanocortin-4 receptor action” refers to an agonistic action or antagonistic action, as well as binding activity.

  Next, the manufacturing method of the compound of this invention is demonstrated.

  The compound of the present invention can be produced by a combination of reactions suitable for the target compound. Typical reaction schemes are illustrated below, but are not limited to the methods described below.

(Manufacturing method 1)
A production method of the compound (3a) in which R ² , R ³ or R ⁴ is hydrogen or alkyl and R ¹ is hydrogen in the general formula (I) is shown below.

(In the process, R ² , R ³ or R ⁴ is hydrogen or alkyl, and other symbols are as defined above.)
Step 1 is a step of obtaining the amine compound (3a) from the amine represented by the compound (1) and the compound (2) having a leaving group.

  This reaction is usually performed at −50 to 200 ° C. (preferably −10 to 100 ° C.) in a solvent that does not adversely influence the reaction in the presence of a base. Examples of the base in this case include alkali metal carbonates such as potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metal hydroxides such as potassium hydroxide, metal hydrides such as sodium hydride, triethylamine, N, N -Amines such as diisopropylethylamine, and solvents include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N Amides such as N-dimethylformamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide. If necessary, sodium iodide, tetrabutylammonium iodide or the like may be used as an additive.

(Manufacturing method 2)

A method for producing compound (3b) in which R ⁴ is hydrogen and R ¹ is hydrogen in general formula (I) is shown below.

(In the process, each symbol is as defined above.)
Step 2 is a step of reacting the amine represented by compound (1) with the ketone or aldehyde represented by compound (4) and then reducing to obtain the amine of compound (3b).

  This reaction is usually carried out in the presence of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like in a solvent that does not adversely influence the reaction at a temperature of 0 to 100 ° C. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, 1,4-dioxane and the like, and if necessary, an acidic catalyst such as acetic acid, p-toluenesulfonic acid, trifluoride. Boron halide / diethyl ether complex or the like may be used.

(Manufacturing method 3)
In the general formula (I), the production methods of the compounds (10) and (12) when R ¹ is hydrogen are shown below.

(In the process, each symbol is as defined above.)
Step 3 is a step of obtaining a sulfonamide derivative represented by the compound (6) by reacting the amine represented by the compound (1) with 2-nitrobenzenesulfonyl chloride represented by the compound (5).

  This reaction can be usually carried out in a solvent that does not affect the reaction in the presence of a base at −50 to 100 ° C., preferably −10 to 50 ° C. In this case, the solvent is, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, and the base is, for example, an alkali metal carbonate such as potassium carbonate, an alkali metal alkoxide such as sodium methoxide, or sodium hydroxide. Amines such as alkali metal hydroxide, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 4-dimethylaminopyridine are used.

  Step 4 is a step of obtaining the amine of compound (10) by carrying out deprotection reaction after obtaining compound (8) from the alcohol represented by compound (6) and compound (7).

  Usually, the reaction of compounds (6) and (7) is usually carried out at −50 to 150 ° C. in the presence of phosphines and azodicarboxylic acid derivatives. Examples of phosphines include triphenylphosphine and tributylphosphine, and examples of azodicarboxylic acid derivatives include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and azodicarbonyldipiperazine. Examples of the solvent include ethers such as tetrahydrofuran, halogenated hydrocarbons such as dichloromethane, hydrocarbons such as toluene, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, Sulfoxides such as dimethyl sulfoxide are used, and these solvents may be mixed at an appropriate ratio. The compound (8) thus obtained is reacted with a thioalcohol such as benzenethiol in the presence of a base usually at −10 to 100 ° C. to effect deprotection to obtain the amine of the compound (10). Examples of the base in this case include alkali metal carbonates such as potassium carbonate and cesium carbonate, amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline and 4-dimethylaminopyridine. Kind is used.

Step 5 is a step in which compound (6) and compound (2) are reacted to obtain compound (11), followed by deprotection reaction to obtain amine of compound (12).
X in the formula in the compound (2) is a leaving group such as halogen, O-mesyl, O-tosyl and the like.

  Usually, the reaction of the compounds (6) and (2) is carried out at −50 to 200 ° C. (preferably −10 to 100 ° C.) in the presence of a base in a solvent that does not adversely influence the reaction. Examples of the base in this case include alkali metal carbonates such as potassium carbonate and cesium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metal hydroxides such as sodium hydroxide, metal hydrides such as sodium hydride, triethylamine, Amines such as N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline and 4-dimethylaminopyridine are used, and examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and dioxane. Halogenated hydrocarbons such as chloroform and dichloromethane, hydrocarbons such as toluene, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide It is needed. These solvents may be mixed at an appropriate ratio. The compound (11) thus obtained can be deprotected by reacting thioalcohol such as benzenethiol with thioalcohol such as benzenethiol in the presence of a base usually at −10 to 100 ° C. to obtain the amine of the compound (12). Examples of the base in this case include alkali metal carbonates such as potassium carbonate and cesium carbonate, amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline and 4-dimethylaminopyridine. Kind is used.

(Manufacturing method 4)
By using compound (10) or (12) as a starting material and reacting with an alkyl halide, the compound of general formula (I) in which R ¹ is alkyl can be produced.

  This reaction is usually performed at −50 to 200 ° C. (preferably −10 to 100 ° C.) in a solvent that does not adversely influence the reaction in the presence of a base. Examples of the base in this case include alkali metal carbonates such as potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metal hydroxides such as potassium hydroxide, metal hydrides such as sodium hydride, triethylamine, N, N -Amines such as diisopropylethylamine, and solvents include ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N Amides such as N-dimethylformamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide. If necessary, sodium iodide, tetrabutylammonium iodide or the like may be used as an additive.

(Manufacturing method 5)

In the general formula (I), R ² and R ³ are combined to form a heterocycle group, R ² , R ³ and R ⁴ are combined to form an aryl group or A method for producing a compound forming a heteroaryl group is shown below.

(In the process, Ar ¹ is a heterocycle group, an aryl group, or a heteroaryl group. Other symbols are as defined above.)
Step 6 is a step in which compound (1) and compound (13) are reacted to obtain compound (14).
X in the formula in the compound (13) is a leaving group such as halogen, O-mesyl, O-tosyl and the like.

  Usually, it is carried out in the presence of a metal catalyst, a metal ligand and a base in a solvent that does not adversely influence the reaction. Examples of the metal catalyst include tris (dibenzylidene) dipalladium and palladium acetate. Examples of the metal ligand include 2- (di-tert-butylphosphino) biphenyl. Examples of the base include cesium carbonate, tripotassium phosphate, sodium tertiary butoxide and the like. The reaction temperature is usually 0 ° C. to the reflux temperature of the solvent. As the solvent, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, and the like are used. These solvents may be mixed and used at an appropriate ratio.

(Intermediate production method 1)
A method for producing compound (1), which is a starting material for production methods 1 to 3, is shown below.

(In the process, Q is tert-butoxycarbonyl (hereinafter abbreviated as “Boc”), benzyloxycarbonyl (hereinafter abbreviated as “Z”), 9H-fluoren-9-ylmethyloxycarbonyl (hereinafter “Fmoc”). And other symbols are as defined above.)
Step 7 is a step of obtaining compound (16) by deprotecting compound (15).

  Usually, when the protecting group is Boc, it adversely affects the reaction of ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. In a solvent that does not reach, an acid such as hydrogen chloride or trifluoroacetic acid can be used for deprotection at -30 to 60 ° C for 10 minutes to 24 hours.

  Step 8 is a reaction in which the amide compound (18) is obtained by condensing the amine represented by the compound (16) and the carboxylic acid represented by the compound (17).

  Usually, in the presence of a condensing agent that activates carboxylic acid, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethylformamide, amides such as N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, etc. (These solvents may be mixed in an appropriate ratio.) In a solvent that does not adversely influence the reaction Done in Examples of the condensing agent include cyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxy Quinoline (EEDQ), carbonyldiimidazole (CDI), diethyl phosphoryl cyanide, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chloroformate, diethylacetyl chloride, And trimethylacetyl chloride. These condensing agents alone or N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo3,4-dihydro-1,2,3-benzotriazine (HOOBT), or It is used in combination with additives such as 4-dimethylaminopyridine (DMAP). The amount of the condensing agent and additive to be used is preferably 1 to 5 molar equivalents relative to compound (16). The reaction temperature is usually −30 to 80 ° C., preferably −10 to 50 ° C.

Step 9 is a step in which compound (18) is deprotected to obtain an amine represented by compound (1).
This reaction can usually be performed in the same manner as in Step 7. Therefore, when the protecting group is Boc, it affects the reaction of ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, and hydrocarbons such as hexane, benzene and toluene. In a solvent that does not reach, deprotection can be performed using an acid such as hydrogen chloride or trifluoroacetic acid at −30 to 60 ° C. for 10 minutes to 24 hours.

(Intermediate production method 2)
Compound (15) which is a starting material of Intermediate Production Method 1, Compound (20) wherein W ¹ is cyclohexyl and W ² is —CONR ^g R ^g , Compound (23) which is —NHCOOR ^g Or the manufacturing method of the compound (25) which is -NHCOR ^g is shown below.

(In the process, each symbol is as defined above.)
Step 10 is a step of obtaining an amide represented by the compound (20) by reacting the carboxylic acid represented by the compound (19) with an amine.

  Usually, in the presence of a condensing agent that activates carboxylic acid, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N, N-dimethylformamide, amides such as N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, etc. (These solvents may be mixed in an appropriate ratio.) In a solvent that does not adversely influence the reaction Done in Examples of the condensing agent include cyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxy Quinoline (EEDQ), carbonyldiimidazole (CDI), diethyl phosphoryl cyanide, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chloroformate, diethylacetyl chloride, And trimethylacetyl chloride. These condensing agents alone or N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo3,4-dihydro-1,2,3-benzotriazine (HOOBT), or It is used in combination with additives such as 4-dimethylaminopyridine (DMAP). The amount of the condensing agent and additive to be used is preferably 1 to 5 molar equivalents relative to compound (14). The reaction temperature is usually −30 to 80 ° C., preferably −10 to 50 ° C. In addition, carboxylic acid (19) in thionyl chloride, oxalyl chloride and the like in an inert solvent (for example, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hexane, By reacting with benzene, toluene and other hydrocarbons), the resulting acid halide and amine are obtained in the presence of a base (for example, alkali metal carbonate such as potassium carbonate, alkali metal such as sodium methoxide). Alkoxide, alkali metal hydroxide such as sodium hydroxide, metal hydride such as sodium hydride, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, 4-dimethylaminopyridine Any amine) In a solvent that does not adversely influence the reaction (for example, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, hydrocarbons such as hexane, benzene and toluene, N N-dimethylformamide, amides such as N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide, etc.) at 0 ° C. to 120 ° C. to give the amide compound (20).

  Step 11 is a step of obtaining amine compound (22) or carbamic acid derivatives (23) and (24) from the carboxylic acid represented by compound (19).

  Usually, the carboxylic acid compound (19) is converted into an acid azide compound (for example, obtained by the reaction of an acid halide obtained from the reaction of the compound (19) with oxalyl chloride and sodium azide) and heated in an organic solvent. By doing so, isocyanate (21) can be obtained (Currius rearrangement). In addition to this, an isocyanate can also be obtained by using an improved method of Curtius rearrangement using diphenyl phosphate azide (DPPA). Furthermore, the amine (22) can be obtained by heating this isocyanate (21) and performing a hydrolysis reaction with water, and the carbamic acid derivative (23) can be obtained by reacting the isocyanate (21) with an alcohol. . When isocyanate (21) is reacted with benzyl alcohol, a carbamic acid derivative represented by compound (24) is obtained. This carbamic acid derivative (24) can be derived into the amine compound (22) using a catalytic reduction method using a metal catalyst such as palladium.

  Step 12 is a step of obtaining an amide represented by the compound (25) from the amine represented by the amine compound (22) and an acid halide or carboxylic acid.

