WO2012026495A1

WO2012026495A1 - Novel hydantoin derivative and medicinal agent comprising same as active ingredient

Info

Publication number: WO2012026495A1
Application number: PCT/JP2011/069063
Authority: WO
Inventors: 佐藤　太朗; 隆史小峰; 誠連佛; 小林　直樹
Original assignee: 杏林製薬株式会社
Priority date: 2010-08-25
Filing date: 2011-08-24
Publication date: 2012-03-01
Also published as: TW201212913A; JP2013230986A

Abstract

The present invention provides a compound which has a potent AMPK activation activity and exhibits an advantageous effect that comes from the AMPK activation activity in vivo. The present invention relates to a hydantoin derivative represented by general formula (1), a pharmacologically acceptable salt of the derivative or a hydrate of the derivative or the pharmacologically acceptable salt.

Description

Novel hydantoin derivatives and pharmaceuticals containing them as active ingredients

The present invention relates to a hydantoin derivative and its addition salt effective as a human AMPK activator for treating lipid metabolism abnormality or diabetes, and a pharmaceutical composition containing these compounds.

In recent years, due to lifestyle changes, the population of obesity has increased, accompanied by hyperlipidemia, hyperglycemia (diabetes) or lifestyle-related diseases represented by hypertension, so-called metabolic syndrome (metabolic syndrome) patients Increase has become a major social problem.

The reason for this is that the above-mentioned lifestyle-related diseases are all major risk factors for arteriosclerosis that cause myocardial infarction, angina pectoris, or stroke. It is because it makes it easy to develop and develop.

As the cause of the disease, visceral fat type obesity, lipid metabolism abnormality, sugar metabolism abnormality or blood pressure abnormality are considered (Non-patent Document 1). Therefore, it is expected that these lifestyle-related diseases can be prevented by improving the energy metabolism abnormality.

Under such circumstances, drugs for controlling blood glucose level and blood lipid concentration are used in combination with pharmacotherapy for diabetic patients with hyperlipidemia and patients with impaired glucose tolerance. As drugs for controlling blood glucose levels, sulfonylurea drugs, thiazolidine drugs or biguanide drugs are widely used.

However, side effects such as hypoglycemia, cardiac hypertrophy, edema or lactic acidosis have been reported in the use of these drugs. As drugs for controlling blood lipid levels, fibrate drugs or statin drugs are widely used, but side effects such as gastrointestinal disorders, liver dysfunction or renal dysfunction have been reported.

Furthermore, in combination therapy, there is a problem of side effects due to the result of interaction between drugs, and it is difficult to say that hyperlipidemia treatment is sufficiently performed in diabetic patients undergoing drug treatment. For this reason, the development of a drug that has a high effect of controlling blood glucose level and blood lipid concentration and is excellent in safety is desired.

On the other hand, research on energy metabolism, obesity or diabetes onset mechanism has progressed, and it has become clear that AMPK (AMP-activated protein kinase) plays an extremely important role (Non-patent Document 2). AMPK is a protein widely present in the living body such as muscle or liver, and its activity increases in a situation where intracellular ATP level decreases, functions as a “metabolic sensor” that promotes metabolism and promotes ATP synthesis. It was known that

However, recent studies have shown that AMPK is not only regulated by intracellular energy levels, but also by muscle exercise, leptin (Non-patent Document 3), adipocyte-derived hormones such as adiponectin (Non-patent Document 4), etc. It has been considered to be an intracellular mediator of activated and triggered fatty acid oxidation or glucose utilization by them.

For example, it is known that AMPK affects fatty acid oxidation in mitochondria through activity control on acetyl CoA carboxylase (ACC).

Thus, it is considered that AMPK is not only activated in the absence of intracellular energy, but also plays an important role in biological energy metabolism or nutrient metabolism. Therefore, activation of AMPK leads to improvement of abnormal sugar metabolism or abnormal lipid metabolism, and can be said to be an excellent molecular target in the prevention of obesity or the treatment of diabetes.

As compounds that activate AMPK, in addition to the aforementioned adipocyte-derived hormone, metformin (non-patent document 5) or AICAR (aminoimidazole carboxide ribonucleotide), which is a therapeutic agent for diabetes, is known.

However, adipocyte-derived hormone is metabolically and chemically unstable and cannot be used as a medicine. In addition, metformin has a weak AMPK activating action, and side effects such as gastrointestinal disorders or lactic acidosis have been reported, and there is a problem in therapeutic effect or safety.

On the other hand, compounds of formulas (A) to (Q) shown in Table 1 are known as compounds for which AMPK activating activity has been reported, but none of them has a benzylhydantoin structure, and the compounds of the present invention And the structure is different.

In addition, an AMPK activating action has been reported for isobenzofuranone derivatives such as DNP-60502 (R) (Non-patent Document 6). However, these isobenzofuranone derivatives do not have a benzylhydantoin structure and are different in structure from the compounds of the present invention.

Further, Patent Document 24 discloses a compound represented by the general formula (S) having anticancer activity. However, the hydantoin derivatives described in the specification are only para-substituted benzylhydantoins, which are completely different from the compounds of the present invention and do not describe any AMPK activation action.

In the formula (S), R ₁ represents an aromatic group or a heterocyclic group, X and Y each independently represent an oxygen atom, a sulfur atom, an alkylene, or the like, and A represents an aromatic group, a heterocyclic monocycle or a heterocyclic group. D represents a phenyl group, a 6-membered ring or a 5-membered heterocyclic group, E represents a phenyl group, a pyridyl group or a pyrimidyl group, and L represents —C (O) —, —S (O) _2. -Or -N (R ₆ ) CO- and the like, j, m, n, p, q and t each independently represent 0 or 1, and T represents the general formula (Ta).

In the formula (Ta), R ₄ independently represents a hydrogen atom, an alkyl group or the like.

Patent Document 25 discloses a compound represented by the general formula (U) having a factor Xa inhibitory action. However, there is no hydantoin derivative in the compounds described in the specification, and there is no description about the AMPK activation action.

In formula (U), D and D ′ represent a hydrogen atom, a cyano group, etc., R ¹ represents a hydrogen atom, a halogen atom, etc., R ² represents a hydrogen atom, ═O, a C _1-4 alkyl group, or the like. R ² is absent or represents a benzene ring which may be substituted with 0-2 R ¹⁰ together with R ^2a , R ³ and R ^{3 ′} are hydrogen, C _1-4 alkyl group, benzyl group, phenyl Z represents a bond or C _1-4 alkylene, A represents a C _3-10 hydrocarbon ring which may be substituted with 0-2 R ⁶ , and B represents X -Y, CONR ³ R ^{3 ',} etc., X represents -C (O) NR ^3- , -NR ³ C (O)-, etc. Y represents 0-2 R ⁶ of C _3-10 substituted group represents such hydrocarbon ring optionally _{C 3-10} and, ^{R 6} is _{_{^{_{(CH 2) n OR 3,}}}} (CH 2) rR 3 R 3 ' Represents ^{etc., R 10} represents a hydrogen atom, a halogen atom.

International Publication No. 2004/034960 International Publication No. 2004/043957 US Patent No. 2005038068 International Publication No. 2006/071095 International Publication No. 2007/002461 International Publication No. 2007/005785 International Publication No. 2007/062568 European Patent Application No. 1754448 International Publication No. 2008/006432 International Publication No. 2008/016278 International Publication No. 2008/133441 International Publication No. 2008/083124 International Publication No. 2009/076631 International Publication No. 2009/066511 International Publication No. 2009/019445 International Publication No. 2009/019446 International Publication No. 2009/028881 International Publication No. 2009/100130 International Publication No. 2010/073011 International Publication No. 2010/036613 International Publication No. 2010/047982 International Publication No. 2010/051206 International Publication No. 2010/051176 International Publication No. 2004/060305 International Publication No. 1997/038984

An object of the present invention is to provide a compound that has a chemical structure different from that of the above-mentioned known compounds, has a strong AMPK activation action, and exhibits an advantageous effect derived from the AMPK activation action in vivo. .

The inventors of the present invention have made extensive studies focusing on the specific role of human AMPK in energy metabolism for the purpose of creating a novel structurally effective drug that is highly effective, durable and safe as a type II diabetes drug. As a result, it has been found that the novel benzylhydantoin derivative of the present invention and an addition salt thereof have an excellent human AMPK activating action and exhibit an excellent blood glucose lowering action and lipid lowering action in vivo.

That is, the present invention is as follows.
1. Hydantoin derivatives represented by the general formula (1) or pharmacologically acceptable salts thereof or hydrates thereof.

[In Formula (1), R ¹ has a hydrogen atom, a C ₁ -C ₆ alkyl group which may have a substituent, a C ₃ -C ₆ cycloalkyl group which may have a substituent, or a substituent. An optionally substituted C ₆ -C ₁₀ aryl group, an optionally substituted C ₇ -C ₁₂ aralkyl group, an optionally substituted 5- or 6-membered aromatic heterocyclic group or substituent Represents a condensed heterocyclic group which may have
X represents C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene, C ₂ -C ₄ alkynylene or general formula (2),
Y represents a single bond, C ₁ -C ₄ alkylene or general formula (5),
Z is a hydrogen atom, a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, or an optionally substituted C ₁ to C ₆ alkoxy group, optionally having C ₃ to C ₆ cycloalkyloxy group, hydroxyl group, nitro group, cyano group, optionally having amino group and substituent Or a C ₆ -C ₁₀ aryl group, a 5- or 6-membered aromatic heterocyclic group which may have a substituent, a condensed heterocyclic group which may have a substituent, or a substituent. Good C ₇ -C ₁₂ aralkyl group, optionally substituted C ₆ -C ₁₀ aryloxy group, optionally substituted C ₇ -C ₁₂ aralkyloxy group, optionally substituted good _C 1 ~ _{C 6} alkylthio group, an optionally substituted _C 6 _{~ C 10} arylthio group Represents an _C 7 _{~ C 12} aralkylthio group which may have a substituent,
Ring A and Ring B are the same or different, and may be a C ₃ to C ₆ cycloalkyl group which may have a substituent, a 5- or 6-membered saturated heterocyclic group which may have a substituent, a substituted A C ₆ -C ₁₀ aryl group which may have a group, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent,
R ² and R ³ are the same or different and are a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, a substituted group. Represents a C ₆ -C ₁₀ aryl group which may have a group or a C ₇ -C ₁₂ aralkyl group which may have a substituent, or R ² and R ³ are bonded to each other, and R ² and R ³ The general formula (6) is represented together with the carbon atom to be bonded]