  Usually, in the case of acid halide, it is carried out at 0 to 120 ° C. in a solvent that does not affect the reaction in the presence of a base. Examples of the base in this case include alkali metal carbonates such as potassium carbonate, alkali metal alkoxides such as sodium methoxide, alkali metal hydroxides such as sodium hydroxide, metal hydrides such as sodium hydride, triethylamine, N, N Examples include amines such as diisopropylethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, and 4-dimethylaminopyridine. Examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, and dioxane, chloroform, and dichloromethane. Halogenated hydrocarbons such as dichloroethane, hydrocarbons such as hexane, benzene and toluene, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and dimethyl sulfoxide Such as sulfoxide compound is used. When obtaining an amide compound represented by (25) from a carboxylic acid and an amine, ethers such as diethyl ether, tetrahydrofuran and dioxane, chloroform, dichloromethane, dichloroethane and the like are usually present in the presence of a condensing agent that activates the carboxylic acid. Halogenated hydrocarbons, hydrocarbons such as hexane, benzene and toluene, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone, and sulfoxides such as dimethyl sulfoxide (these solvents are They may be mixed at an appropriate ratio.) The reaction is carried out in a solvent that does not adversely influence the reaction. Examples of the condensing agent include cyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide (EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxy Quinoline (EEDQ), carbonyldiimidazole (CDI), diethyl phosphoryl cyanide, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chloroformate, diethylacetyl chloride, And trimethylacetyl chloride. These condensing agents alone or N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo3,4-dihydro-1,2,3-benzotriazine (HOOBT), or It is used in combination with additives such as 4-dimethylaminopyridine (DMAP). The amount of the condensing agent and additive to be used is preferably 1 to 5 molar equivalents relative to compound (22). The reaction temperature is usually −30 to 80 ° C., preferably −10 to 50 ° C.

(Intermediate production method 3)
In compound (15) which is a starting material of intermediate production method 1, W ¹ is cyclohexyl, and W ² is —CH ₂ P (P is N 3 (azide group), CN (cyano group), heteroaryl The production method of the compound (30) is as follows.

(In the process, P means N3 (azido group), CN (cyano group), heteroaryl, etc. The other symbols are as defined above.)
Step 13 is a step of obtaining compound (27) from compound (26).

  In this reaction, the benzene ring of the compound (26) can be converted into a cyclohexane ring by hydrogenation using a metal catalyst such as PtO 2 or Rh / C in a solvent such as acetic acid or alcohol. In this case, it is often necessary to carry out the reaction under high pressure conditions.

  Step 14 is a step of obtaining an alcohol represented by compound (28) from compound (27).

  Usually, an alcohol form can be obtained from an ester form by carrying out a reduction reaction using lithium aluminum hydride or the like in a solvent that does not affect the reaction (for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.). .

  Step 15 is a step of obtaining compound (29) from compound (28).

  Usually, it is carried out at −30 to 60 ° C. in a solvent that does not affect the reaction using methanesulfonyl chloride in the presence of a base. Examples of the base include pyridine and triethylamine, and examples of the solvent include dichloromethane and 1,2-dichloroethane. Moreover, when p-toluenesulfonyl chloride is used instead of methanesulfonyl chloride, it can be derived into the tosylate compound of (28) under the same conditions.

Step 16 is a step of obtaining compound (30) from compound (29).
When it is desired to obtain a compound in which P of compound (30) is heteroaryl, the desired product can be obtained by reacting with a heterocyclic anion such as triazole. In the case of triazole, the target substance is obtained by selecting dimethylformamide or the like as the solvent and reacting in the presence of a base such as sodium hydride. When it is desired to obtain a compound in which P is N3 (azido group) or CN (cyano group), it can be obtained by performing a substitution reaction with sodium azide or sodium cyanide. In this case, N, N-dimethylformamide, dimethyl sulfoxide or the like is used as the solvent. Furthermore, they can be derivatized to amines by reduction. As a method, it can be obtained by catalytic reduction using palladium, platinum, nickel or the like, reduction by metal hydride, reduction using triphenylphosphine, thiol, sulfide, diborane, or transition metal. The obtained amine can be reacted with an acid halide or an alkylsulfonyl halide in a solvent that does not affect the reaction in the presence of a base to obtain an amide or a sulfonamide.
The compound thus obtained can be used as compound (15).

(Intermediate Production Method 4)
The manufacturing method of the compound (2) used for manufacturing method 1 and 3 is shown below.

(In the process, each symbol is as defined above.)
Step 17 is a step of obtaining a compound (32) having a leaving group from a commercially available product or an alcohol (31) obtainable by a known method.

  In general, an alkyl halide can be obtained as the compound (32) by reacting the alcohol compound (31) with thionyl chloride or triphenylphosphine and carbon tetrachloride (carbon tetrabromide). Alternatively, the compound (31) which is an alcohol form can be reacted with an alkylsulfonyl halide to be converted into an alkyl sulfonic acid ester as the compound (32).

  Compound (32) can be used as compound (2) in production methods 1 and 3.

(Intermediate Production Method 5)
The manufacturing method of the compound (4) in the manufacturing method 2 is shown below.

(In the process, each symbol is as defined above.)
Step 18 is a step of obtaining a ketone or aldehyde represented by compound (34) by oxidizing a commercially available product or an alcohol compound (33) obtainable by a known method. Compound (34) can be used as compound (4) in Production Method 2.

  Usually, a ketone can be obtained from a secondary alcohol and an aldehyde can be obtained from a primary alcohol by using a known oxidation method.

(Method 6 for producing intermediate)
(In the process, each symbol is as defined above.)
In compound (4) in production method 2, the production method in the case where R ³ is H is shown below.

  Step 19 is a step of obtaining aldehyde (36) from ester (35) which can be obtained by a commercially available product or a known method.

  Usually, the ester can be converted into the aldehyde by using a reducing agent such as diisopropylaluminum hydride. In the reaction, hexane can be used as a solvent, and aldehyde can be obtained by reduction at a low temperature such as −78 ° C. using hexane, toluene, dichloromethane or the like.

  Step 20 is a step of obtaining an aldehyde compound (36) from a commercially available product or an ester compound (35) obtainable by a known method via an alcohol compound (37).

  Usually, the ester form of compound (35) can be reduced to an alcohol form using a known method such as lithium aluminum hydride as a reducing agent, and the alcohol form can be converted to an aldehyde form using a known oxidation method. .

  Step 21 is a step of obtaining aldehyde (36) from carboxylic acid (38) via ester (35) or amide (39).

Usually, the carboxylic acid form of compound (38) can be converted into an ester form using a known method, and an aldehyde can be obtained from the ester form using the method of Step 19 or Step 20. Further, carboxylic acid (38) and morpholine, or carboxylic acid and N, O-dimethylhydroxylamine are led to amides (39) and (40). Reduction can also give an aldehyde.

The compound of general formula (I) and each intermediate obtained as described above are isolated and purified by ordinary chemical operations such as extraction, crystallization, recrystallization, and various chromatography.

  As the salt of the compound of the general formula (I), an acid addition salt or a base addition salt can be used, but the type of the salt is not particularly limited as long as it is physiologically acceptable.

  A salt of the compound of the general formula (I), or a hydrate or solvate thereof can be produced from the piperidine derivative of the general formula (I) by a known method.

  When the compound of general formula (I) or a salt thereof contains an optically active substance, it can be separated into individual optical isomers by an ordinary optical resolution means. Alternatively, an optically active compound of general formula (I) or a salt thereof may be synthesized using an optically pure starting material or a compound having a known configuration.

  One or more of the compounds of the formula (I) of the present invention or salts thereof may be administered to a patient as they are, but preferably an active ingredient and a pharmacologically and pharmaceutically acceptable additive. In addition, it can be provided as a formulation in a form well known to those skilled in the art.

  The compound of the present invention is adjusted to an appropriate dosage form (powder, injection, tablet, capsule, topical preparation, etc.) together with appropriate diluents and other additives that are usually used, and then, according to the dosage form. It can be administered to humans or animals by an appropriate administration method (for example, intravenous administration, oral administration, transdermal administration, topical administration, etc.).

  As pharmacologically and pharmaceutically acceptable additives, excipients, disintegrants, binders, lubricants, coating agents, dyes, diluents, bases, tonicity agents, etc. should be used. I can do it.

  Examples of preparations suitable for oral administration include tablets, capsules, powders, fine granules, granules, solutions, syrups, etc. Examples of preparations suitable for parenteral administration include injections and infusions. Or a suppository.

  In preparations suitable for oral administration, excipients, disintegrants, binders, lubricants, coating agents or bases can be used as additives. Moreover, when administering the compound of this invention with respect to the patient used as the treatment object, you may use together the other agent suitable for the treatment of a target disease, and the compound of this invention.

  The administration route of the medicament of the present invention is not particularly limited, and can be administered orally or parenterally. Dosage depends on age, weight, general health, sex, diet, administration time, administration method, excretion rate, combination of drugs, patient's condition being treated at the time, or other factors. It is decided in consideration. The compound of the present invention, optical isomers thereof or pharmaceutically acceptable salts thereof can be safely used with low toxicity, and the daily dose thereof depends on the patient's condition and body weight, type of compound, route of administration, etc. Depending on, for example, parenterally, about 0.01 to 50 mg / person / day, preferably 0.01 to 20 mg / person / day, is administered subcutaneously, intravenously, intramuscularly or rectally, orally It is desirable to administer about 0.01 to 150 mg / person / day, preferably 0.1 to 100 mg / person / day.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples. “Room temperature” in the following Reference Examples and Examples represents 0 to 30 ° C. Moreover, the solvent ratio in the case of using a mixed solvent shows a volume ratio.

  The infrared absorption spectrum was measured by a diffuse reflection method using a Fourier transform infrared spectrophotometer.

The mass spectrum was measured using LC-MS (liquid chromatograph mass spectrometer), and Chromolith SpeedROD RP-18e (4.6 × 50 mm) (manufactured by Merck) was used for the column. As measurement conditions, a mixed solvent of liquid A (0.05% trifluoroacetic acid / water) and liquid B (0.05% trifluoroacetic acid / acetonitrile) was used as the solvent, and liquid A: liquid B = from 95: 5. Gradient elution was performed in 2 minutes so that A liquid: B liquid = 0: 100. The measurement mode of MS was measured using an ESI (electrospray ionization) method.

NMR (nuclear magnetic resonance spectrum) was measured at 300 MHz unless otherwise specified. ^For the chemical shift of ¹ H-NMR, tetramethylsilane (TMS) was used as an internal standard, and relative delta (δ) values were expressed in ppm. Coupling constants represent trivial multiplicity in hertz (Hz), meaning s is a single line, d is a double line, t is a triple line, q is a quadruple line, m is a multiple line, and br is a broad absorption peak To do. Other abbreviations used in the text have the following meanings.
CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide THF: tetrahydrofuran DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HOBt: 1-hydroxy- 1H-benzotriazole IR: infrared absorption spectrum Me: methyl Et: ethyl Boc: tert-butoxycarbonyl
Ts: p-toluenesulfonyl
Ac: Acetyl
¹ H-NMR: Proton nuclear magnetic resonance spectrum Rt: Retention time.

Reference Example 1 1-tert-butoxycarbonyl-4-cyclohexyl-4- (tert-butylaminocarbonyl) piperidine 1-tert-butoxycarbonyl-4-cyclohexyl-4-piperidinecarboxylic acid (50.0 g) and dimethylformamide Ogitalyl chloride (15.7 mL) was added to a methylene chloride solution (500 mL) of (4.97 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methylene chloride, t-butylamine (500 mL) was added at room temperature, and the mixture was stirred for 18 hours at room temperature. The reaction solution was concentrated under reduced pressure, and ethyl acetate (1.00 L) and 0.5 mol / L hydrochloric acid (1.00 L) were added to the residue for liquid separation, and the aqueous layer was removed. The aqueous layer was extracted three times with ethyl acetate (300 mL), and the organic layers were combined and washed with saturated brine (300 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; chloroform to chloroform-ethyl acetate = 10: 1) to obtain the title compound (28.1 g).
¹ H-NMR (CDCl ₃ ): δ0.92-1.88 (15H, m), 1.36 (9H, s), 1.45 (9H, s), 2.83 (2H, br), 3.94 (2H, br), 5.29 ( 1H, brs).