[In the formula (2), T represents a single bond, C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene or C ₂ -C ₄ alkynylene;
U represents a single bond, C ₁ -C ₄ alkylene or C ₂ -C ₄ alkenylene;
A is a carbonyl group, an oxygen atom, —S (O) _p — (p represents an integer selected from 0 to 2), —NR ⁴ — (R ⁴ is a hydrogen atom, C ₁ which may have a substituent) C ₆ alkyl group, optionally substituted C ₇ to C ₁₂ aralkyl group, optionally substituted C ₆ to C ₁₀ aryl group, optionally substituted C ₁ to C ₆ aliphatic acyl group, optionally substituted C ₁ -C ₆ alkylsulfonyl group, optionally substituted 5-membered or 6-membered aromatic heterocyclic group or optionally substituted Represents a good condensed heterocyclic group), —N (R ⁵ ) SO ₂ —, —SO ₂ N (R ⁵ ) — (R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having substituent (s). Or a C ₇ to C ₁₂ aralkyl group which may have a substituent), a general formula (3) or a general formula (4)]

[In Formula (3), L ¹ represents a single bond, an oxygen atom or —NR ⁵ —, and R ⁵ represents the same meaning as described above]

[In Formula (4), L ² represents a single bond or an oxygen atom, and R ⁵ represents the same meaning as described above.]

[In the formula (5), Q ¹ represents an oxygen atom, —S (O) _q — (q represents an integer selected from 0 to 2), —NR ⁶ — (R ⁶ represents a hydrogen atom, and has a substituent. An optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₇ -C ₁₂ aralkyl group, an optionally substituted C ₆ -C ₁₀ aryl group, and an optionally substituted group. Good C ₁ -C ₆ aliphatic acyl group, optionally substituted C ₁ -C ₆ alkylsulfonyl group, optionally substituted 5- or 6-membered aromatic heterocyclic group or substituent Or a carbonyl group, and h and j are the same or different and each represents an integer of 0 to 2]

[In the formula (6), Q ² is a single bond, methylene, oxygen atom, —S (O) _r — (r represents an integer selected from 0 to 2) or —NR ⁷ — (R ⁷ is a hydrogen atom, An optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₇ -C ₁₂ aralkyl group, an optionally substituted C ₆ -C ₁₀ aryl group, a substituent A C ₁ -C ₆ aliphatic acyl group which may have a substituent, a C ₁ -C ₆ alkylsulfonyl group which may have a substituent, a 5-membered or 6-membered aromatic complex which may have a substituent Represents a condensed heterocyclic group which may have a cyclic group or a substituent, and m and n are the same or different and represent 1 or 2]
2. The hydantoin derivative according to the preceding item ₁ , wherein X is C ₁ -C ₄ alkylene or the general formula (2a) or a pharmaceutically acceptable salt thereof or a hydrate thereof in the general formula (1).

[In the formula (2a), T ¹ represents a single bond or C ₁ -C ₄ alkylene,
U ¹ represents a single bond or C ₁ -C ₄ alkylene,
A ¹ is an oxygen atom, a sulfur atom, —NR ^4a —, (R ^4a is a hydrogen atom, an optionally substituted C ₁ to C ₆ alkyl group or an optionally substituted C ₇ to C _12. An aralkyl group), —N (R ^5a ) SO ₂ —, —SO ₂ N (R ^5a ) — (R ^5a is a C ₁ -C ₆ alkyl group or substituent optionally having a hydrogen atom or a substituent) Represents a C ₇ to C ₁₂ aralkyl group which may have a general formula (3a) or a general formula (4a)]

[In Formula (3a), L ^1a represents a single bond or —NR ^5a —, and R ^5a represents the same meaning as described above.]

[In formula (4a), R ^5a is as defined above.]
3. The hydantoin derivative according to the preceding item 1 or 2, wherein the X is represented by the general formula (2b) in the general formula (1), or a pharmacologically acceptable salt thereof, or a hydrate thereof.

[In formula (2b), T ¹ represents a single bond or C ₁ -C ₄ alkylene, and A ² represents general formula (3b) or general formula (4a)].

[In the formula (3b), R ^{5a ′} represents a hydrogen atom, a C ₁ to C ₆ alkyl group which may have a substituent or a C ₇ to C ₁₂ aralkyl group which may have a substituent, and R ^5a Represents the same meaning as described above]

[In formula (4a), R ^5a is as defined above.]
4). In the general formula (1), Z represents a hydrogen atom, a halogen atom, an optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted C ₃ -C ₆ cycloalkyloxy group, Nitro group, cyano group, optionally substituted amino group, optionally substituted C ₆ -C ₁₀ aryloxy group, optionally substituted C ₇ -C ₁₂ aralkyloxy group A C ₁ -C ₆ alkylthio group which may have a substituent, a C ₆ -C ₁₀ arylthio group which may have a substituent, or a C ₇ -C ₁₂ aralkylthio group which may have a substituent. 4. The hydantoin derivative according to any one of the preceding items 1 to 3, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
5. In the general formula (1), Ring A and Ring B are the same or different and may have a C ₃ -C ₆ cycloalkyl group which may have a substituent, or C ₆ -C which may have a substituent. _{A 10-} aryl group, a 5- or 6-membered saturated heterocyclic group that may have a substituent, a 5- or 6-membered aromatic heterocyclic group that may have a substituent, or a substituent 5. The hydantoin derivative or a pharmaceutically acceptable salt thereof according to any one of the above items 1 to 4, which is represented by a good condensed heterocyclic group, or a hydrate thereof.
6). 6. The hydantoin derivative or a pharmaceutically acceptable salt thereof according to any one of the preceding items 1 to 5, wherein Ring A is represented by the general formula (7) in the general formula (1), or a hydrate thereof.

[In the formula (7), V ¹ , V ² , V ³ and V ⁴ are the same or different and each represents a nitrogen atom or C—R ⁸ (R ⁸ may have a hydrogen atom, a halogen atom or a substituent. May have a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group which may have a substituent, a C ₁ -C ₆ alkoxy group which may have a substituent, or a substituent C ₃ -C ₆ cycloalkyloxy group, hydroxyl group, nitro group, cyano group, hydroxycarbonyl group, C ₁ -C ₆ alkoxycarbonyl group, amino group which may have a substituent, may have a substituent C ₆ -C ₁₀ aryloxy group, optionally substituted C ₇ -C ₁₂ aralkyloxy group, optionally substituted C ₁ -C ₆ alkylthio group, optionally substituted C ₆ ~ _{C 10} arylthio group, or which may _C 7 ~ have a substituent Represents a represents) a ₁₂ aralkylthio group]
7. Hydantoin derivatives represented by the general formula (1a) or pharmacologically acceptable salts thereof or hydrates thereof.

[In Formula (1a), R ^1a has a hydrogen atom, a C ₁ -C ₆ alkyl group which may have a substituent, a C ₃ -C ₆ cycloalkyl group which may have a substituent, or a substituent. An optionally substituted C ₆ -C ₁₀ aryl group or an optionally substituted C ₇ -C ₁₂ aralkyl group,
X ^a represents the general formula (2c),
Y ^a represents a single bond, methylene, oxygen atom, sulfur atom or —NR ^6a — (R ^6a represents a hydrogen atom or an optionally substituted C ₁ -C ₆ alkyl group);
Z ^a is a hydrogen atom, an optionally substituted C ₁ to C ₆ alkoxy group, an optionally substituted C ₃ to C ₆ cycloalkyloxy group, or an optionally substituted C _6. It represents ~ _{C 10} aryloxy group,
Ring A ^a represents ^a C ₆ -C ₁₀ aryl group which may have a substituent or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent,
Ring B ^a is an optionally substituted C _{3 ~} C ₆ cycloalkyl group, a saturated heterocyclic group of 5- or 6-membered and may have a substituent, an optionally substituted C ₆ ~ C ₁₀ represents an aromatic heterocyclic group of the aryl group or 5-membered may have a substituent or 6-membered,
R ^2a and R ^3a are the same or different and are a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group or a substituted group. Or a C ₆ -C ₁₀ aryl group which may have a group, or R ^2a and R ^3a are bonded to each other, together with the carbon atom to which R ^2a and R ^3a are bonded, the general formula (6a)]

[In the formula (2c), T ² represents a single bond or methylene,
A ³ represents General Formula (3c) or General Formula (4b)]

[In Formula (3c), R ^5b and R ^{5b ′} are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a substituent]

[In formula (4b), R ^5b represents the same meaning as described above]

[In the formula (6a), Q ^2a represents a single bond, methylene, oxygen atom, sulfur atom, —NR ^7a — (R ^7a represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a substituent) M and n are the same or different and represent 1 or 2]
8). 8. The hydantoin derivative or the pharmacologically acceptable salt thereof according to item 7 represented by the general formula (1b) or a hydrate thereof.

[In the formula (1b), R ^1b represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a general formula (8);
^Xb represents general formula (9), general formula (10), or general formula (11),
Y ^b represents an oxygen atom or a sulfur atom,
Z ^b represents a hydrogen atom or a C ₁ -C ₆ alkoxy group,
Ring A ^b represents a _C 6 _{~ C 10} aryl group or pyridyl group,
Ring B ^b is (1) a C ₃ -C ₆ cycloalkyl group,
(2) a piperidinyl group optionally substituted with a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ aliphatic acyl group or a C ₂ -C ₇ alkoxycarbonyl group, or (3) a halogen atom, C ₁ -C _{A 6} alkyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₇ alkoxycarbonyl group, a cyano group, an amino group optionally substituted with 1 or 2 C ₁ -C ₆ alkyl groups, a hydroxycarbonyl group, or Represents a C ₆ -C ₁₀ aryl group optionally substituted by an aminocarbonyl group,
R ^2b and R ^3b are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group or general formula (12), or R ^2b and R ^3b are bonded to each other. , R ^2b and R ^3b represent the general formula (6b) together with the carbon atom to which they are bonded]

[In the formula (8), R ⁹ represents a hydroxyl group, a C ₇ to C ₁₂ aralkyloxy group or a 3- to 6-membered cyclic amino group, and v represents an integer of 1 to 6]

[In the formula (12), R ¹⁰ represents a hydroxycarbonyl group or a C ₈ to C ₁₃ aralkyloxycarbonyl group, and w represents an integer of 1 to 6]

[In formula (6b), m and n are as defined above]
9. 9. The hydantoin derivative or the pharmacologically acceptable salt thereof or the hydrate thereof according to item 7 or 8 represented by general formula (1c).