Reference Example 2 Toluene of 1-tert-butoxycarbonyl-4-cyclohexyl-4-[(benzyloxycarbonyl) amino] piperidine 1-tert-butoxycarbonyl-4-cyclohexyl-4-piperidinecarboxylic acid (62.3 g) To the solution (300 mL) was added triethylamine (33.5 mL) diphenyl phosphate azide (55.0 g). The reaction solution was stirred for 12 hours under reflux, then cooled to room temperature, benzyl alcohol (64.8 g) was added, and the mixture was further stirred for 10 hours under reflux. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (1.00 L) was added to the residue, and the organic layer was washed successively with water, 1.0 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (58.8 g).
¹ H-NMR (CDCl ₃ ): δ0.88-1.82 (24H, m), 1.44 (9H, s), 2.8-2.95 (2H, m), 3.82-4.04 (2H, br), 4.44 (1H, s ), 5.05 (2H, s), 7.2-7.4 (5H, m).

Reference Example 3 1-tert-Butoxycarbonyl-4-cyclohexyl-4-aminopiperidine Water (51%) 10% palladium-carbon as a catalyst in an ethanol solution (300 mL) of the title compound (58.8 g) of Reference Example 2 (3.50 g) was added, and the mixture was stirred at room temperature for 10 hours under a hydrogen gas stream. The catalyst was removed using celite, and the reaction solution was concentrated under reduced pressure to obtain the title compound (39.9 g).
¹ H-NMR (CDCl ₃ ): δ 0.88-1.88 (17H, m), 1.45 (9H, s), 3.05-3.20 (2H, m), 3.70-3.90 (2H, brs).

Reference Example 4 1-tert-Butoxycarbonyl-4-cyclohexyl-4- (isobutyrylamino) piperidine A methylene chloride solution containing the title compound (15.0 g) of Reference Example 3 and triethylamine (7.40 mL) ( (200 mL) was added dropwise isobutyl chloride (6.79 g) under ice-cooling, and the reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (300 mL) was added to the residue, and the organic layer was washed successively with 1.0 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution (300 mL) twice and saturated brine (300 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (18.3 g).
¹ H-NMR (CDCl ₃ ): δ0.88-1.82 (14H, m), 1.16 (6H, d), 1.45 (9H, s), 1.82-1.98 (1H, m), 2.30-2.45 (1H, m ), 2.75-2.90 (2H, m), 3.95 (2H, br), 4.93 (1H, s).

Reference Example 5 tert-butyl [(1R) -2- {4-[(tert-butylamino) carbonyl] -4-cyclohexylpiperidin-1-yl} -1- (4-chlorobenzyl) -2-oxoethyl Carbamate To a methylene chloride solution (80.0 mL) of the title compound (44.2 g) of Reference Example 1 was added trifluoroacetic acid (20 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes and concentrated under reduced pressure. Chloroform (500 mL) and saturated aqueous sodium hydrogen carbonate solution (700 mL) were added to the residue, and the mixture was separated. The aqueous layer was extracted three times with chloroform (200 mL), and the organic layers were combined and washed with saturated brine (500 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a white solid (28.6 g). A solution of white solid (18.5 g) and N-tert-butoxycarbonyl-D-4-chlorophenylalanine (25.0 g) in methylene chloride (500 mL) was cooled with ice under HOBt (14.9 g), WSC (18.7 g). ) And N-methylmorpholine (30.6 mL) were sequentially added, and the reaction solution was warmed to room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (700 mL) was added to the residue, and the organic layer was twice with 0.5 mol / L hydrochloric acid (500 mL), twice with a saturated aqueous sodium hydrogen carbonate solution (300 mL) and saturated brine (300 mL). ). The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 2: 1 to 1: 1) to give the title compound (27.7 g). It was.
¹ H-NMR (CDCl ₃ ): δ0.80-1.91 (14H, m), 1.32, 1.36 (9H, 2s), 1.42 (9H, s), 2.52-3.89 (6H, m), 4.35-5.56 (4H m), 7.04-7.28 (4H, m).

Reference Example 6 N- (tert-butyl) -4-cyclohexyl-1- (4-chloro-D-phenylalanyl) piperidine-4-carboxamide Methylene chloride of the title compound (27.7 g) of Reference Example 5 Trifluoroacetic acid (40.0 mL) was added to the solution (120 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, chloroform (300 mL) and a 1.0 mol / L aqueous sodium hydroxide solution (300 mL) were added to the residue and the phases were separated, and the aqueous layer was removed. The aqueous layer was extracted 3 times with chloroform (200 mL), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (20.4 g).
¹ H-NMR (CDCl ₃ ): δ0.77-2.04 (17H, m), 1.33, 1.36 (9H, 2s), 2.50-3.08 (4H, m), 3.46-3.64 (1H, m), 3.88-3.97 (1H, m), 4.51 (1H, brd), 5.24 (1H, brd), 7.08-7.28 (4H, m).

Reference Example 7 tert-butyl [(1R) -2- {4-[(tert-butylamino) carbonyl] -4-cyclohexylpiperidin-1-yl} -1- (4-fluorobenzyl) -2-oxoethyl Carbamate To the title compound of Reference Example 1 (15.0 g), a 4.0 mol / L hydrochloric acid-dioxane solution (300 mL) was added at room temperature, and the mixture was stirred at room temperature for 16 hours. After the reaction liquid was concentrated under reduced pressure, chloroform (300 mL) and a 1.0 mol / L aqueous sodium hydroxide solution (300 mL) were added to the residue for liquid separation, and the aqueous layer was removed. The aqueous layer was extracted twice with chloroform (300 mL), the organic layers were combined and washed with saturated brine (300 mL), and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the obtained residue and N-tert-butoxycarbonyl-D-4-fluorophenylalanine (13.9 g) in methylene chloride (200 mL) under ice cooling, HOBt (8.77 g), WSC (11.0 g) and N -Methylmorpholine (13.5 mL) was sequentially added, and the reaction solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (500 mL) was added to the residue, and the organic layer was twice with 0.5 mol / L hydrochloric acid (200 mL), twice with a saturated aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (300 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 2: 1 to 1: 1) to obtain the title compound (21.0 g).
¹ H-NMR (CDCl ₃ ): δ0.76-1.87 (14H, m), 1.32, 1.35 (9H, 2s), 1.41 (9H, s), 2.52-2.63 (2H, m), 2.92 (2H, dd ), 3.04 (1H, t), 3.57 (1H, brd), 4.43 (brd), 4.75-4.85 (1H, m), 5.20 (1H, brd), 5.41 (1H, dd).

Reference Example 8 N- (tert-butyl) -4-cyclohexyl-1- (4-fluoro-D-phenylalanyl) piperidine-4-carboxamide To the title compound (20.8 g) of Reference Example 7 at room temperature A 4.0 mol / L hydrochloric acid-dioxane solution (100 mL) was added, and the mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. Chloroform (300 mL) and a 1.0 mol / L aqueous sodium hydroxide solution (500 mL) were added to the residue for liquid separation, and the aqueous layer was removed. The aqueous layer was extracted twice with chloroform (200 mL), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (16.1 g).
¹ H-NMR (CDCl ₃ ): δ0.77-2.00 (17H, m), 1.33, 1.36 (9H, 2s), 2.54-3.10 (4H, m), 3.52-3.66 (1H, m), 3.88-3.96 (1H, m), 4.50 (1H, brd), 5.24 (1H, brd), 6.94-7.20 (4H, m).

Reference Example 9 N- [4-cyclohexyl-1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -2-methylpropanamide hydrochloride hydrochloride The title compound of Reference Example 4 (15.8 g ) Was added 4.0 mol / L hydrochloric acid-ethyl acetate solution (100 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue and N-tert-butoxycarbonyl-D-4-chlorophenylalanine (22.5 g) in dimethylformamide (250 mL) were added at room temperature to HOBt (14.0), WSC ( 17.5 g) and N-methylmorpholine (29.5 mL) were sequentially added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (500 mL) and saturated brine (500 mL) were added to the reaction solution and the phases were separated, and the aqueous layer was extracted twice with ethyl acetate (250 mL). The organic layers were combined and washed successively with 0.5 mol / L hydrochloric acid (250 mL) twice, saturated aqueous sodium hydrogen carbonate solution (300 mL) twice, and saturated brine (500 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 5: 1 to 1: 1). The residue obtained by concentration under reduced pressure was diluted with ethyl acetate (100 mL), a 4.0 mol / L hydrochloric acid-ethyl acetate solution (100 mL) was added at room temperature, and the mixture was stirred for 1 hour. Isopropyl alcohol (200 mL) and diisopropyl alcohol (50 mL) were added to the reaction solution, and the precipitated white solid was filtered off and dried under reduced pressure to obtain the title compound (15.5 g).
IR: 3312, 2927, 2853, 1665, 1540, 1492, 1462, 1410cm ^-1 .
MS (ESI) m / z 434 (M + H) ^<+> .

Reference Example 10 N- [4-cyclohexyl-1- (4-fluoro-D-phenylalanyl) piperidin-4-yl] -2-methylpropanamide Chlorination of the title compound of Reference Example 4 (6.69 g) To a methylene solution (20.0 mL) was added trifluoroacetic acid (20 mL) at room temperature, and the mixture was stirred for 3 hours and concentrated under reduced pressure. To the residue were added methylene chloride (300 mL), N-tert-butoxycarbonyl-D-4-fluorophenylalanine (9.15 g), and HOBt (4.95 g), WSC (6.20 g) and N-methyl under ice cooling. Morpholine (9.4 mL) was added sequentially. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate (500 mL) was added to the residue, 1 mol / L hydrochloric acid (300 mL) twice, 1 mol / L aqueous sodium hydroxide solution (300 mL) twice and saturated brine (300 mL) successively. Washed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a white solid (7.39 g). The obtained white solid was dissolved in methylene chloride (100 mL), trifluoroacetic acid was added at room temperature, and the mixture was stirred for 2 hours. The solvent was distilled off from the reaction solution under reduced pressure, and ethyl acetate (300 mL) and saturated aqueous sodium hydrogen carbonate solution (200 mL) were added to the residue for liquid separation, and the aqueous layer was removed. The aqueous layer was extracted three times with ethyl acetate (200 mL), and the organic layers were combined and washed with saturated brine (500 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (5.96 g).
IR: 3314, 2929, 2854, 1647, 1539, 1510, 1450, 1366cm ^-1 .
MS (ESI) m / z 418 (M + H) ^<+> .

Reference Example 11 N-tert-butyl (2R) -2- (morpholin-4-ylcarbonyl) pyrrolidine-1-carboxylate
To a methylene chloride solution (1.16 L) of N-tert-butoxycarbonyl-D-proline (99.8 g) and morpholine (48.5 mL) was added WSC (132.3 g) and HOBt (107 g) under ice-cooling. Then, it heated up to room temperature and stirred for 2 hours. The reaction mixture was washed successively with 0.5 mol / L hydrochloric acid (1.00 L) and saturated aqueous sodium hydrogen carbonate solution (1.00 L), and the aqueous layer was extracted twice with methylene chloride (500 mL). The organic layers were combined, washed with saturated brine (500 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 1: 1) to obtain the title compound (119 g).
¹ H-NMR (CDCl ₃ ): δ1.42, 1.46 (9H, 2s), 1.76-2.22 (4H, m), 3.41-3.80 (10H, m), 4.50-4.67 (1H, m).