[In the formula (1c), R ¹¹ represents a halogen atom, a C ₂ -C ₇ alkoxycarbonyl group, a cyano group, or an amino group optionally substituted by 1 or 2 C ₁ -C ₆ alkyl groups, R ^1b , R ^2b , R ^3b and Z ^b are as defined above.
10. The compound represented by the general formula (1) is
(R) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
(S) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-5,5-dimethylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
3- (2,4-dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenyl] benzamide,
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-tert-butoxycarbonylpiperidin-1-yloxy) phenylmethyl] benzamide;
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenylthio) phenylmethyl] benzamide,
5- (2,4-Dioxo-8-oxa-1,3-diazaspiro [4.5] decan-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide ,
5- (2,4-dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-3-butylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-3-cyclopropylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
5- (2,4-dioxo-3- (2-hydroxyethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
5- (2,4-dioxo-3- (2-morpholinoethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide or 5- (2 , 4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-cyanophenoxy) phenylmethyl] benzamide, or a pharmaceutically acceptable salt thereof, or Their hydrates.
11. 11. A pharmaceutical comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of items 1 to 10 or an hydrate thereof as an active ingredient.
12 11. An AMPK activator comprising as an active ingredient at least one of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of 1 to 10 above or a hydrate thereof.
13. 11. A lipid lowering agent comprising as an active ingredient at least one of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of 1 to 10 above or a hydrate thereof.
14 11. A prophylactic or therapeutic agent for arteriosclerosis comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of items 1 to 10 above.
15. 11. A prophylactic or therapeutic agent for diabetes comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of items 1 to 10 above.
16. 11. A prophylactic or therapeutic agent for obesity comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of items 1 to 10 above as an active ingredient.
17. 11. A cancer therapeutic agent comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of 1 to 10 above or hydrates thereof as an active ingredient.

The novel hydantoin derivative and its addition salt of the present invention have an excellent AMPK activating action and an excellent blood glucose lowering action and lipid lowering action in vivo. These compounds of the present invention are effective as a hypoglycemic agent and a lipid-lowering agent, particularly as a blood glucose uptake promoting agent in the liver and a lipid-lowering agent.

The compound of the present invention is a hydantoin derivative represented by the following general formula (1) or a pharmacologically acceptable salt thereof or a hydrate thereof.

In the formula (1), R ¹ has a hydrogen atom, a C ₁ to C ₆ alkyl group which may have a substituent, a C ₃ to C ₆ cycloalkyl group which may have a substituent, and a substituent. An optionally substituted C ₆ to C ₁₀ aryl group, an optionally substituted C ₇ to C ₁₂ aralkyl group, an optionally substituted 5-membered or 6-membered aromatic heterocyclic group or substituent; It represents a condensed heterocyclic group that may have.

R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group which may have a substituent, or a C ₃ -C ₆ cycloalkyl group which may have a substituent in order to exhibit an excellent AMPK activation action. Or a C ₇ -C ₁₂ aralkyl group which may have a substituent, more preferably a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₃ -C ₆ cycloalkyl group, Particularly preferred is an atom, a C ₁ -C ₆ alkyl group, or a C ₃ -C ₆ cycloalkyl group.

In the formula (1), X represents C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene, C ₂ -C ₄ alkynylene or the following general formula (2).

In the formula (2), T represents a single bond, C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene or C ₂ -C ₄ alkynylene;
U represents a single bond, C ₁ -C ₄ alkylene or C ₂ -C ₄ alkenylene;
A is a carbonyl group, an oxygen atom, —S (O) _p — (p represents an integer selected from 0 to 2), —NR ⁴ — (R ⁴ is a hydrogen atom, C ₁ which may have a substituent) C ₆ alkyl group, optionally substituted C ₇ to C ₁₂ aralkyl group, optionally substituted C ₆ to C ₁₀ aryl group, optionally substituted C ₁ to C ₆ aliphatic acyl group, optionally substituted C ₁ -C ₆ alkylsulfonyl group, optionally substituted 5-membered or 6-membered aromatic heterocyclic group or optionally substituted Represents a good condensed heterocyclic group), —N (R ⁵ ) SO ₂ —, —SO ₂ N (R ⁵ ) — (R ⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having substituent (s). Or a C ₇ to C ₁₂ aralkyl group which may have a substituent), the following general formula (3) or the following general formula (4).

In the formula (3), L ¹ represents a single bond, an oxygen atom or —NR ⁵ —, and R ⁵ represents the same meaning as described above.

In Formula (4), L ² represents a single bond or an oxygen atom, and R ⁵ represents the same meaning as described above.

X preferably represents C ₁ -C ₄ alkylene or the following general formula (2a) in order to represent an excellent AMPK activation action, and more preferably X is represented by the following general formula (2b). preferable.

In formula (2a), T ¹ represents a single bond or C ₁ -C ₄ alkylene,
U ¹ represents a single bond or C ₁ -C ₄ alkylene,
A ¹ is an oxygen atom, a sulfur atom, —NR ^4a —, (R ^4a is a hydrogen atom, an optionally substituted C ₁ to C ₆ alkyl group or an optionally substituted C ₇ to C _12. An aralkyl group), —N (R ^5a ) SO ₂ —, —SO ₂ N (R ^5a ) — (R ^5a is a C ₁ -C ₆ alkyl group or substituent optionally having a hydrogen atom or a substituent) Represents a C ₇ to C ₁₂ aralkyl group which may have a general formula (3a) or a general formula (4a).

In the formula (3a), L ^1a represents a single bond or —NR ^5a —, and R ^5a has the same meaning as described above.

In the formula (4a), R ^5a represents the same meaning as described above.

In the formula (2b), T ¹ represents a single bond or C ₁ -C ₄ alkylene, and A ² represents the following general formula (3b) or the general formula (4a).

In the formula (3b), R ^{5a ′} represents a hydrogen atom or a C ₁ to C ₆ alkyl group which may have a substituent or a C ₇ to C ₁₂ aralkyl group which may have a substituent, and R ^5a represents It represents the same meaning as described above.

In the formula (1), Y represents a single bond, C ₁ -C ₄ alkylene or the general formula (5). Y is particularly preferably an oxygen atom in order to exhibit an excellent AMPK activation action.

In formula (5), Q ¹ is an oxygen atom, —S (O) _q — (q represents an integer selected from 0 to 2), —NR ⁶ — (R ⁶ is a hydrogen atom, has a substituent) May have a C ₁ -C ₆ alkyl group, an optionally substituted C ₇ -C ₁₂ aralkyl group, an optionally substituted C ₆ -C ₁₀ aryl group, and may have a substituent A C ₁ -C ₆ aliphatic acyl group, an optionally substituted C ₁ -C ₆ alkylsulfonyl group, an optionally substituted 5- or 6-membered aromatic heterocyclic group or substituent; Represents a condensed heterocyclic group which may be present) or a carbonyl group, and h and j are the same or different and each represents an integer of 0 to 2.

In the formula (1), Z represents a hydrogen atom, a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, or a substituent. An optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted C ₃ -C ₆ cycloalkyloxy group, a hydroxyl group, a nitro group, a cyano group, an optionally substituted amino group, A C ₆ -C ₁₀ aryl group which may have a substituent, a 5- or 6-membered aromatic heterocyclic group which may have a substituent, a condensed heterocyclic group which may have a substituent, a substituent C ₇ -C ₁₂ aralkyloxy group which may have a group, C ₆ -C ₁₀ aryloxy group which may have a substituent, C ₇ -C ₁₂ aralkyloxy group which may have a substituent, substituted which may have a group _C 1 ~ _{C 6} alkylthio group, an optionally substituted _C 6 _{~ C 10} a Have a Ruchio groups or substituents represents an C _{7 ~} C ₁₂ aralkyl thio group.

Z represents a hydrogen atom, a halogen atom, a C ₁ to C ₆ alkoxy group which may have a substituent, or a C ₃ to C ₆ cyclo group which may have a substituent in order to exhibit an excellent AMPK activation action. Alkyloxy group, nitro group, cyano group, amino group optionally having substituent, C ₆ -C ₁₀ aryloxy group optionally having substituent, C ₇ -C optionally having substituent _{12 an} aralkyloxy group, an optionally substituted C ₁ -C ₆ alkylthio group, an optionally substituted C ₆ -C ₁₀ arylthio group, or an optionally substituted C ₇ -C ₁₂ It is preferably an aralkylthio group, more preferably a C ₁ -C ₆ alkoxy group which may have a substituent or a C ₃ -C ₆ cycloalkyloxy group which may have a substituent, ₁ ~ _{C 6} alkoxy group or _C 3 ~ _{C 6} Further preferably a cycloalkyl group, particularly preferably C 1 _~ C ₆ alkoxy group.

In the formula (1), Ring A and Ring B are the same or different, and may be a C ₃ to C ₆ cycloalkyl group which may have a substituent, a 5-membered or 6-membered which may have a substituent. Saturated heterocyclic group, optionally substituted C ₆ -C ₁₀ aryl group, optionally substituted 5- or 6-membered aromatic heterocyclic group or optionally substituted condensed Represents a heterocyclic group.

Ring A and Ring B are the same or different from each other in order to exhibit an excellent AMPK activation action, and may have a C ₃ to C ₆ cycloalkyl group which may have a substituent, or C which may have a substituent. ₆ -C ₁₀ aryl group, optionally substituted 5-membered or 6-membered saturated heterocyclic group, optionally substituted 5-membered or 6-membered aromatic heterocyclic group or substituted It is preferably a condensed heterocyclic group that may be used.

Ring A is a 5-membered or 6-membered saturated heterocyclic group which may have a substituent, a C ₆ -C ₁₀ aryl group which may have a substituent, or An optionally substituted 5-membered or 6-membered aromatic heterocyclic group is preferable, a 5-membered or 6-membered saturated heterocyclic group, a C ₆ -C ₁₀ aryl group, or a 5-membered or 6-membered aromatic heterocyclic group. A ring group is more preferred, and a C ₆ -C ₁₀ aryl group is particularly preferred.

Specifically, Ring A is preferably, for example, the following general formula (7).

In formula (7), V ¹ , V ² , V ³ , and V ⁴ are the same or different, and may be a nitrogen atom or C—R ⁸ (R ⁸ may have a hydrogen atom, a halogen atom, or a substituent. A C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted C ₁ -C ₆ alkoxy group, and an optionally substituted C ₃ to C ₆ cycloalkyloxy group, hydroxyl group, nitro group, cyano group, hydroxycarbonyl group, C ₁ to C ₆ alkoxycarbonyl group, optionally substituted amino group, optionally substituted C ₆ to C ₁₀ aryloxy group, C ₇ to C ₁₂ aralkyloxy group which may have a substituent, C ₁ to C ₆ alkylthio group which may have a substituent, C which may have a substituent ₆ to C ₁₀ arylthio group or C ₇ to C optionally having substituent (s) ₁₂ represents an aralkylthio group).

Ring B is preferably a C ₆ -C ₁₀ aryl group which may have a substituent in order to exhibit an excellent AMPK activation action, and is a halogen atom, a C ₁ -C ₆ alkyl group or 1 or 2 C atoms. _A C ₆ -C ₁₀ aryl group that may be substituted with any of the amino groups that may be substituted with ₁ to C ₆ alkyl groups is more preferred, and may be substituted with 1 to 3 halogen atoms A C ₆ -C ₁₀ aryl group is particularly preferred.

In the formula (1), R ² and R ³ are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group which may have a substituent, or a C ₃ -C which may have a substituent. _{A 6} cycloalkyl group, an optionally substituted C ₆ -C ₁₀ aryl group or an optionally substituted C ₇ -C ₁₂ aralkyl group, or R ² and R ³ are bonded; with bonded carbon atoms of R ² and ^{R 3} represents the general formula (6).

In the formula (6), Q ² represents a single bond, methylene, oxygen atom, —S (O) _r — (r represents an integer selected from 0 to 2), —NR ⁷ — (R ⁷ represents a hydrogen atom, substituted A C ₁ -C ₆ alkyl group which may have a group, a C ₇ -C ₁₂ aralkyl group which may have a substituent, a C ₆ -C ₁₀ aryl group which may have a substituent, a substituent C ₁ -C ₆ aliphatic acyl group which may have, C ₁ -C ₆ alkylsulfonyl group which may have a substituent, 5-membered or 6-membered aromatic heterocyclic ring which may have a substituent Represents a condensed heterocyclic group which may have a group or a substituent, and m and n are the same or different and represent 1 or 2;

Specific examples of the compound of the present invention include a hydantoin derivative represented by the following general formula (1a), a pharmacologically acceptable salt thereof, or a hydrate thereof.

In formula (1a), R ^1a has a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, and a substituent. An optionally substituted C ₆ -C ₁₀ aryl group or an optionally substituted C ₇ -C ₁₂ aralkyl group,
X ^a represents the general formula (2c),
Y ^a represents a single bond, methylene, oxygen atom, sulfur atom or —NR ^6a — (R ^6a represents a hydrogen atom or an optionally substituted C ₁ -C ₆ alkyl group);
Z ^a is a hydrogen atom, an optionally substituted C ₁ to C ₆ alkoxy group, an optionally substituted C ₃ to C ₆ cycloalkyloxy group, or an optionally substituted C _6. It represents ~ _{C 10} aryloxy group,
Ring A ^a represents ^a C ₆ -C ₁₀ aryl group which may have a substituent or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent,
Ring B ^a is an optionally substituted C _{3 ~} C ₆ cycloalkyl group, a saturated heterocyclic group of 5- or 6-membered and may have a substituent, an optionally substituted C ₆ ~ C ₁₀ represents an aromatic heterocyclic group of the aryl group or 5-membered may have a substituent or 6-membered,
R ^2a and R ^3a are the same or different and are a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group or a substituted group. Represents a C ₆ -C ₁₀ aryl group which may have a group, or R ^2a and R ^3a are bonded to each other, together with the carbon atom to which R ^2a and R ^3a are bonded, the general formula (6a).

In formula (2c), T ² represents a single bond or methylene, and A ³ represents general formula (3c) or general formula (4b).

In formula (3c), R ^5b and R ^{5b ′} are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a substituent.

In the formula (4b), R ^5b represents the same meaning as described above.

In the formula (6a), Q ^2a represents a single bond, a methylene, an oxygen atom, a sulfur atom, —NR ^7a — (R ^7a represents a hydrogen atom or an optionally substituted C ₁ -C ₆ alkyl group). And m and n are the same or different and represent 1 or 2.

The compound of the present invention is preferably a compound represented by the above general formula (1a), more preferably a compound represented by the following general formula (1b), and represented by the following general formula (1c). More preferably, it is a compound.

In the formula (1b), R ^1b represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or the general formula (8),
^Xb represents general formula (9), general formula (10), or general formula (11),
Y ^b represents an oxygen atom or a sulfur atom,
Z ^b represents a hydrogen atom or a C ₁ -C ₆ alkoxy group,
Ring A ^b represents a _C 6 _{~ C 10} aryl group or pyridyl group,
Ring B ^b is (1) a C ₃ -C ₆ cycloalkyl group,
(2) a piperidinyl group optionally substituted with a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ aliphatic acyl group or a C ₂ -C ₇ alkoxycarbonyl group, or (3) a halogen atom, C ₁ -C _{A 6} alkyl group, a C ₁ -C ₆ alkoxy group, a C ₂ -C ₇ alkoxycarbonyl group, a cyano group, an amino group optionally substituted with 1 or 2 C ₁ -C ₆ alkyl groups, a hydroxycarbonyl group, or Represents a C ₆ -C ₁₀ aryl group optionally substituted by an aminocarbonyl group,
R ^2b and R ^3b are the same or different and each represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group, general formula (12), or R ^2b and R ^3b are bonded to each other. , R ^2b and R ^3b together with the carbon atom to which general formula (6b) is represented.

In the formula (8), R ⁹ represents a hydroxyl group, a C ₇ to C ₁₂ aralkyloxy group or a 3 to 6-membered cyclic amino group, and v represents an integer of 1 to 6.

In the formula (12), R ¹⁰ represents a hydroxycarbonyl group or a C ₈ to C ₁₃ aralkyloxycarbonyl group, and w represents an integer of 1 to 6.

In the formula (6b), m and n have the same meaning as described above.

In the formula (1c), R ¹¹ represents a halogen atom, a C ₂ -C ₇ alkoxycarbonyl group, a cyano group, or an amino group optionally substituted with 1 or 2 C ₁ -C ₆ alkyl groups, ^1b , R ^2b , R ^3b and Z ^b are as defined above.

The compound represented by the general formula (1) includes (R) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2 from the viewpoint of an excellent AMPK activating action. -Methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
(S) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-5,5-dimethylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
3- (2,4-dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenyl] benzamide,
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-tert-butoxycarbonylpiperidin-1-yloxy) phenylmethyl] benzamide;
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenylthio) phenylmethyl] benzamide,
5- (2,4-Dioxo-8-oxa-1,3-diazaspiro [4.5] decan-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide ,
5- (2,4-dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-3-butylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-3-cyclopropylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
5- (2,4-dioxo-3- (2-hydroxyethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
5- (2,4-dioxo-3- (2-morpholinoethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide or 5- (2 , 4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-cyanophenoxy) phenylmethyl] benzamide is preferred.

The definition in the formula of the compound represented by the present invention will be described below.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Examples of the “C ₁ -C ₆ alkyl group” include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a t-butyl group, an n-pentyl group, and an n-hexyl group. And straight chain or branched hydrocarbon groups having 1 to 6 carbon atoms.

Examples of the “C ₃ -C ₆ cycloalkyl group” include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

Examples of the “C ₆ -C ₁₀ aryl group” include a phenyl group and a naphthyl group.

Examples of the “C ₇ -C ₁₂ aralkyl group” include a benzyl group, a naphthylmethyl group, a phenethyl group, and a phenylpropyl group.

Examples of the “C ₁ -C ₆ alkoxy group” include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butyloxy group, t-butyloxy group, n-pentyloxy group or n-hexyloxy group. Groups.

Examples of the “C ₃ -C ₆ cycloalkyloxy group” include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

Examples of the “C ₆ -C ₁₀ aryloxy group” include a phenoxy group and a naphthoxy group.

Examples of the “C ₇ -C ₁₂ aralkyloxy group” include a benzyloxy group and a phenethyloxy group.

Examples of the “C ₂ -C ₇ alkoxycarbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, and a t-butyloxycarbonyl group.

Examples of the “C ₈ -C ₁₃ aralkyloxycarbonyl group” include a benzyloxycarbonyl group.

Examples of the “C ₁ -C ₆ alkylthio group” include methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, t-butylthio group, n-pentylthio group, and n-hexylthio group. Can be mentioned.

Examples of the “C ₆ -C ₁₀ arylthio group” include a phenylthio group and a naphthylthio group.

Examples of the “C ₇ -C ₁₂ aralkylthio group” include a benzylthio group and a phenethylthio group.

Examples of the “C ₁ -C ₆ alkylsulfinyl group” include a methanesulfinyl group and an ethanesulfinyl group.

Examples of the “C ₆ -C ₁₀ arylsulfinyl group” include a benzenesulfinyl group and a naphthylsulfinyl group.

Examples of the “C ₁ -C ₆ alkylsulfonyl group” include a methanesulfonyl group and an ethanesulfonyl group.

Examples of the “C ₆ -C ₁₀ arylsulfonyl group” include a benzenesulfonyl group and a naphthylsulfonyl group.

Examples of the “C ₁ -C ₆ alkylsulfonyloxy group” include a methanesulfonyloxy group and an ethanesulfonyloxy group.

Examples of the “C ₆ -C ₁₀ arylsulfonyloxy group” include a benzenesulfonyloxy group and a naphthylsulfonyloxy group.

Examples of the “C ₁ -C ₆ aliphatic acyl group” include a formyl group, an acetyl group, and a propanoyl group.