(Reference Example 12) N-tert-butoxycarbonyl-D-prolinal To a tetrahydrofuran solution (460 mL) of the title compound (13.1 g) of Reference Example 11 was added lithium aluminum hydride (2.73 g) under ice-cooling, and ice-cooled. Stir for 1 hour. A 5% aqueous potassium hydrogen sulfate solution (100 mL) was added to the reaction solution while stirring under ice-cooling, the reaction solution was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure and extracted twice with diethyl ether (150 mL). did. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 4: 1 to 1: 1) to obtain the title compound (4.83 g). .
¹ H-NMR (CDCl ₃ ): δ1.43, 1.46 (9H, 2s), 1.84-2.19 (4H, m), 3.38-3.61 (2H, m), 4.02-4.23 (1H, m), 9.46-9.56 (1H, m).

  The compounds of Reference Examples 1 to 12 are shown below.

Reference Example 13 N-tert-butoxycarbonyl-D-proline methyl ester
Sodium hydrogen carbonate (14.6 g) and methyl iodide (36.2 mL) were added to a solution of N-tert-butoxycarbonyl-D-proline (25.0 g) in dimethylformamide (232 mL) under ice cooling, and the mixture was added at room temperature for 8 hours. Stir. Ethyl acetate-hexane = 1: 1 (500 mL) and 0.5 mol / L hydrochloric acid (1.00 L) were added to the reaction solution and the phases were separated, and the organic layer was removed. The aqueous layer was extracted three times with ethyl acetate-hexane = 1: 1 (300 mL), and the organic layers were combined and washed successively with aqueous sodium thiosulfate solution (500 mL) and saturated brine (300 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (26.60 g).
¹ H-NMR (CDCl ₃ ): δ1.41, 1.46 (9H, 2s), 1.79-2.02 (3H, m), 2.12-2.30 (1H, m), 3.34-3.60 (2H, m), 3.72 (3H , s), 4.20-4.35 (1H, m).

(Reference Example 14) N-tert-butoxycarbonyl-D-prolinol To a tetrahydrofuran solution (232 mL) of the title compound (26.6 g) of Reference Example 13 was added lithium aluminum hydride (13.8 g) under ice cooling, and ice was added. Stir for 2 minutes under cooling. While stirring the reaction solution, water (13.8 mL) was added under ice-cooling, and an aqueous sodium hydroxide solution (41.4 mL) and water (41.4 mL) were sequentially added. The precipitated white precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 1: 1) to obtain the title compound (12.0 g).
¹ H-NMR (CDCl ₃ ): δ1.47 (9H, s), 1.68-2.07 (4H, m), 3.27-3.35 (1H, m), 3.41-3.49 (1H, m), 3.55-3.68 (2H m), 3.96 (1H, br), 4.77-4.79 (1H, brm).

(Reference Example 15) N-methyl-D-prolinol To a tetrahydrofuran solution (93.0 mL) of the title compound of Reference Example 14 (9.98 g), lithium aluminum hydride (4.40 g) was added under ice cooling, followed by ice cooling. Stir for 6 hours under. While stirring the reaction solution under ice cooling, water (4.40 mL), 4 mol / L aqueous sodium hydroxide solution (17.6 mL), and water (17.6 mL) were sequentially added. The precipitated white precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 1: 1) to obtain the title compound (5.34 g).
¹ H-NMR (CDCl ₃ ): δ1.66-1.95 (4H, m), 2.24-2.40 (2H, m), 2.34 (3H, s), 2.74 (1H, brd), 3.05-3.10 (1H, m ), 3.40-3.45 (1H, m), 3.63-3.67 (1H, m).

Reference Example 16 N-methyl-D-prolinal dimethyl sulfoxide (5.36 mL) in methylene chloride (125 mL) at −45 ° C. under the conditions of oxalyl chloride (6.66 mL) and the title compound of Reference Example 15 (2.24 g) ) And triethylamine (20.85 mL) were added sequentially. The reaction solution was stirred at -45 ° C for 30 minutes and then stirred at room temperature for 90 minutes. The reaction solution was washed twice with water (100 mL), and then the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether (100 mL) was added to the residue, the precipitated white solid was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.95 g).
¹ H-NMR (CDCl ₃ ): δ1.74-2.09 (4H, m), 2.25-2.74 (2H, m), 2.41 (3H, s), 3.12-3.19 (1H, m), 9.48 (1H, d ).

Reference Example 17 N-methyl-L-prolinal dimethylsulfoxide (1.87 mL) in methylene chloride solution (44.0 mL) at −45 ° C. under the conditions of oxalyl chloride (2.32 mL), N-methyl-L-prolinol (1.83 g) and triethylamine (7.26 mL) were added sequentially. The reaction solution was stirred at −45 ° C. for 30 minutes and then stirred at room temperature for 2 hours. The reaction solution was washed twice with water (100 mL), and then the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Diethyl ether (30 mL) was added to the residue, the precipitated white solid was removed using celite, and the filtrate was concentrated under reduced pressure to give the title compound as a crude product (1.06 g). This crude product was used in the next reaction as it was.

Reference Example 18 N-ethyl-D-prolinol
Lithium aluminum hydride (2.88 g) was added to a tetrahydrofuran solution (120 mL) of N-ethyl-D-proline methyl ester (10.4 g) under ice cooling, and the mixture was warmed to room temperature and stirred for 20 minutes. While stirring the reaction solution under ice cooling, water (2.88 mL), 4.0 mol / L aqueous sodium hydroxide solution (8.64 mL), and water (8.64 mL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. did. The reaction solution was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure to obtain the title compound (7.59 g).
¹ H-NMR (CDCl ₃ ): δ1.10 (3H, t), 1.69-1.89 (4H, m), 2.18-2.30 (2H, m), 2.54-2.58 (1H, m), 2.58-2.86 (1H m), 2.88 (1H, br), 3.14-3.21 (1H), 3.38 (1H, brd), 3.62 (1H, dd).

Reference Example 19 N-ethyl-D-prolinal dimethyl sulfoxide (6.64 mL) in methylene chloride solution (250 mL) at −55 ° C. under oxalyl chloride (8.25 mL) and the title compound of Reference Example 18 (7.98 g) ) And triethylamine (25.8 mL) were sequentially added, and the mixture was stirred at −40 ° C. for 1 hour and then at room temperature for 1 hour. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, the precipitated white solid was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (7.45 g).
¹ H-NMR (CDCl ₃ ): δ1.10 (3H, t), 1.69-2.08 (4H, m), 2.15-2.35 (1H, m), 2.42-2.57 (1H, m), 2.62-2.72 (1H m), 2.84-2.89 (1H, m), 9.49 (1H, d).

Reference Example 20 N-isopropyl-D-proline methyl ester
To a chloroform solution (31.0 mL) of D-proline methyl ester (4.00 g), acetone (11.4 mL) and acetic acid (1.93 mL) were added at room temperature, and the mixture was stirred for 30 minutes at room temperature. Sodium borohydride (9.70 g) was added and stirred at room temperature for 1 hour. Chloroform (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added to the reaction solution, and the mixture was separated to remove the aqueous layer. The aqueous layer was extracted three times with chloroform (50 mL), and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.62 g).
¹ H-NMR (CDCl ₃ ): δ1.07 (6H, d), 1.76-2.18 (4H, m), 2.59 (1H, q), 2.75-2.84 (1H, m), 3.08-3.15 (1H, m ), 3.43 (1H, dd), 3.71 (3H, s).

(Reference Example 21) N-isopropyl-D-prolinol To a tetrahydrofuran solution (42.0 mL) of the title compound of Reference Example 20 (3.61 g), lithium aluminum hydride (999 mg) was added under ice cooling, and under ice cooling. Stir for 1 hour. While stirring the reaction solution under ice-cooling, water (1.00 mL), 4 mol / L aqueous sodium hydroxide solution (3.00 mL) and water (3.00 mL) were sequentially added and stirred at room temperature for 1 hour. The white precipitate was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.44 g).
¹ H-NMR (CDCl ₃ ): δ 1.05 (6H, dd), 1.64-1.91 (4H, m), 2.52-2.61 (1H, m), 2.85-2.99 (3H, m), 3.08 (1H, br) , 3.32 (1H, dd), 3.54 (1H, dd).

Reference Example 22 N-isopropyl-D-prolinal dimethyl sulfoxide (1.68 mL) in methylene chloride solution (63.0 mL) at −55 ° C. under the conditions of oxalyl chloride (2.09 mL) and the title compound of Reference Example 21 (2 .24 g) and triethylamine (6.54 mL) were sequentially added and stirred at −40 ° C. for 1 hour and then at room temperature for 1 hour. Water (50 mL) was added to the reaction solution for liquid separation, and the aqueous layer was removed. The aqueous layer was extracted twice with methylene chloride (30 mL), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (50 mL) was added to the residue, the precipitated white solid was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.91 g).
¹ H-NMR (CDCl ₃ ): δ1.06 (6H, dd), 1.71-2.01 (4H, m), 2.55 (1H, q), 2.42-2.57 (1H, m), 2.71-2.84 (1H, m ), 3.10-3.17 (1H, m), 9.48 (1H, d).

Reference Example 23 N-propyl-D-proline methyl ester
Propionaldehyde (2.68 mL) and acetic acid (1.92 mL) were added to a chloroform solution (31.0 mL) of D-proline methyl ester (4.00 g) at room temperature, stirred for 30 minutes at room temperature, and then triacetoxyborohydride Sodium (9.18 g) was added. After the reaction solution was stirred for 1 hour at room temperature, chloroform (100 mL) and a saturated aqueous sodium hydrogen carbonate solution (100 mL) were added for liquid separation, and the aqueous layer was removed. The aqueous layer was extracted 3 times with chloroform (50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (5.35 g).
¹ H-NMR (CDCl ₃ ): δ0.90 (3H, t), 1.45-1.57 (2H, m), 1.75-1.98 (3H, m), 2.06-2.17 (1H, m), 2.34 (2H, m ), 2.57-2.63 (1H, m), 3.12-3.22 (2H, m), 3.73 (3H, s).

(Reference Example: 24) N-propyl-D-prolinol To a tetrahydrofuran solution (62 mL) of the title compound of Reference Example 23 (5.34 g), lithium aluminum hydride (1.48 g) was added under ice cooling, and then ice-cooled. For 1 hour. While stirring the reaction solution under ice-cooling, water (1.50 mL), 4.0 mol / L aqueous sodium hydroxide solution (4.50 mL) and water (4.50 mL) were sequentially added, and the mixture was stirred for 1 hour at room temperature. The white precipitate was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.90 g).
¹ H-NMR (CDCl ₃ ): δ 0.91 (3H, t), 1.30-1.94 (6H, m), 2.17-2.27 (2H, m), 2.52-2.69 (2H, m), 2.90 (1H, br) , 3.13-3.19 (1H, m), 3.34-3.40 (1H, m), 3.63 (1H, dd).

Reference Example 25 N-propyl-D-prolinal dimethylsulfoxide (2.72 mL) in methylene chloride solution (63.0 mL) at −45 ° C. under the conditions of oxalyl chloride (3.37 mL) and the title compound of Reference Example 24 (3 .62 g) and triethylamine (10.6 mL) were sequentially added and stirred at −40 ° C. for 30 minutes, and then stirred at room temperature for 30 minutes. Water (50 mL) was added to the reaction solution for liquid separation, and the aqueous layer was removed. The aqueous layer was extracted twice with methylene chloride (30 mL), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (50 mL) was added to the residue, the precipitated white solid was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.31 g).
¹ H-NMR (CDCl ₃ ): δ 1.06 (6H, dd), 1.71-2.01 (4H, m), 2.55 (1H, q), 2.42-2.57 (1H, m), 2.71-2.84 (1H, m) 3.10-3.17 (1H, m), 9.48 (1H, d).