Examples of the “C ₇ -C ₁₂ aromatic acyl group” include a benzoyl group.

The “3- to 6-membered cyclic amino group” is a 3- to 6-membered saturated cyclic group containing one or more nitrogen atoms. Examples of the “3- to 6-membered cyclic amino group” include an aziridyl group, an azetidyl group, a pyrrolidyl group, a piperidyl group, a piperazyl group, a morpholyl group, or a thiomorpholyl group.

The “5-membered or 6-membered saturated heterocyclic group” is a 5-membered or 6-membered saturated cyclic group containing one or more nitrogen, oxygen and / or sulfur atoms. Examples of the “5-membered or 6-membered saturated heterocyclic group” include pyrrolidyl group, piperidyl group, piperazyl group, morpholyl group, thiomorpholyl group, tetrahydrofuranyl group, and pyranyl group.

The “5-membered or 6-membered aromatic heterocyclic group” is a 5-membered or 6-membered aromatic ring group containing 1 to 3 nitrogen, oxygen and / or sulfur atoms. Examples of the “5-membered or 6-membered aromatic heterocyclic group” include furanyl group, thienyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, isoxazolyl group, isothiazolyl group, triazolyl group, oxadiazolyl group, thiadiazolyl group , Pyridyl group, pyrimidyl group, pyridazyl group or pyratyl group.

“Fused heterocyclic group” means a benzene condensed ring of “5-membered or 6-membered aromatic heterocyclic group” or two fragrances arbitrarily selected from “5-membered or 6-membered aromatic heterocyclic group” A condensed ring group composed of a heterocyclic group. As the `` fused heterocyclic group '', for example, indolyl group, benzoxazolyl group, benzothiazolyl group, benzofuranyl group, benzothienyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, quinoxalyl group, imidazopyridyl group, Examples include a pyrazolopyridyl group or an imidazopyrimidyl group.

“C ₁ -C ₆ alkyl group which may have a substituent”, “C ₃ -C ₆ cycloalkyl group which may have a substituent”, “C ₆ -C which may have a substituent” ₁₀ aryl group ”,“ optionally substituted C ₇ -C ₁₂ aralkyl group ”, optionally substituted C ₁ -C ₆ alkoxy group”, “optionally substituted C _“3 -C ₆ cycloalkyloxy group”, “optionally substituted C ₆ -C ₁₀ aryloxy group”, “optionally substituted C ₇ -C ₁₂ aralkyloxy group”, “substituted” C ₂ -C ₇ alkoxycarbonyl group which may have a group ”,“ C ₈ -C ₁₃ aralkyloxycarbonyl group which may have a substituent ”,“ C ₁ -C which may have a substituent ” ₆ alkylthio group "," an optionally substituted _C 6 _{~ C 10} arylthio group "," substituted Good _C 7 _{~ C 12} aralkylthio group which may have "," an optionally substituted _C 1 ~ _{C 6} alkylsulfonyl group "," an optionally substituted _C 6 _{~ C 10} aryl “Sulfonyl group”, “optionally substituted C ₁ -C ₆ alkylsulfonyloxy group”, “optionally substituted C ₆ -C ₁₀ arylsulfonyloxy group”, “with substituent C ₁ -C ₆ aliphatic acyl group ”,“ C ₇ -C ₁₂ aromatic acyl group optionally having substituent ”,“ 3-6 membered cyclic amino optionally having substituent ” A group, a 5- or 6-membered saturated heterocyclic group which may have a substituent, a 5- or 6-membered aromatic heterocyclic group which may have a substituent, and a substituent. Examples of the “substituent” in the condensed heterocyclic group which may have include, for example, a halogen atom, 1 to 3 Optionally substituted with Gen atoms _C 1 ~ _{C 6} alkyl _group, C 3 ~ _{C 6} cycloalkyl group, one to three optionally substituted with a halogen atom _C 1 ~ _{C 6} alkoxy group, _{C 7} -C ₁₂ aralkyloxy group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, C ₂ -C ₇ alkoxycarbonyl group, C ₈ -C ₁₃ aralkyloxycarbonyl Group, hydroxyl group, nitro group, amino group optionally substituted by 1 or 2 C ₁ -C ₆ alkyl groups, 3- to 6-membered cyclic amino group, cyano group, hydroxycarbonyl group, formyl group or aminocarbonyl Groups.

Examples of the “amino group which may have a substituent” include an amino group which may be substituted with one or two C ₁ to C ₆ alkyl groups, and examples thereof include an amino group and a methylamino group. Or a dimethylamino group is mentioned.

Examples of “C ₁ -C ₄ alkylene” include linear or branched alkylene having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene, methylethylene or dimethylmethylene.

Examples of “C ₂ -C ₄ alkenylene” include linear or branched alkenylene having 1 to 4 carbon atoms such as vinylene, propenylene or methylethenylene.

Examples of “C ₂ -C ₄ alkynylene” include linear or branched alkynylene having 1 to 4 carbon atoms such as ethynylene, propynylene, or 3-methylpropynylene.

The compound of the present invention can be converted into a pharmacologically acceptable salt if necessary. Examples of pharmacologically acceptable salts include inorganic acid salts such as “hydrochloric acid, hydrobromic acid, sulfuric acid”, “acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, methanesulfonic acid, tosylic acid”. Or a basic salt with a base such as “sodium salt, potassium salt, calcium salt”.

Further, the compound of the present invention and its pharmacologically acceptable salt may be an inner salt, anhydride, hydrate or solvate thereof.

The compounds of the present invention include optical isomers based on asymmetric carbon, geometric isomers, stereoisomers, tautomers and the like, and all such isomers and mixtures thereof are of the present invention. It is included in the range.

The pharmaceutical of the present invention can be administered by parenteral means such as oral or subcutaneous, intravenous or intramuscular.

In order to use the compound of the present invention, a pharmacologically acceptable salt thereof or a hydrate thereof as a medicine, it may be in the form of a solid composition, a liquid composition or other composition, and is optimal as necessary. Is selected. The medicament of the present invention can also be produced by blending a pharmacologically acceptable carrier with the compound of the present invention. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusters, solubilizers or aqueous or non-aqueous solvents are added, and tablets are prepared by conventional formulation techniques. , Pills, capsules, granules, powders, powders, solutions, emulsions, suspensions or injections.

The compound of the present invention has an excellent AMPK activating action, and exhibits an excellent blood glucose lowering action and lipid lowering action in vivo. The compound of the present invention is useful as an active ingredient of an AMPK activator, lipid lowering agent, arteriosclerosis preventive or therapeutic agent, diabetes preventive or therapeutic agent, obesity preventive or therapeutic agent, or cancer therapeutic agent.

The compound represented by the general formula (1) which is the compound of the present invention can be produced by the method shown in Production Method 1 or a combination of known methods.

[Production Method 1]

In the formula, W ¹ represents a leaving group, R ^a represents a C ₁ -C ₆ alkyl group which may have a substituent or a C ₇ -C ₁₂ aralkyl group which may have a substituent, R ¹ , R ² , R ³ , X, Y, Z, Ring A and Ring B have the same meaning as described above.

Here, examples of the leaving group represented by W ¹ include a halogen atom, an optionally substituted C ₁ to C ₆ alkylsulfonyloxy group, a phenylsulfonyloxy group, or a p-tolylsulfonyloxy group. And a C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with a C ₁ -C ₆ alkyl group.

Conversion of the compound represented by the general formula (13) and the compound represented by the general formula (14) to the compound represented by the general formula (15) (Step 1-A) can be carried out by using an appropriate solvent such as methanol. A compound represented by general formula (13) and a compound represented by general formula (14) using a reducing agent such as sodium triacetoxyborohydride in ethanol, dichloromethane, chloroform, acetic acid or a mixture thereof Can be carried out at 0 to 100 ° C. for 5 minutes to 24 hours.

Conversion of the compound represented by the general formula (16) and the compound represented by the general formula (17) into the compound represented by the general formula (15) (Step 1-B) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide or N-methylpyrrolidinone or a mixture thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen A compound represented by the general formula (16) and a compound represented by the general formula (17) at −78 ° C. to 120 ° C. for 10 minutes to 100 hours in the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine. It can be performed by reacting.

Conversion from the compound represented by the general formula (15) to the compound represented by the general formula (18) (Step 1-C) is carried out by using an appropriate solvent such as toluene, tetrahydrofuran, dichloromethane, chloroform or N, N- In dimethylformamide or a mixture thereof, the compound represented by the general formula (15) and an isocyanate such as methyl isocyanate, ethyl isocyanate, phenyl isocyanate, or trimethylsilyl isocyanate are added in the presence of a base such as pyridine or triethylamine as necessary. The reaction can be carried out by reacting at ˜150 ° C. for 5 minutes to 48 hours.

In the case where R ¹ represents a hydrogen atom, the compound represented by the general formula (15) in the presence of an acid such as hydrochloric acid or acetic acid in a suitable solvent such as tetrahydrofuran, 1,4-dioxane, methanol or ethanol, or a mixture thereof. It can also be carried out by reacting a compound represented by the above with an isocyanate such as sodium isocyanate or potassium isocyanate at 0 to 130 ° C. for 5 minutes to 12 hours.

Conversion of the compound represented by the general formula (18) to the compound represented by the general formula (1) (Step 1-D) is carried out by using an appropriate solvent such as toluene, tetrahydrofuran, dichloromethane or N, N-dimethylformamide. Or in a mixed solution thereof, etc., in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine, if necessary. Alternatively, the reaction can be carried out by reacting the compound represented by the general formula (18) at 0 to 130 ° C. for 5 minutes to 12 hours in the presence of an acid such as hydrochloric acid or acetic acid.

The compound represented by the general formula (1), which is the compound of the present invention, can also be synthesized by the synthesis method shown in Production Method 2.

[Production Method 2]

In the formula, R ¹ , R ² , R ³ , R ^a , W ¹ , X, Y, Z, Ring A, and Ring B are as defined above.

Conversion of the compound represented by general formula (13) and the compound represented by general formula (19) into the compound represented by general formula (20) (step 2-A) is the same as step 1-A. It can be done by a method.

Conversion of the compound represented by the general formula (16) and the compound represented by the general formula (21) into the compound represented by the general formula (20) (step 2-B) is the same as in step 1-B. It can be done by a method.

Conversion of the compound represented by the general formula (20) and the compound represented by the general formula (22) to the compound represented by the general formula (23) (Step 2-C) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide or N-methylpyrrolidinone or a mixture thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen A compound represented by the general formula (20) and a compound represented by the general formula (22) at −78 ° C. to 120 ° C. for 10 minutes to 100 hours in the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine. It can be performed by reacting.

Conversion from the compound represented by the general formula (23) to the compound represented by the general formula (1) (Step 2-D) is carried out by using an appropriate solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide. , Methanol or ethanol or a mixed solution thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine The reaction can be carried out by reacting the compound represented by the general formula (23) at 0 to 130 ° C. for 5 minutes to 12 hours in the presence of a base.

The compound represented by the general formula (1) which is the compound of the present invention can also be synthesized by the synthesis method shown in Production Method 3.

[Production Method 3]

In the formula, R ¹ , R ² , R ³ , W ¹ , X, Y, Z, Ring A, and Ring B are as defined above.

Conversion of the compound represented by the general formula (24) and the compound represented by the general formula (25) into the compound represented by the general formula (1) (Step 3-A) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide, N-methylpyrrolidinone or a mixed solution thereof such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen A compound represented by the general formula (24) and a compound represented by the general formula (25) at −78 ° C. to 120 ° C. for 10 minutes to 100 hours in the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine. It can be performed by reacting.

Among the compounds represented by the general formula (1) that are the compounds of the present invention, the compound represented by the general formula (1e) can also be synthesized by the synthesis method shown in Production Method 4.

[Production Method 4]

In the formula, R ^1d is an ^optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, and an optionally substituted C _6- A C ₁₀ aryl group, an optionally substituted C ₇ to C ₁₂ aralkyl group, an optionally substituted 5-membered or 6-membered aromatic heterocyclic group, or an optionally substituted condensed group Represents a heterocyclic group, W ² represents a leaving group or boric acid, and R ² , R ³ , X, Y, Z, Ring A, and Ring B have the same meaning as described above.

Here, as the leaving group represented by W ² , a halogen atom, a C ₁ -C ₆ alkylsulfonyloxy group which may have a substituent, a phenylsulfonyloxy group or a p-tolylsulfonyloxy group such as a lower group. And a C ₆ -C ₁₀ arylsulfonyloxy group which may be substituted with an alkyl group.

In the conversion of the compound represented by the general formula (1d) and the compound represented by the general formula (26) to the compound represented by the general formula (1e) (Step 4-A), W ² represents a leaving group. In the case of expression, it can be carried out by the same method as in Step 3-A.

When W ² represents boric acid, pyridine, triethylamine, 4- (dimethyl) in a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide or a mixture thereof. Amino) bases such as pyridine, sodium carbonate or cesium carbonate, metals such as copper acetate, and compounds represented by the general formula (1d) in the presence of a ligand such as pyridine, triethylamine or 2,2-bipyridine if necessary The reaction can be carried out by reacting the compound represented by the formula (26) at 0 to 150 ° C. for 30 minutes to 48 hours.

The compound represented by the general formula (1d), of the production method 1 may be produced according to the manufacturing technique when R ¹ represents a hydrogen atom.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compound represented by the general formula (1f) can also be synthesized by the synthesis method shown in Production Method 5.

[Production Method 5]

In the formula, A ^a represents an oxygen atom, a sulfur atom, —NR ⁴ —, PG ¹ represents a protecting group, R ^1d , R ² , R ³ , T, U, W ¹ , Y, Z, Ring A, Ring B represents the same meaning as described above.

Here, the protecting group represented by PG ¹ includes an optionally substituted C ₁ -C ₆ aliphatic acyl group, C ₁ -C ₆ alkoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyl. Examples thereof include a benzyl group which may have a substituent such as a group, a trimethylsilyl group, a silyl group such as tert-butyldimethylsilyl, or a phthalimide group.

Conversion of the compound represented by the general formula (27) and the compound represented by the general formula (28) to the compound represented by the general formula (1f) (step 5-A) is carried out by using an appropriate solvent such as toluene. , Hexane, tetrahydrofuran, diethyl ether, dichloromethane, N, N-dimethylformamide, N-methylpyrrolidine, dimethyl sulfoxide or acetone or a mixture thereof, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride In the presence of a base such as sodium methoxide, potassium tert-butoxide, pyridine, triethylamine or N, N-dimethylaniline, an appropriate iodide salt, such as sodium iodide, potassium iodide or tetrabutyl iodide, is used as necessary. Ammonium or the like is added to form a general formula (27) A compound represented by the general formula (28) compound represented by can be carried out by reacting for 1 to 100 hours at -15 ~ 120 ° C..

Conversion from the compound represented by the general formula (27a) to the compound represented by the general formula (29) (Step 5-B) can be carried out without a solvent or an appropriate solvent such as dichloromethane, chloroform, tetrahydrofuran or benzene or these By reacting the compound represented by the general formula (27a) at −20 to 80 ° C. for 0.5 to 6 hours using a halogenating agent such as thionyl chloride, phosphorus oxychloride or thionyl bromide. It can be carried out. Or a suitable sulfonylating agent such as methanesulfonyl chloride or trifluoromethanesulfonic acid in the presence of a base such as triethylamine or pyridine in a suitable solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide or a mixture thereof. The reaction can be carried out by reacting the compound represented by the general formula (27a) at −20 to 60 ° C. for 0.5 to 3 hours using an anhydride or the like.

In addition, a compound represented by the general formula (27a) is obtained by using carbon tetrabromide, carbon tetrachloride or iodine in the presence of triphenylphosphine in a suitable solvent such as dichloromethane, chloroform or tetrahydrofuran or a mixture thereof. It can also be carried out by reacting at −20 to 60 ° C. for 0.5 to 3 hours.

Conversion of the compound represented by the general formula (29) and the compound represented by the general formula (30) into the compound represented by the general formula (1f) (step 5-C) is carried out by using an appropriate solvent such as toluene. 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide or N-methylpyrrolidinone or a mixture thereof, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogen In the presence of a base such as sodium chloride, triethylamine, diisopropylethylamine or pyridine, the compound represented by the general formula (29) and the compound represented by the general formula (30) at −78 ° C. to 120 ° C. for 10 minutes to 100 hours. It can be performed by reacting.

Conversion from the compound represented by the general formula (31) to the compound represented by the general formula (27) (Step 5-D) can be performed by a known method such as Protecting Groups in Organic Synthesis [John Wiley and Sons (1999). )] And the like.

For example, a method using an acid, a base, ultraviolet rays, hydrazine, tetrabutylammonium fluoride, trimethylsilyl iodide, or the like, or a reduction method may be mentioned.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compound represented by the general formula (1g) can also be synthesized by the synthesis method shown in Production Method 6.

[Production Method 6]

In the formula, Ring A ¹ may have a C ₆ -C ₁₀ aryl group which may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent, or a substituent. It represents a good fused heterocyclic group, and U, Y, Z, R ^1d , R ² , R ³ and Ring B have the same meaning as described above.

Conversion of the compound represented by the general formula (27a) and the compound represented by the general formula (30a) into the compound represented by the general formula (1g) (Step 6-A) is carried out by using an appropriate solvent such as toluene. In the presence of an organophosphorus compound such as triphenylphosphine or tributylphosphine in hexane or tetrahydrofuran or a mixture thereof, an electrophilic agent such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or dipiperidine azodicarboxylate is used. The reaction can be carried out by reacting the compound represented by (27a) with the compound represented by the general formula (30a) at 0 to 60 ° C. for 3 to 24 hours. Alternatively, it is represented by the general formula (27a) using a phospholane compound such as cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane in an appropriate solvent such as toluene, benzene, hexane, tetrahydrofuran, or a mixed solution thereof. The reaction can be carried out by reacting the compound and the compound represented by the general formula (30a) at room temperature to 120 ° C. for 1 to 24 hours.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compound represented by the general formula (1h) can also be synthesized by the synthesis method shown in Production Method 7.

[Production Method 7]

In the formula, R ^a and R ^b are the same or independently a C ₁ to C ₆ alkyl group or a C ₇ to C ₁₂ aralkyl group which may have a substituent, or R ^a and R ^b are together. Represents a C ₂ -C ₄ straight chain alkylene, wherein T ^a represents ^a single bond, C ₁ -C ₃ alkylene, C ₂ -C ₃ alkenylene or C ₂ -C ₃ alkynylene, and U ^a Represents a single bond, C ₁ -C ₃ alkylene or C ₂ -C ₃ alkenylene, R ¹ , R ² , R ³ , R ⁴ , T, U, Y, Z, Ring A, Ring B are the same as those described above. Represents significance.

Conversion of the compound represented by the general formula (27b) and the compound represented by the general formula (32) into the compound represented by the general formula (1h) (Step 7-A) is carried out by using an appropriate solvent such as methanol. , Lithium borohydride, hydrogenation in the presence of acids such as hydrochloric acid, hydrobromic acid or acetic acid, or Lewis acids such as aluminum chloride or zinc chloride in ethanol, dichloromethane or chloroform or a mixture thereof. Using a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, the compound represented by the general formula (27b) and the compound represented by the general formula (32) are heated at 0 to 80 ° C. The reaction can be carried out by reacting for 1 to 24 hours.

The conversion from the compound represented by the general formula (33) and the compound represented by the general formula (30b) to the compound represented by the general formula (1h) (Step 7-B) is the same as in Step 7-A. It can be done by a method.

The conversion from the compound represented by the general formula (34) to the compound represented by the general formula (33) (Step 7-C) is described in, for example, Protecting Groups in Organic Synthesis (John Wiley and Sons (1999)). This can be done by deprotection according to the above method.

For example, in the absence of a solvent or an appropriate solvent such as water, acetic acid, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof, an acid such as hydrochloric acid, sulfuric acid or nitric acid is used. ) Is hydrolyzed at 0 to 100 ° C. for 1 to 48 hours.

Or metal such as palladium activated carbon, palladium activated carbon-ethylenediamine complex, platinum activated carbon, platinum oxide or rhodium-supported alumina in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof. The reaction can be carried out by reducing the compound represented by the general formula (34) at 0 to 80 ° C. for 0.5 to 12 hours in the presence of a catalyst in a hydrogen atmosphere at normal pressure to 0.5 MPa.