Reference Example 26 N-isobutyl-D-proline methyl ester
To a chloroform solution (31.0 mL) of D-proline methyl ester (4.00 g) was added isobutyraldehyde (3.40 mL) and acetic acid (1.92 mL) at room temperature, and the mixture was stirred for 30 minutes at room temperature. Sodium borohydride (9.18 g) was added and stirred at room temperature for 1 hour. Chloroform (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added to the reaction solution, and the mixture was separated, and the aqueous layer was removed. The aqueous layer was extracted 3 times with chloroform (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (4.00 g).
¹ H-NMR (CDCl ₃ ): δ0.90 (3H, t), 1.61-1.99 (4H, m), 2.02-2.15 (1H, m), 2.22 (1H, dd), 2.30-2.43 (2H, m ), 3.10-3.19 (2H, m), 3.71 (3H, s).

Reference Example 27 N-isobutyl-D-prolinol A solution of the title compound of Reference Example 26 (4.00 g) in tetrahydrofuran (42 mL) was cooled with ice, and lithium aluminum hydride (1.03 g) was added under ice cooling. Stir for hours. While stirring the reaction solution under ice-cooling, water (1.00 mL), 4.0 mol / L aqueous sodium hydroxide solution (3.00 mL) and water (3.00 mL) were sequentially added, and the mixture was stirred for 1 hour at room temperature. The white precipitate was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.77 g).
¹ H-NMR (CDCl ₃ ): δ0.90 (6H, dd), 1.62-1.93 (5H, m), 2.13-2.34 (3H, m), 2.50-2.56 (1H, m), 2.90 (1H, br ), 3.12-3.18 (1H, m), 3.36 (1H, brd), 3.62 (1H, dd).

Reference Example 28 N-isobutyl-D-prolinal dimethyl sulfoxide (1.76 mL) in methylene chloride solution (63.0 mL) at −45 ° C. under the conditions of oxalyl chloride (2.18 mL), the title compound of Reference Example 27 (2 .57 g) and triethylamine (6.82 mL) were sequentially added, and the mixture was stirred at −40 ° C. for 30 minutes and then at room temperature for 30 minutes. Water (50 mL) was added to the reaction solution for liquid separation, the aqueous layer was removed, and the aqueous layer was extracted twice with methylene chloride (30 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether (50 mL) was added to the residue, the precipitated white solid was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.52 g).
¹ H-NMR (CDCl ₃ ): δ1.06 (6H, dd), 1.61-2.01 (5H, m), 2.21-2.34 (3H, m), 2.80-2.86 (1H, m), 3.44-3.52 (1H m), 9.43 (1H, d).

Reference Example 29 (R) -N-tert-butoxycarbonyl-4-hydroxy-D-proline methyl ester Methyl (280 mL) under ice-cooling, oxalyl chloride (40.8 mL), 4-hydroxy-D-proline, Methanol solution (190 mL) of hydrochloride (63.9 g) was added sequentially. The reaction mixture was stirred for 18 hours at room temperature, concentrated under reduced pressure, and diethyl ether (500 mL) was added. After the mixture was stirred for 5 hours, the white powder was collected by filtration and dried under reduced pressure. This white powder and triethylamine (46.1 mL) were dissolved in methylene chloride (330 mL), di-t-butyl dicarbonate (43.3 g) was added under ice-cooling, and the reaction mixture was allowed to warm to room temperature for 28 hours. Stir. Methylene chloride (500 mL) and 0.5 mol / L hydrochloric acid (500 mL) were added to the reaction solution for liquid separation, and the aqueous layer was extracted twice with methylene chloride (300 mL). The organic layers were combined, washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (40.6 g).
¹ H-NMR (CDCl ₃ ): δ1.42, 1.47 (9H, 2s), 2.06-2.13 (1H, m), 2.26-2.40 (1H, m), 3.30-3.74 (3H, m), 3.79 (3H , d), 4.28-4.40 (2H, m).

Reference Example 30 (S) -N-tert-butoxycarbonyl-4-fluoro-D-proline methyl ester To a methylene chloride solution (612 mL) of the title compound (15.0 g) of Reference Example 29 at −78 ° C. under three After adding N, N-diethylaminosulfur fluoride (12.1 mL), the mixture was stirred for 25 hours while warming to room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (500 mL) and saturated aqueous sodium hydrogen carbonate solution (300 mL) were added to the residue to separate the layers. The aqueous layer was extracted twice with ethyl acetate (200 mL), the organic layers were combined, washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 4: 1 to 1: 1) to obtain the title compound (10.7 g).
¹ H-NMR (CDCl ₃ ): δ1.42, 1.47 (9H, 2s), 1.98-2.22 (1H, m), 2.48-2.66 (1H, m), 3.53-3.71 (1H, m), 3.79-3.99 (1H, m), 4.37-4.50 (1H, m), 5.21 (1H, brd).

  The compounds of Reference Examples 13 to 30 are shown below.

Reference Example 31 (S) -N-tert-butoxycarbonyl-4-fluoro-D-prolinol To a solution of the title compound of Reference Example 30 (2.52 g) in tetrahydrofuran (21.0 mL) was added lithium hydride under ice-cooling. Aluminum (482 mg) was added and stirred for 15 minutes under ice cooling. While stirring the reaction solution under ice-cooling, water (482 uL), 4 mol / L aqueous sodium hydroxide solution (1.45 mL) and water (1.45 mL) were sequentially added, and the mixture was stirred for 1 hour at room temperature. The white precipitate was removed using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.40 g).
¹ H-NMR (CDCl ₃ ): δ1.48 (9H, s), 1.64-1.83 (1H, m), 2.27-2.34 (1H, m), 3.33-3.61 (2H, m), 3.74-3.91 (2H m), 4.09-4.19 (1H, m), 4.88 (1H, brd), 5.10 (1H, brd).

(Reference Example 32) (S) -N-tert-butoxycarbonyl-4-fluoro-D-prolinal To the methylene chloride solution (200 mL) of the title compound (8.63 g) of Reference Example 31 and dimethyl sulfoxide (80.0 mL). Under ice cooling, triethylamine (14.3 mL) and pyridine sulfur trioxide complex (12.8 g) were added, and the mixture was stirred under ice cooling for 3 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate-hexane = 1: 1 (200 mL) and water (200 mL) were added to the residue, and the mixture was separated, and the aqueous layer was removed. The aqueous layer was extracted three times with ethyl acetate-hexane = 1: 1 (200 mL), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.55 g).
¹ H-NMR (CDCl ₃ ): δ1.44, 1.49 (9H, 2s), 1.88-2.59 (1H, m), 3.48-3.68 (1H, m), 3.77-4.03 (1H, m), 4.24-4.43 (1H, m), 5.13-5.32 (1H, m), 9.44-9.58 (1H, m).

(Reference Example 33) N-tert-butoxycarbonyl-4-oxo-D-proline methyl ester A solution of the title compound of Reference Example 29 (26.6 g) and dimethyl sulfoxide (100 mL) in methylene chloride (220 mL) was cooled with ice. Triethylamine (39.2 mL) and a pyridine sulfur trioxide complex (34.5 g) were added, and the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate-hexane = 1: 1 (300 mL) and water (300 mL) were added to the residue, and the mixture was separated, and the aqueous layer was removed. The aqueous layer was extracted 3 times with ethyl acetate-hexane = 1: 1 (200 mL), and the organic layers were combined, washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 5: 1) to obtain the title compound (23.7 g).
¹ H-NMR (CDCl ₃ ): δ 1.46, 1.48 (9H, 2s), 2.59 (1H, d), 2.88-3.02 (1H, m), 3.77 (3H, s), 3.90 (2H, m), 4.70-4.83 (1H, m).

Reference Example 34 (R) -N-tert-butoxycarbonyl-4-morpholinyl-D-proline methyl ester To a solution of the title compound of Reference Example 33 (4.00 g) and morpholine (1.72 mL) in chloroform (33 mL) Acetic acid (1.02 mL) was added at room temperature, and after stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (5.02 g) was added. After stirring the reaction solution at room temperature for 15 hours, chloroform (50 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL) were added to the reaction solution, and the mixture was separated, and the aqueous layer was removed. The aqueous layer was extracted three times with chloroform (20 mL), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 5: 1 to 1: 1) to obtain the title compound (5.09 g).
¹ H-NMR (CDCl ₃ ): δ1.41, 1.46 (9H, 2s), 1.77-1.91 (1H, m), 2.38-2.54 (5H, m), 2.70-2.85 (1H, m), 3.23 (1H , t, J = 9.8 Hz), 3.60-3.90 (8H, m), 4.21-4.32 (1H, m).

(Reference Example 35) (R) -N-tert-butoxycarbonyl-4-morpholinyl-D-prolinol Hydrogenated to a tetrahydrofuran solution (33.0 mL) of the title compound (5.09 g) of Reference Example 34 under ice-cooling. After adding lithium aluminum (779 mg) and stirring for 20 minutes, water (780 uL), 4.0 mol / L sodium hydroxide aqueous solution (2.34 mL), and water (2.34 mL) were sequentially added while stirring under ice cooling. It was. The precipitated white precipitate was removed using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 1: 1) to obtain the title compound (2.51 g).
¹ H-NMR (CDCl ₃ ): δ 1.47 (9H, s), 1.63-1.83 (1H, m), 2.19-2.28 (1H, m), 2.42-2.73 (5H, m), 3.17 (1H, brt ), 3.48-4.03 (8H, m), 5.15 (1H, br).

Reference Example 36 (R) -N-tert-butoxycarbonyl-4-morpholinyl-D-prolinal A solution of the title compound of Reference Example 35 (1.42 g) and dimethyl sulfoxide (10.0 mL) in methylene chloride (25.0 mL) ) Were added with triethylamine (1.80 mL) and pyridine sulfur trioxide complex (1.58 g) under ice-cooling, and stirred for 3 hours under ice-cooling. Water (50 mL) was added to the reaction solution, and the mixture was separated to remove the aqueous layer. The aqueous layer was extracted three times with methylene chloride (20 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate-hexane = 1: 1 (30 mL) and water (30 mL) were added to the residue, and the mixture was separated to remove the aqueous layer. The aqueous layer was extracted three times with ethyl acetate-hexane = 1: 1 (30 mL), the organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.08 g).
¹ H-NMR (CDCl ₃ ): δ1.44, 1.48 (9H, 2s), 1.63 (1H, br), 1.91-2.12 (1H, m), 2.15-2.26 (1H, m), 2.41-2.52 (4H m), 2.72-2.84 (1H, m), 3.35-3.47 (1H, m), 3.56-3.74 (5H, m), 3.99-4.16 (1H, m), 9.41-9.48 (1H, m).

Reference Example 37 N-tert-butoxycarbonyl-4-methylene-D-proline methyl ester
Triphenylphosphine methyl bromide (4.67 g) was added to a tetrahydrofuran suspension (18.0 mL) of tert-butoxy potassium (1.47 g) at room temperature. The reaction mixture was stirred at 50 ° C. for 30 min, and a solution (5 mL) of the title compound (2.12 g) of Reference Example 33 in tetrahydrofuran was added at room temperature. The reaction solution was stirred at 50 ° C. for 1 hour, concentrated under reduced pressure, ethyl acetate (30 mL) and 0.5 mol / L hydrochloric acid (30 mL) were added, and the mixture was separated, and the aqueous layer was removed. The aqueous layer was extracted twice with ethyl acetate (15 mL), and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 5: 1 to 2: 1) to obtain the title compound (1.00 g).
¹ H-NMR (CDCl ₃ ): δ1.45 (9H, d), 2.62 (1H, brd), 2.96 (1H, brq), 3.73 (3H, s), 4.07 (2H, brd), 4.45 (1H, ddd), 5.00 (2H, br).

Reference Example 38 (R) -N-tert-butoxycarbonyl-4-methyl-D-proline methyl ester To a methanol solution (8.20 mL) of the title compound (990 mg) of Reference Example 37 in 10% palladium in a nitrogen atmosphere -Carbon (873 mg) was added at room temperature. After putting under hydrogen atmosphere, the reaction solution was stirred at room temperature for 5 hours. The catalyst was removed using celite and concentrated under reduced pressure to give the title compound (1.01 g).
¹ H-NMR (CDCl ₃ ): δ1.03-1.07 (3H, m), 1.46-1.61 (10H, m), 1.74-1.89 (1H, m), 2.15-2.43 (2H, m), 2.98 (1H , t), 3.72 (3H, s), 4.09-4.38 (1H, m).

Reference Example 39 (R) -N-tert-butoxycarbonyl-4-methyl-D-prolinol To a solution of the title compound of Reference Example 38 (963 mg) in tetrahydrofuran (120 mL) under ice-cooling, lithium aluminum hydride (187 mg) ) And stirred for 20 minutes under ice-cooling. While stirring the reaction solution under ice cooling, water (187 uL), 4.0 mol / L aqueous sodium hydroxide solution (561 uL) and water (561 uL) were sequentially added, and the mixture was stirred for 30 minutes at room temperature. The precipitated white precipitate was removed using celite, followed by concentration under reduced pressure to obtain the title compound (840 mg).
¹ H-NMR (CDCl ₃ ): δ1.01-1.08 (4H, m), 1.47 (9H, m), 1.58-1.68 (1H, m), 2.05-2.31 (2H, m), 2.70-2.98 (1H m), 3.37-4.25 (4H, m).

(Reference Example 40) (R) -N-tert-butoxycarbonyl-4-methyl-D-prolinal To a methylene chloride solution (19.0 mL) of the title compound (825 mg) of Reference Example 39 at room temperature, dimethyl sulfoxide (8. 00 mL) was added, and the mixture was cooled under ice cooling, and triethylamine (1.39 mL) and pyridine sulfur trioxide complex (1.22 g) were added. The reaction solution was stirred under ice-cooling for 30 minutes and then concentrated under reduced pressure. To the residue were added water (30 mL) and ethyl acetate-hexane = 1: 1 (50 mL), and the aqueous layer was removed. The aqueous layer was extracted twice with ethyl acetate-hexane = 1: 1 (20 mL), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (813 mg).
¹ H-NMR (CDCl ₃ ): δ1.03-1.09 (3H, m), 1.42, 1.47 (9H, 2s), 2.07-2.39 (3H, m), 2.92-3.09 (1H, m), 3.60-3.80 (1H, m), 3.99-4.17 (1H, m), 9.38-9.62 (1H, m).

Reference Example 41 (R) -N-tert-butoxycarbonyl-4-tosyl-D-proline methyl ester To a solution of the title compound of Reference Example 29 (10.0 g) in pyridine (25 mL) -methylene chloride (84 mL) was added ice. Under cooling, p-toluenesulfonyl chloride (10.1 g) was added, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. Water (100 mL) and citric acid (80 g) were added to the reaction mixture, and the mixture was stirred and separated. The aqueous layer was extracted three times with methylene chloride (300 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 5: 1 to 2: 1) to obtain the title compound (9.01 g).
¹ H-NMR (CDCl ₃ ): δ1.40, 1.44 (9H, 2s), 2.34-2.52 (1H, m), 2.45 (3H, s), 3.54-3.75 (5H, m), 4.31-4.46 (1H m), 5.00-5.09 (1H, m), 7.35 (2H, brd), 7.76 (2H, brd).

(Reference Example 42) (R) -N-tert-butoxycarbonyl-4-acetylthio-D-proline methyl ester To a dimethylformamide solution (26.5 mL) of the title compound (4.22 g) of Reference Example 41 at room temperature, Potassium acetate (1.54 g) was added. Stir at 70 ° C. for 5 hours. Ethyl acetate-hexane = 1: 1 (100 mL) and 0.5 mol / L hydrochloric acid (50 mL) were added to the reaction solution, and the mixture was separated to remove the aqueous layer. The aqueous layer was extracted three times with ethyl acetate-hexane = 1: 1 (20 mL), and the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 5: 1 to 2: 1) to obtain the title compound (2.70 g).
¹ H-NMR (CDCl ₃ ): δ1.41, 1.46 (9H, 2s), 2.15-2.45 (2H, m), 2.33 (3H, s), 3.28-3.46 (1H, m), 3.75 (3H, s ), 3.91-4.09 (2H, m), 4.26-4.42 (1H, m).

(Reference Example 43) (R) -N-tert-butoxycarbonyl-4-methylthio-D-prolinol A solution of the title compound of Reference Example 42 (2.25 g) in tetrahydrofuran (37.0 mL) was hydrogenated under ice-cooling. Lithium aluminum (530 mg) was added, and the reaction solution was stirred for 2 hours under ice cooling. While stirring the reaction solution under ice-cooling, water (580 uL) was added, and 4 mol / L hydrochloric acid (1.74 mL) and water (1.74 mL) were sequentially added. The precipitated white precipitate was removed by Celite filtration and concentrated under reduced pressure. Methyl iodide (4.33 mL) was added to a residue and potassium carbonate (1.44 g) in methanol (17.4 mL) at room temperature. The reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and chloroform (30.0 ml) and 0.5 mol / L hydrochloric acid aqueous solution (20.0 mL) were added to the residue to separate it, and the aqueous layer was removed. The aqueous layer was extracted 3 times with chloroform (20 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate-hexane = 2: 1 to 1: 1) to obtain the title compound (998 mg).
¹ H-NMR (CDCl ₃ ): δ1.48 (9H, 2s), 1.88-2.07 (2H, m), 2.13 (3H, s), 3.25-3.70 (5H, m), 3.99 (1H, br), 4.25 (1H, brd).

(Reference Example 44) (R) -N-tert-butoxycarbonyl-4-methylthio-D-prolinal To the title compound (998 mg) of Reference Example 43 and dimethyl sulfoxide (8.1 mL) in a methylene chloride solution (20.0 mL) Triethylamine (1.34 mL) and pyridine sulfur trioxide complex (1.28 g) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate-hexane = 1: 1 (40.0 mL) and 0.5 mol / L hydrochloric acid (40.0 mL) were added to the reaction solution, and the mixture was separated to remove the aqueous layer. The aqueous layer was extracted three times with ethyl acetate-hexane = 1: 1 (30 mL), the organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (986 mg). Obtained.
¹ H-NMR (CDCl ₃ ): δ1.43, 1.47 (9H, 2s), 2.01-2.39 (2H, m), 1.81-2.56 (2H, m), 2.14 (3H, s), 3.56-3.72 (1H m), 3.16-3.86 (3H, m), 4.23-4.42 (1H, m), 9.52-9.62 (1H, m).

  The compounds of Reference Examples 31 to 44 are shown below.

Example 1 N- {1- [4-Chloro-N- (1-methylpiperidin-4-yl) -D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropane Amide, dihydrochloride The title compound of Reference Example 9 (150 mg) and 1-methyl-4-piperidone (43.0 uL) were dissolved in tetrahydrofuran, and sodium triacetoxyborohydride (106 mg) and acetic acid (22 0.0 uL) was added and stirred at room temperature for 12 hours. A 1.0 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, methanol and a 4.0 mol / L hydrochloric acid-dioxane solution were added to form a hydrochloride, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (184 mg).
MS (ESI) m / z 531 (M + H) ⁺
Rt (min) 1.11.

Example 2 N- {1- [N- (1-Benzylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide -Dihydrochloride The title compound (156 mg) was obtained in the same manner as in Example 1 using the title compound (150 mg) of Reference Example 9 and 1-benzyl-4-piperidone (65.0 uL).
MS (ESI) m / z 607 (M + H) ⁺
Rt (min) 1.19.

Example 3 N- {1- [N- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide -Hydrochloride salt The title compound (150 mg) was obtained by using the title compound of Reference Example 9 (150 mg) and 1-acetyl-4-piperidone (43.0 uL) in the same manner as in Example 1.
MS (ESI) m / z 559 (M + H) ⁺
Rt (min) 1.22.

Example 4 N- (tert-butyl) -1- (4-chloro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexyl Piperidine-4-carboxyamide dihydrochloride The title compound of Reference Example 6 (300 mg) and the title compound of Reference Example 16 (226 mg) were dissolved in chloroform, and sodium triacetoxyborohydride (521 mg) and acetic acid ( 124 uL) was added and stirred at room temperature for 17 hours. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, then methanol and 4 mol / L hydrochloric acid-dioxane solution were added to form a hydrochloride, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (62.2 mg).
MS (ESI) m / z 545 (M + H) ⁺
Rt (min) 1.26.

Example 5 N- [1- (4-Chloro-N-{[(2R) -1-ethylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl ] -2-Methylpropanamide dihydrochloride The title compound of Reference Example 9 (300 mg) and the title compound of Reference Example 19 (131 mg) were dissolved in chloroform, and cooled with ice, sodium triacetoxyborohydride (263 mg) and acetic acid (42.8 uL) was added and stirred at room temperature for 23 hours. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, methanol and a 4.0 mol / L hydrochloric acid-dioxane solution were added to form a hydrochloride, the solvent was distilled off, and the residue was dried under reduced pressure to obtain the title compound (57.6 mg).
MS (ESI) m / z 545 (M + H) ⁺
Rt (min) 1.18.

Example 6 N- [1- (4-Chloro-N-{[(2R) -1-isopropylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl ] -2-Methylpropanamide dihydrochloride The title compound (315 mg) was prepared by using the title compound of Reference Example 9 (300 mg) and the title compound of Reference Example 22 (127 mg) in the same manner as in Example 6. Obtained.
MS (ESI) m / z 559 (M + H) ⁺
Rt (min) 1.20.

  The compounds of Examples 1 to 6 are shown below.

Example 7 N- [1- (4-Chloro-N-{[(2R) -1-butylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl ] -2-Methylpropanamide dihydrochloride The title compound (255 mg) was obtained by using the title compound of Reference Example 9 (300 mg) and the title compound of Reference Example 25 (137 mg) in the same manner as in Example 6. Obtained.
MS (ESI) m / z 559 (M + H) ⁺
Rt (min) 1.22.

Example 8 N- [1- (4-Chloro-N-{[(2R) -1-isobutylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl ] -2-Methylpropanamide dihydrochloride The title compound (190 mg) was prepared by using the title compound of Reference Example 9 (300 mg) and the title compound of Reference Example 28 (139 mg) in the same manner as in Example 6. Obtained.
MS (ESI) m / z 572 (M + H) ⁺
Rt (min) 1.26.

Example 9 N- [1- (4-Fluoro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl ] -2-Methylpropanamide 2 trifluoroacetate The title compound of Reference Example 10 (250 mg) and the title compound of Reference Example 16 (226 mg) were dissolved in chloroform, and sodium triacetoxyborohydride (254 mg) was cooled with ice. Acetic acid (70 uL) was added and stirred at room temperature for 10 hours. A 1.0 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography using trifluoroacetic acid-containing water / acetonitrile as a mobile layer, and the eluate was dried under reduced pressure to obtain the title compound (314 mg).
MS (ESI) m / z 515 (M + H) ⁺
Rt (min) 1.10.

Example 10 N- (1- {4-Chloro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropane Amide dihydrochloride The title compound of Reference Example 9 (200 mg) and the title compound of Reference Example 12 (84.6 mg) were dissolved in chloroform, and sodium triacetoxyborohydride (130 mg) and acetic acid (26.4 uL) were cooled with ice. ) And stirred at room temperature for 17 hours. A 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in methanol, added with 4.0 mol / L hydrochloric acid-ethyl acetate solution, and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain the title compound (43.3 mg).
MS (ESI) m / z 517 (M + H) ⁺
Rt (min) 1.13.

Example 11 N- (1- {4-Chloro-N-[(2S) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropane Amide The title compound (43.3 mg) was obtained by using the title compound of Reference Example 9 (200 mg) and the crude product of Reference Example 17 (84.7 mg) in the same manner as in Example 10.
MS (ESI) m / z 518 (M + H) ⁺
Rt (min) 1.12.