Among the compounds represented by the general formula (1) that are the compounds of the present invention, the compound represented by the general formula (1i) can also be synthesized by the synthesis method shown in Production Method 8.

[Production Method 8]

In the formula, R ¹ , R ² , R ³ , R ⁵ , R ^a , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above.

Conversion of the compound represented by the general formula (35) and the compound represented by the general formula (30c) into the compound represented by the general formula (1i) (Step 8-A) is carried out by using a suitable solvent such as dichloromethane, In chloroform, tetrahydrofuran, diethyl ether or N, N-dimethylformamide or a mixture thereof, a base such as pyridine, triethylamine, N-methylmorpholine or 4- (dimethylamino) pyridine, and if necessary, N-hydroxybenzotriazole, N Dicyclohexylcarbodiimide, 3- (3-dimethylaminopropyl) -1-ethyl in the presence of a reaction aid such as -hydroxysuccinimide or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine Carbodiimide hydrochloride, diethyl cyanophosphate, dipheny Using a condensing agent such as phosphoric acid azide or carbonyldiimidazole, the compound represented by the general formula (35) and the compound represented by the general formula (30c) are reacted at −15 to 120 ° C. for 0.5 to 24 hours. It can be performed by reacting.

In addition, the compound represented by the general formula (35) may be used in the absence of a solvent or in a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixture thereof, as necessary, with pyridine or triethylamine. In the presence of a base such as thionyl chloride, thionyl bromide, acetic anhydride or ethyl chlorocarbonate, the compound represented by the general formula (35) is reacted at −15 to 50 ° C. for 5 minutes to 6 hours to give a carboxyl group. Is converted to a reactive derivative group such as acid chloride, acid bromide or acid anhydride, and then in a suitable solvent such as toluene, tetrahydrofuran, dichloromethane or N, N-dimethylformamide or a mixture thereof, pyridine, triethylamine or Represented by the general formula (30c) in the presence of a base such as 4- (dimethylamino) pyridine. That a compound can be carried out by reacting 15 minutes to 12 hours at -78 ~ 50 ° C..

Conversion from the compound represented by the general formula (36) to the compound represented by the general formula (35) (Step 8-B) can be carried out without a solvent or in a suitable solvent such as water, acetic acid, methanol, ethanol, In dichloromethane, tetrahydrofuran or 1,4-dioxane or a mixture thereof, an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid or nitric acid, or a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate Can be used by hydrolyzing the compound represented by the general formula (36) at 0 to 150 ° C. for 0.5 to 100 hours.

In addition, metals such as palladium activated carbon, palladium activated carbon-ethylenediamine complex, platinum activated carbon, platinum oxide, or rhodium-supported alumina in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide, or a mixture thereof. The reaction can also be carried out by reducing the compound represented by the general formula (36) at 0 to 80 ° C. for 0.5 to 12 hours in the presence of a catalyst in a hydrogen atmosphere at normal pressure to 0.5 MPa.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compound represented by the general formula (1j) can also be synthesized by the synthesis method shown in Production Method 9.

[Production Method 9]

In the formula, R ¹ , R ² , R ³ , R ⁵ , T, U, Y, Z, Ring A and Ring B have the same meaning as described above.

The conversion from the general formula (27b) and the general formula (37) to the general formula (1j) (step 9-A) can be performed by the same method as in the step 8-A.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compound represented by the general formula (1k) can also be synthesized by the synthesis method shown in Production Method 10.

[Production method 10]

In the formula, A ^b represents an oxygen atom or —NR ⁵ —, and R ¹ , R ² , R ³ , R ⁵ , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above. .

Conversion of the compound represented by the general formula (27c) and the compound represented by the general formula (30c) into the compound represented by the general formula (1k) (Step 10-A) is carried out by using an appropriate solvent such as toluene. , Tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixture thereof, etc., if necessary, using a carbonyldiimidazole in the presence of a base such as pyridine or triethylamine, and a compound represented by the general formula (27c) The reaction can be carried out by reacting the compound represented by the formula (30c) at 0 to 60 ° C. for 0.5 to 12 hours.

When the compound represented by the general formula (1k) is a compound in which R ⁵ is a hydrogen atom, the production of the compound represented by the general formula (1k) (Step 10-B) can be carried out using an appropriate solvent, for example, A compound represented by the general formula (27c) and a general formula (38) in the presence of a base such as pyridine or triethylamine in toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixture thereof, if necessary. The reaction can also be carried out by reacting the compound obtained at 0 to 60 ° C. for 0.5 to 12 hours.

Compound represented by the general formula (1k) is, if ^{A b} is a compound which is -NH-, production of the compound represented by the general formula (1k) (Step 10-C) has the general formula (35) In a suitable solvent such as toluene, benzene, diphenyl ether, tetrahydrofuran, acetonitrile, N, N-dimethylformamide or a mixture thereof, diphenyl phosphate azide and 0 in the presence of a base such as pyridine or triethylamine. It can also be carried out by reacting at −120 ° C. for 0.5 to 12 hours and then reacting with the general formula (30c) at 0 to 80 ° C. for 1 to 12 hours.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compound represented by the general formula (1l) can also be synthesized by the synthesis method shown in Production Method 11.

[Production Method 11]

Conversion of the compound represented by the general formula (27b) and the compound represented by the general formula (30d) into the compound represented by the general formula (1l) (step 11-A) is the same method as in step 10-A Can be performed.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compounds represented by the general formula (1m) and the general formula (1n) can also be synthesized by the synthesis method shown in the production method 12.

[Production method 12]

In the formula, W ³ represents a halogen atom, r and t are the same or different and are 0, 1 or 2, and r + t represents 0, 1 or 2, k represents 2, 3 or 4, R ^1d , R ² , R ³ , Y, Z, Ring A and Ring B have the same meaning as described above.

The conversion from the compound represented by the general formula (29a) and the compound represented by the general formula (32a) to the compound represented by the general formula (1m) (step 12-A) is first performed by the general formula (29a). In the absence of solvent or in an appropriate solvent such as toluene, tetrahydrofuran or benzene or a mixture thereof, an organic phosphorus compound such as triphenylphosphine or triethyl phosphite is used at −78 to 120 ° C. After reacting for 1 to 12 hours, sodium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide or potassium tert- in a suitable solvent such as toluene, tetrahydrofuran, diethyl ether or dimethyl sulfoxide or a mixture thereof. In the presence of a base such as butoxide, it is represented by the general formula (32a). Compound can be carried out by reacting 1 to 12 hours at -78 ~ 120 ° C..

Conversion of the compound represented by the general formula (33a) and the compound represented by the general formula (39) into the compound represented by the general formula (1m) (step 12-B) is the same method as in step 12-A Can be performed.

Conversion from the compound represented by the general formula (1m) to the compound represented by the general formula (1n) (Step 12-C) can be carried out by using a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran or N, N -In the presence of a metal catalyst such as palladium activated carbon, palladium activated carbon-ethylenediamine complex, platinum activated carbon, platinum oxide or rhodium-supported alumina in dimethylformamide or a mixed solution thereof, in the hydrogen atmosphere at atmospheric pressure to 0.5 MPa, the general formula (1 m ) Is reduced at 0 to 80 ° C. for 0.5 to 12 hours.

Among the compounds represented by the general formula (1) which are the compounds of the present invention, the compound represented by the general formula (1o) can also be synthesized by the synthesis method shown in Production Method 13.

[Production method 13]

In the formula, R ^1d , R ² , R ³ , W ³ , Y, Z, Ring A, Ring B, r, and t have the same meaning as described above.

Conversion of the compound represented by the general formula (29aa) and the compound represented by the general formula (40) into the compound represented by the general formula (1o) (Step 13-A) is carried out by using an appropriate solvent such as toluene. In the presence of a base such as sodium hydride, n-butyllithium, lithium amide or potassium carbonate, etc. in tetrahydrofuran, diethyl ether, dimethyl sulfoxide, hexamethylphosphoric triamide, or a mixture thereof, an appropriate iodide salt may be used as necessary. For example, by adding sodium iodide, copper (I) iodide, tetrabutylammonium iodide, or the like, the compound represented by the general formula (29aa) and the compound represented by the general formula (40) are converted to -78. The reaction can be carried out by reacting at ˜120 ° C. for 1 to 12 hours.

In the present specification, among the compound represented by the general formula (16), the compound represented by the general formula (13), the compound represented by the general formula (25), and the compound represented by the general formula (25) The compound represented by the general formula (25a) can be synthesized by the synthesis method shown in Production Method 14.

[Production Method 14]

In the formula, R ^c represents a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted C ₇ -C ₁₂ aralkyl group, and W ¹ , X, Y, Z, Ring A and Ring B have the same meaning as described above.

Conversion from the compound represented by the general formula (41) to the compound represented by the general formula (25a) (Step 14-A) is carried out by using an appropriate solvent such as tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol. A compound represented by the general formula (41) using a reducing agent such as lithium borohydride, borane / dimethyl sulfide complex, lithium aluminum hydride or diisobutylaluminum hydride in ethanol, dichloromethane, or a mixed solution thereof; The reaction can be carried out at 78 to 110 ° C. for 1 to 24 hours.

Conversion from the compound represented by the general formula (41) to the compound represented by the general formula (13) (Step 14-B) is carried out by using an appropriate solvent such as tetrahydrofuran, diethyl ether, methanol, ethanol or dichloromethane, or these. Can be carried out by reacting the compound represented by the general formula (41) at −78 to 60 ° C. for 1 to 24 hours using a reducing agent such as diisobutylaluminum hydride.

Conversion of the compound represented by the general formula (25a) to the compound represented by the general formula (13) (Step 14-C) is carried out by using an appropriate solvent such as toluene, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide or acetone. Alternatively, the compound represented by the general formula (25a) is reacted with an oxidizing agent such as Jones reagent, PCC, PDC, manganese dioxide or oxalic chloride (Swern oxidation) at −78 to 80 ° C. for 1 to 48 hours. Can be performed.

Conversion of the compound represented by the general formula (13) to the compound represented by the general formula (25a) (Step 14-D) is carried out by using a suitable solvent such as tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol. A compound represented by the general formula (13) is -78 using a reducing agent such as lithium borohydride, sodium borohydride, lithium aluminum hydride or diisobutylaluminum hydride in ethanol, dichloromethane or a mixture thereof. It can be carried out by reacting at ˜150 ° C. for 1 to 24 hours.