Example 12 N- (tert-butyl) -1- {4-fluoro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidine-4-carboxamide The title compound (108 mg) was obtained by using the title compound of Reference Example 8 (120 mg) and the title compound of Reference Example 12 (112 mg) in the same manner as in Example 10.
MS (ESI) m / z 515 (M + H) ⁺
Rt (min) 1.16.

  The compounds of Examples 7 to 12 are shown below.

Example 13 N- [1- (4-Chloro-N-{[(2R, 4R) -4-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4 -Il] -2-methylpropanamide dihydrochloride The title compound (341 mg) was prepared by using the title compound of Reference Example 9 (300 mg) and the title compound of Reference Example 40 (192 mg) in the same manner as in Example 10. )
MS (ESI) m / z 531 (M + H) ⁺
Rt (min) 1.16.

Example 14 N- [1- (4-Chloro-N-{[(2R, 4S) -4- (methylthio) pyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine -4-yl] -2-methylpropanamide dihydrochloride The title compound was prepared by using the title compound of Reference Example 9 (200 mg) and the title compound of Reference Example 44 (147 mg) in the same manner as in Example 10. (204 mg) was obtained.
MS (ESI) m / z 563 (M + H) ⁺
Rt (min) 1.18.

Example 15 N- (1- {4-Fluoro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropane Amide dihydrochloride The title compound (323 mg) was obtained by using the title compound of Reference Example 10 (300 mg) and the title compound of Reference Example 12 (287 mg) in the same manner as in Example 10.
MS (ESI) m / z 501 (M + H) ⁺
Rt (min) 1.08.

Example 16 N- (tert-butyl) -1- (4-chloro-N-{[(2R, 4S) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4 -Cyclohexylpiperidine-4-carboxamide dihydrochloride The title compound (236 mg) was prepared by using the title compound of Reference Example 6 (250 mg) and the title compound of Reference Example 32 (294 mg) in the same manner as in Example 10. Got.
MS (ESI) m / z 549 (M + H) ⁺
Rt (min) 1.24.

Example 17 N- (tert-butyl) -1- (4-fluoro-N-{[(2R, 4S) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4 -Cyclohexylpiperidine-4-carboxamide dihydrochloride The title compound (199 mg) was prepared by using the title compound of Reference Example 8 (250 mg) and the title compound of Reference Example 32 (252 mg) in the same manner as in Example 10. Got.
MS (ESI) m / z 533 (M + H) ⁺
Rt (min) 1.20.

Example 18 N- [1- (4-Fluoro-N-{[(2R, 4R) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4 -Il] -2-methylpropanamide dihydrochloride The title compound (194 mg) was prepared by using the title compound of Reference Example 10 (300 mg) and the title compound of Reference Example 32 (313 mg) in the same manner as in Example 10. )
MS (ESI) m / z 519 (M + H) ⁺
Rt (min) 1.10.

  The compounds of Examples 13 to 18 are shown below.

Example 19 N- [1- (4-Chloro-N-{[(2R, 4R) -4-morpholin-4-ylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4- Cyclohexylpiperidin-4-yl] -2-methylpropanamide trihydrochloride Using the title compound of Reference Example 9 (900 mg) and the title compound of Reference Example 36 (707 mg) by using the same procedure as in Example 10. The title compound (893 mg) was obtained.
MS (ESI) m / z 602 (M + H) ⁺
Rt (min) 1.11.

  The compound of Example 19 is shown below.

  The pharmacological test results for the compounds of the experimental examples are described below.

(Experimental Example 1) Cloning of human type 4 receptor and method for obtaining stable expression strain Since human melanocortin type 4 receptor is a gene consisting of one exon structure, genomic (500 ng) derived from human blood cells is used as a template, Amplification was performed by the PCR method. Primers were designed based on cDNA base sequences registered in Genbank. As a forward primer (hMC4R-F), 5′-GGTACCATGGTGAACTCCACCCACCGT-3 ′ (SEQ ID NO: 1) was used. As a reverse primer (hMC4R-R), 5′-CTCGAGTAATATCTGCTAGACAAGTCACAAAGG-3 ′ (SEQ ID NO: 2) was used. The above primer set (F, R) was added at 20 pmol each, and PCR reaction was performed with Peltier Thermal Cycler PTC-200 (MJ Reseach) using Takara Ex Taq (Takara Shuzo) (reaction conditions: 2 at 98 ° C). After incubation for 30 minutes for 30 minutes, each denaturation, annealing, and extension reaction set at 96 ° C. for 30 seconds (denaturation), 65 ° C. for 30 seconds (annealing), and 72 ° C. for 2 minutes (extension) was performed 35 times, and then 72 Incubation at 0 ° C. for 6 minutes).

The gene fragment of the desired size (1011 base pairs) is separated and recovered by agarose gel electrophoresis, subcloned into the pT7-Blue vector (Novagen), and the target sequence is obtained using the autosequencer: ABI PRISM 377 Genetic Analyzer (Applied Biosystems) It was confirmed. In order to transfer to an expression vector for mammalian cells, the plasmid used for subcloning was digested with KpnI and XhoI (restriction enzyme recognition sequence introduced into the primer set), and the DNA fragment was recovered in the same manner as described above. The resulting DNA fragment was mixed with animal cell expression plasmid pcDNA3.1 (+) (invitrogen) treated with the same restriction enzyme, ligated using Ligation High (TOYOBO), animal cell expression construct hMC4R / pcDNA3.1 (+) Was obtained. Furthermore, Escherichia coli competent cell DH5α (TOYOBO) was transformed and amplified with hMC4R / pcDNA3.1 (+). This construct was introduced into mammalian cells CRE-Luc / HEK293 into which a cAMP-responsive reporter gene (CRE-Luciferase) had been introduced using Fugene6. Thereafter, in order to obtain a stable expression strain, the HEK293-derived strain was cultured in DMEM (10% FBS) supplemented with 100 ug / mL Hygromycin and 400 ug / mL G418 (37 ° C., 5% CO ₂ ), and was simply obtained by limiting dilution. One clone strain (hMC4R / CRE-Luc / HEK293 cells) was obtained.

(Experimental example 2) Measurement of activity of compound against melanocortin-4 receptor The hMC4R / CRE-Luc / HEK293 cells obtained as described above were usually used in a 75 cm ² cell culture flask, 5% CO ₂ , 37 ° C. The cells were cultured in DMEM medium (Sigma, phenol red (+)) containing 10% FCS (Gibco BRL), 100 μg / mL hyglomycin (WAKO) and 400 μg / mL G418 (Nacalai Tesque). At the time of activity measurement, hMC4R / CRE-Luc / HEK293 cells subcultured are detached with trypsin (Gibco BRL), suspended in serum-free DMEM medium (Sigma, phenol red (-)), 22 × 10 ⁴ Cells adjusted to a cell density of cells / mL were seeded at 90 μL / well in 96-well white plates (Sumilon MS8096W) and cultured overnight at 37 ° C. with 5% CO ₂ . The test compound was dissolved using DMSO and diluted sequentially to a concentration 200 times the final concentration on the well. DMSO was used as a negative control. The DMSO solution of the serially diluted compound was diluted 20 times with PBS (Gibco BRL) containing 1% BSA (Sigma), and this was diluted to 10 μL / well in the cell culture solution of the 96-well plate prepared from the previous day as described above. Added in increments. After 4 to 5 hours, Bright-Glo (Promega) was added to each well at 10 μL / well, stirred, and luminescence intensity was measured for each well using ARVO (Perkin Elmer). The average value of the measured luciferase luminescence intensity was calculated for each test compound, and these were used as the representative values of the luminescence intensity when each test compound was stimulated. EC ₅₀ values and Emax were calculated using Prism (ver. 4.02, GraphPad Software, Inc.).

  The results are shown below.

  Since the compound represented by the formula (I) of the present invention strongly acts as an agonist on the melanocortin-4 receptor (MC4R), various diseases (for example, obesity, sexual dysfunction, and sexual intercourse dysfunction) Can be useful as a preventive, therapeutic or ameliorating agent.

Claims (21)

The following general formula (I)

{Wherein R ¹ is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;
R ² is
(1) a hydrogen atom,
(2) an alkyl group having 1 to 8 carbon atoms,
(3) (CR ^a R ^b ) _n C _3-8 cycloalkyl group,
(4) (CR ^a R ^b ) _n aryl group,
(5) (CR ^a R ^b ) _n heteroaryl group,
(6) (CR ^a R ^b ) _n heterocycle group,
_{^{(7) (CR a R b}} ) n -N (R 1c) C (O) R 2c,
_{^{(8) (CR a R b}} ) n -N (R 1c) S (O) m R 2c,
_{^{(9) (CR a R b}} ) n -N (R 1c) (R 2c),
_{^{(10) (CR a R b}} ) n -C (O) OR 1c,
_{^{(11) (CR a R b}} ) n -C (O) N (R 1c) (R 2c),
(12) (CR ^a R ^b ) _n -OR ^1c ,
[Cycloalkyl group (3) in the above ^{R 2,} an aryl group (4), heteroaryl groups (5), heterocyclic group (6), 1-4 selected from ^{R d} or oxo optionally Each of the substituents may be the same or different, when the number of the substituents is 2 or more.
n is 0, 1, 2 or 3;
m is 0, 1 or 2;
R ^a , R ^b , R ^1c and R ^2c may be the same or different and each represents (1) a hydrogen atom,
(2) an alkyl group having 1 to 8 carbon atoms,
(3) an aryl group,
(4) arylalkyl group (C1-C4 alkyl group),
(5) a hydroxy group,
(6) It is a C1-C4 hydroxyalkyl group,
Furthermore, R ^a and R ^b may together form a C _3-8 cycloalkyl group. ]
R ¹ and R ² may be taken together to form a heterocycle group (the heterocycle group is substituted with 1 to 4 groups selected from R ^{d and} oxo). In addition, when there are two or more substituents, each of the substituents may be the same or different.
R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or a hydroxy group,
R ² and R ³ may be taken together to form a cycloalkyl group or heterocycle group having 3 to 10 carbon atoms (the cycloalkyl group or heterocycle group is selected from R ^d or oxo). 1 to 4 selected groups may be substituted, and when further substituted with two or more of the substituents, each of the substituents may be the same or different.
R ² , R ³ and R ⁴ may be taken together to form an aryl group or heteroaryl group (the aryl group or heteroaryl group is selected from R ^{d and} oxo 1 -4 groups may be substituted, and when the number of substituents is 2 or more, each of the substituents may be the same or different).
[R ^d of R ^{1 to} R ⁴ is
(1) a halogen atom,
(2) a cyano group,
(3) an alkyl group having 1 to 8 carbon atoms,
(4) a cycloalkyl group having 3 to 8 carbon atoms,
(5) an aryl group,
(6) arylalkyl group (C1-C4 alkyl group),
(7) heteroaryl group,
(8) heterocycle group,
(9) -OR ^1d ,
^{_{(10) -NH-SO 2 R}} 1d,
(11) -N (R ^1d ) (R ^2d ),
(12) -NH-C (O) R ^1d ,
(13) -C (O) OR ^1d ,
(14) -C (R ^1d ) (R ^2d ) —N (R ^3d ) (R ^4d ),
(15) -C (O) R ^1d ,
_{(16) -SO 2 -N (R} 1d) (R 2d),
(17) -S (O) _m -R ^1d ,
(18) _-CF 3,
(19) indicates -OCF ₃
The (4) cycloalkyl group, (5) aryl group, (6) arylalkyl group, (7) heteroaryl group, and (8) heterocycle group in R ^d are a halogen atom, a cyano group, or a carbon number of 1 to 8. And when the number of the substituents is 2 or more, each of the substituents may be the same or different,
m is 0, 1 or 2;
R ^1d , R ^2d , R ^3d and R ^4d may be the same or different,
(1) a hydrogen atom,
(2) an alkyl group having 1 to 8 carbon atoms,
(3) an aryl group,
(4) arylalkyl group (C1-C4 alkyl group),
(5) indicates a heteroaryl group,
The (3) aryl group, (4) arylalkyl group and (5) heteroaryl group of R ^1d , R ^2d , R ^3d and R ^4d are substituted with an alkyl group having 1 to 8 carbon atoms, a halogen atom or a cyano group. Further, when there are two or more substituents, each of the substituents may be the same or different. ]
R ⁵ is
(1) a hydrogen atom,
(2) an alkyl group having 1 to 8 carbon atoms,
(3) (CHR ^e ) _p C _3-8 cycloalkyl group,
(4) (CHR ^e ) _p aryl group,
(5) (CHR ^e ) _p heteroaryl group,
(6) (CHR ^e ) _p O (CHR ^e ) _{p is an} aryl group,
[Cycloalkyl group (3) in the above ^{R 5,} aryl group (4) or (6), heteroaryl groups (5) may be substituted with 1-4 ^{R f,} is ^{R f} In the case of two or more, each R ^f may be the same or different,
p is 0, 1 or 2;
^Re is
(1) a hydrogen atom,
(2) an alkyl group having 1 to 8 carbon atoms,
(3) an aryl group,
(4) arylalkyl group (C1-C4 alkyl group),
(5) indicates a cycloalkyl group;
R ^f has the same ^meaning as R ^d . ]
W ¹ is
(1) a hydrogen atom,
(2) an alkyl group having 1 to 8 carbon atoms,
_{(3) (CH 2) q} C 3-8 cycloalkyl group,
(4) (CH ₂ ) _q aryl group,
_{(5) (CH} 2) _q heteroaryl group,
(6) (CH ₂ ) _q heterocycle group,
W ² is
(1) a hydrogen atom,
(2) an alkyl group having 1 to 8 carbon atoms,
_{(3) (CH 2) q} C 3-8 cycloalkyl group,
(4) (CH ₂ ) _q aryl group,
_{(5) (CH} 2) _q heteroaryl group,
_{(6) (CH} 2) _q heterocyclic group,
(7) (CH ₂ ) _q cyano group,
_{(8) (CH 2) q} -C (O) N (R 1g) (R 2g),
_{(9) (CH 2) q} -C (O) OR 1g,
_{(10) (CH 2) q} -N (R 1g) C (O) R 2g,
_{(11) (CH 2) q} -N (R 1g) C (O) OR 2g,
_{(12) (CH 2) q} -N (R 1g) C (O) N (R 2g) (R 3g),
_{(13) (CH 2) q} -N (R 1g) S (O) N (R 2g) (R 3g),
_{(14) (CH 2) q} -S (O) m R 1g,
_{(15) (CH 2) q} -SO 2 N (R 1g) (R 2g),
_{(16) (CH 2) q} -OC (O) R 1g,
_{(17) (CH 2) q} -OC (O) OR 1g,
_{(18) (CH 2) q} -OC (O) N (R 1g) (R 2g),
_{(19) (CH 2) q} -N (R 1g) (R 2g),
_{(20) (CH 2) q} -N (R 1g) S (O) m R 2g,
_{(21) (CH 2) q} -C (O) N (R 1g) (CH 2) q N (R 2g) (R 3g),
_{(22) (CH 2) q} -C (O) N (R 1g) (CH 2) q N (R 2g) S (O) m R 3g,
₍₂₃₎ in _{(CH 2) q -N (R} 1g) C (O) (CH 2) q N (R 2g) it is (R ^{3 g)} [the ^{W 1, W 2,}
q is 0, 1, 2 or 3;
m is 0, 1 or 2;
R ^1g , R ^2g and R ^3g may be the same or different and each represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. ] Is shown. }
Or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof. The piperidine derivative according to claim 1, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, wherein R ¹ is a hydrogen atom or -CH ₃ . The piperidine derivative according to claim 2, wherein R ⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The following general formula (II)

[In the general formula (II), R ¹ , R ³ and R ^{4 in} the general formula (I) are hydrogen atoms;
R ⁵ is a (4) (CHR ^e ) _p aryl group, R ^e is a hydrogen atom, p = 1, and the aryl group is a phenyl group,
General formula ^{(II) R 2, R f} , W 1, W 2 , respectively, indicating that the ^{R 2,} R ^f of formula ^(I), W 1, ^{W 2} synonymous. ]
The piperidine derivative of Claim 1 represented by these, its pharmacologically acceptable salt, or those hydrates or solvates. The piperidine derivative according to claim 4, wherein n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. R ² is (3) (CR ^a R ^b ) _n C _3-8 cycloalkyl group, (4) (CR ^a R ^b ) _n aryl group, (5) (CR ^a R ^b ) _n heteroaryl group, (6 6. The piperidine derivative according to claim 5, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, which is ^a (CR ^a R ^b ) _n heterocycle group. (3) in R ² is cyclohexyl, cycloheptyl, cyclopentyl,
(4) is phenyl, naphthyl,
(5) is furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolinyl, oxazolinyl, pyranyl, thiazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazinyl, triazinyl, indolyl, indolinyl, benzoimidazolyl Benzoxazolyl, quinolyl, isoquinolyl, isothiazolyl,
The piperidine derivative according to claim 6 or a pharmacologically acceptable salt thereof, or a hydrate thereof, or Solvate. The following general formula (III)

[In the general formula (III), R ¹ and R ^{4 in} the general formula (I) are hydrogen atoms,
R ² and R ³ together form a cycloalkyl group having 3 to 10 carbon atoms or a heterocycle group (in general formula (III), abbreviated as “Ar”). , R ^d or oxo may be substituted with 1 to 4 groups, and when further substituted with 2 or more of the substituents, each of the substituents may be the same or different. May be good.)
R ⁵ is a (4) (CHR ^e ) _p aryl group, R ^e is a hydrogen atom, p = 1, and the aryl group is a phenyl group,
^{R d, R f, W 1} , W 2 of the general formula (III), respectively, showing ^R d in the general formula ^(I), the R ^f, the same meaning as W 1, ^{W 2.} ]
The piperidine derivative of Claim 1 represented by these, its pharmacologically acceptable salt, or those hydrates or solvates. The cycloalkyl group of Ar is cyclohexyl, cycloheptyl, cyclopentyl, adamantyl, and the heterocycle group is pyrrolidinyl, imidazolidinyl, oxazolidinyl, piperidino, piperidyl, piperazinyl, morpholino, morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, quinoxylidinyl The piperidine derivative according to claim 8 or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof, which is selected. The piperidine derivative or a pharmacologically acceptable one thereof according to claim 4, wherein the (CH ₂ ) _q C _3-8 cycloalkyl group of W ¹ is selected from cyclohexyl, cycloheptyl, and cyclopentyl. Its salts, or their hydrates or solvates. W ² is (3) (CH ₂ ) _q C _3-8 cycloalkyl group,
(4) (CH ₂ ) _q aryl group,
_{(5) (CH} 2) _q heteroaryl group,
_{(6) (CH} 2) _q heterocyclic group,
_{(8) (CH 2) q} -C (O) N (R 1g) (R 2g),
_{(10) (CH 2) q} -N (R 1g) C (O) R 2g,
_{(14) (CH 2) q} -S (O) m R 1g,
_{(20) (CH 2) q} -N (R 1g) S (O) m R 2g,
_{(21) (CH 2) q} -C (O) N (R 1g) (CH 2) q N (R 2g) (R 3g),
_{(22) (CH 2) q} -C (O) N (R 1g) (CH 2) q N (R 2g) S (O) m R 3g,
_{(23) (CH 2) q} -N (R 1g) C (O) (CH 2) q N (R 2g) (R 3g) in which the piperidine derivative or a pharmaceutically acceptable according to claim 10 Or a hydrate or solvate thereof. W ² is,
q = 1,
The C _3-8 cycloalkyl group in (3) is cyclohexyl, cycloheptyl, cyclopentyl;
The aryl group in (4) is phenyl or naphthyl;
The heteroaryl group of (5) is furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolinyl, oxazolinyl, pyranyl, thiazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazinyl, triazinyl, indolyl, indolinyl, Benzimidazolyl, benzoxazolyl, quinolyl, isoquinolyl, isothiazolyl,
The piperidine derivative according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the heterocycle group of (6) is selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, piperidino, piperidyl, piperazinyl, morpholino, morpholinyl. Or a hydrate or solvate thereof. The piperidine derivative or a pharmaceutically acceptable salt thereof according to claim 11, wherein ( ² ) of W ² is selected from the following substituents.

Acetylamide, propanamide, butanamide, 2-methylpropanamide, 2,2-dimethylpropanamide. Any piperidine derivative selected from the following compounds, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
N- {1- [4-chloro-N- (1-methylpiperidin-4-yl) -D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide,
N- {1- [N- (1-benzylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide,
N- {1- [N- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -4-cyclohexylpiperidin-4-yl} -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- (tert-butyl) -1- (4-chloro-N-{[1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Chloro-N-{[1-ethylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-isopropylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-butylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[1-isobutylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Fluoro-N-{[1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- (1- {4-chloro-N- [pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- {4-fluoro-N- [pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Chloro-N-{[4-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide
N- [1- (4-Chloro-N-{[4- (methylthio) pyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide ,
N- (1- {4-fluoro-N- [pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- (4-chloro-N-{[4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxamide;
N- (tert-butyl) -1- (4-fluoro-N-{[4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Fluoro-N-{[4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- [1- (4-Chloro-N-{[4-morpholin-4-ylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide. Any piperidine derivative selected from the following compounds, or a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
N- [1- (4-Chloro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- (tert-butyl) -1- (4-chloro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4-carboxy Amide,
N- [1- (4-Chloro-N-{[(2R) -1-ethylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Chloro-N-{[(2R) -1-isopropylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Chloro-N-{[(2R) -1-butylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Chloro-N-{[(2R) -1-isobutylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- [1- (4-Fluoro-N-{[(2R) -1-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methyl Propanamide,
N- (1- {4-chloro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- {4-fluoro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidine-4-carboxamide;
N- [1- (4-Chloro-N-{[(2R, 4R) -4-methylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2 -Methylpropanamide,
N- [1- (4-Chloro-N-{[(2R, 4S) -4- (methylthio) pyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2-methylpropanamide,
N- (1- {4-fluoro-N-[(2R) -pyrrolidin-2-ylmethyl] -D-phenylalanyl} -4-cyclohexylpiperidin-4-yl) -2-methylpropanamide,
N- (tert-butyl) -1- (4-chloro-N-{[(2R, 4S) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4 -Carboxamide,
N- (tert-butyl) -1- (4-fluoro-N-{[(2R, 4S) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4 -Carboxamide,
N- [1- (4-Fluoro-N-{[(2R, 4R) -4-fluoropyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidin-4-yl] -2 -Methylpropanamide,
N- [1- (4-Chloro-N-{[(2R, 4R) -4-morpholin-4-ylpyrrolidin-2-yl] methyl} -D-phenylalanyl) -4-cyclohexylpiperidine-4- Yl] -2-methylpropanamide. A medicament or pharmaceutical composition comprising the piperidine derivative according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient. A melanocortin-4 receptor agonist comprising the piperidine derivative according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient.   A melanocortin-4 receptor agonist comprising as an active ingredient the piperidine derivative according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, wherein the melanocortin-4 receptor action is an agonistic action. A preventive or therapeutic agent for obesity or hyperphagia, comprising the piperidine derivative according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient. The improvement agent of sexual dysfunction which uses the piperidine derivative in any one of Claims 1-15, or its pharmacologically acceptable salt as an active ingredient. The infertility improving agent which uses the piperidine derivative in any one of Claims 1-15, or its pharmacologically acceptable salt as an active ingredient.