The conversion from the compound represented by the general formula (25a) to the compound represented by the general formula (25) (step 14-E) can be performed by the same method as in step 5-B.

Conversion of the compound represented by the general formula (25a) to the compound represented by the general formula (16) (Step 14-F) is carried out by using an appropriate solvent such as chlorobenzene, acetonitrile, ethylene glycol, N, N-dimethyl. Electrophilic agent such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or dipiperidine azodicarboxylate in the presence of an organic phosphorus compound such as triphenylphosphine or tributylphosphine in formamide, dimethyl sulfoxide or hexamethylphosphoric triamide or a mixture thereof After reacting the compound represented by the general formula (25a) with phthalimide or a salt thereof at 0 to 60 ° C. for 1 to 24 hours, a suitable solvent such as methanol, ethanol or tetrahydrofuran, or a mixture thereof, etc. Medium, acid, base It can be carried out by the using a hydrazine is reacted for 1 to 24 hours at 0 ~ 100 ° C..

Conversion from the compound represented by the general formula (13) to the compound represented by the general formula (16) (Step 14-G) is carried out by using an appropriate solvent such as methanol, ethanol, dichloromethane or chloroform, or a mixture thereof. Medium, lithium borohydride, sodium borohydride, sodium cyanoborohydride or triacetoxy in the presence of acids such as hydrochloric acid, hydrobromic acid or acetic acid, or Lewis acids such as aluminum chloride or zinc chloride as required Using a reducing agent such as sodium borohydride, the compound represented by the general formula (13) is reacted with hydroxylamine or the like at 0 to 60 ° C. for 0.5 to 24 hours, and then in a suitable solvent such as dichloromethane. , Tetrahydrofuran, ethanol, or a mixture thereof, such as iron, palladium, or zinc Under medium presence, if necessary, the presence of an acid such as acetic acid or hydrochloric acid, can be carried out by reacting 1 to 24 hours in a hydrogen stream under 0 ~ 80 ° C..

Alternatively, after reacting the compound represented by the general formula (13) with acetamide or methyl carbamate at 0 to 60 ° C. for 1 to 24 hours, an appropriate solvent such as tetrahydrofuran, methanol or ethanol, or a mixture thereof, etc. The reaction can also be carried out by reacting with acid or base at 0 to 80 ° C. for 1 to 24 hours.

Conversion of the compound represented by the general formula (25) to the compound represented by the general formula (16) (Step 14-H) is carried out by using a suitable solvent such as chlorobenzene, acetonitrile, ethylene glycol, N, N-dimethyl. In the presence of formamide, dimethyl sulfoxide or hexamethylphosphoric triamide or a mixture thereof, the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine In the following, after reacting the compound represented by the general formula (25) with phthalimide or a salt thereof at 0 to 60 ° C. for 3 to 24 hours, in a suitable solvent such as methanol, ethanol or tetrahydrofuran or a mixture thereof, acid, Such as using a group or a hydrazine can be carried out by reacting 1 to 24 hours at 0 ~ 80 ° C..

The conversion from the compound represented by the general formula (42) to the compound represented by the general formula (16) (Step 14-I) is carried out in a suitable solvent such as methanol, ethanol or tetrahydrofuran or a mixture thereof. The reaction is carried out by reacting the compound represented by the general formula (42) with hydrogen at −15 to 80 ° C. for 1 to 48 hours in the presence of aqueous ammonia in the presence of a metal catalyst such as palladium carbon, Raney nickel or platinum oxide. Can do.

Further, in an appropriate solvent such as water, ethanol, tetrahydrofuran or dichloromethane or a mixture thereof, an acid such as aluminum chloride or sulfuric acid or cobalt chloride is added as necessary, and lithium aluminum hydride or borohydride is added. The reaction can be performed by reacting with a reducing agent such as sodium at 0 to 80 ° C. for 1 to 48 hours.

In the compound represented by the general formula (41), R ^c represents a C ₁ to C ₆ alkyl group which may have a substituent or a C ₇ to C ₁₂ aralkyl group which may have a substituent. Conversion to a compound in which R ^c represents a hydrogen atom is carried out in the absence of a solvent or in a suitable solvent such as water, acetic acid, methanol, ethanol, tetrahydrofuran, 1,4-dioxane or a mixture thereof, hydrochloric acid, sulfuric acid or nitric acid. Or a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and the compound represented by the general formula (41) is hydrolyzed at 0 to 100 ° C. for 1 to 48 hours. This can be done by decomposing.

Conversion (14-J) from the compound represented by the general formula (43) to the compound represented by the general formula (42) is carried out by using an appropriate solvent such as water, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile. , N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, toluene or xylene, or a mixture thereof, if necessary, triphenylphosphine, tolylphosphine, 2-dicyclohexylphosphino-2 ′, Metal catalyst such as tetrakistriphenylphosphine, trisdibenzylideneacetone palladium, palladium acetate or copper iodide in the presence of a ligand such as 6'-dimethoxybiphenyl or diphenylphosphinoferrocene, a base such as sodium carbonate, cesium carbonate or triethylamine In the presence Cyan zinc, with a cyanating agent such as potassium ferricyanide or sodium cyanide may be performed by causing 1 to 48 hours at 0 ~ 250 ° C..

In the present specification, among the compounds represented by the general formulas (13), (41) and (42), the compound represented by the general formula (44) can be synthesized by the synthesis method shown in the production method 15.

[Production Method 15]

In the formula, J ^a represents a formyl group, a cyano group, and COOR ^a , and A ^a , R ^a , T, U, W ¹ , Y, Z, Ring A, and Ring B have the same meanings as described above.

Conversion of the compound represented by general formula (45) and the compound represented by general formula (28) into the compound represented by general formula (44) (step 15-A) is the same method as in step 5-A. Can be performed.

The conversion from the compound represented by the general formula (45a) to the compound represented by the general formula (46) (step 15-B) can be performed by the same method as that for the compound represented by step 5-B.

Conversion of the compound represented by the general formula (46) and the compound represented by the general formula (30) into the compound represented by the general formula (44) (step 15-C) is the same method as in step 5-C. Can be performed.

Among the compounds represented by the general formula (44), the compound represented by the general formula (44a) can also be synthesized by the synthesis method shown in Production Method 16.

[Production Method 16]

In the formula, J ^a , U, Y, Z, Ring A ¹ and Ring B have the same meaning as described above.

The conversion of the compound represented by general formula (30a) and the compound represented by general formula (45a) into the compound represented by general formula (44a) (step 16-A) is the same as step 6-A. It can be done by a method.

Among the compounds represented by the general formula (44), the compound represented by the general formula (44b) can also be synthesized by the synthesis method shown in Production Method 17.

[Production Method 17]

Wherein, ^{J b} represents a cyano ^{^{^{^{group, COOR a, R 4, R}}}} a, T, T a, U, U a, Y, Z, Ring A, is Ring B represents the same meaning as those described above.

The conversion of the compound represented by the general formula (45b) and the compound represented by the general formula (32) into the compound represented by the general formula (44b) (step 17-A) is the same as step 7-A. It can be done by a method.

The conversion from the compound represented by the general formula (47) and the compound represented by the general formula (30b) to the compound represented by the general formula (44b) (step 17-B) is the same as step 7-A. It can be done by a method.

Among the compounds represented by the general formula (44), the compound represented by the general formula (44c) can also be synthesized by the synthesis method shown in Production Method 18.

[Production Method 18]

In the formula, J ^a , R ⁵ , T, U, Y, Z, Ring A, and Ring B have the same meaning as described above.

Conversion of the compound represented by the general formula (30c) and the compound represented by the general formula (48) into the compound represented by the general formula (44c) (step 18-A) is the same method as in step 8-A. Can be performed.

Among the compounds represented by the general formula (44), the compound represented by the general formula (44d) can also be synthesized by the synthesis method shown in Production Method 19.

[Production Method 19]

Conversion of the compound represented by the general formula (45b) and the compound represented by the general formula (37) into the compound represented by the general formula (44d) (step 19-A) is the same method as in step 8-A. Can be performed.

Among the compounds represented by the general formula (44), the compound represented by the general formula (44e) can also be synthesized by the synthesis method shown in Production Method 20.

[Production Method 20]

^{^{Wherein, J a, R 5, T}} , U, Y, Z, Ring A, Ring B, the ^{A b} represents the same meaning as those described above.

The conversion of the compound represented by the general formula (30c) and the compound represented by the general formula (45c) into the compound represented by the general formula (44e) (step 20-A) is the same as step 10-A. It can be done by a method. *

In the case where the compound represented by the general formula (44e) is a compound in which R ⁵ is a hydrogen atom, the compound represented by the general formula (38) and the compound represented by the general formula (45c) The conversion to the compound represented by 44e) (Step 20-B) can be carried out by the same method as in Step 10-B.

Compound represented by the general formula (44e) is in the case A ^b is a compound which is a -NH-, a compound represented by the general formula (49) and the general formula (30c) generally from the compounds represented by formula Conversion to the compound represented by (44e) (Step 20-C) can be carried out in the same manner as in Step 10-C.

Among the compounds represented by the general formula (44), the compound represented by the general formula (44f) can also be synthesized by the synthesis method shown in the production method 21.

[Production method 21]

Conversion of the compound represented by the general formula (45b) and the compound represented by the general formula (30d) into the compound represented by the general formula (44f) (step 21-A) is the same method as in step 10-A Can be performed.

Among the compounds represented by the general formula (44), the compounds represented by the general formula (44g) and the general formula (44h) can also be synthesized by the synthesis method shown in the production method 22.

[Production method 22]

In the formula, J ^b , W ³ , Y, Z, Ring A, Ring B, r, t, and k have the same meaning as described above.

The conversion of the compound represented by the general formula (46a) and the compound represented by the general formula (32a) into the compound represented by the general formula (44g) (step 22-A) is the same as step 12-A. It can be done by a method.

Conversion of the compound represented by the general formula (47a) and the compound represented by the general formula (39) into the compound represented by the general formula (44g) (step 22-B) is the same method as in step 12-A Can be performed.

The conversion from the compound represented by the general formula (44g) to the compound represented by the general formula (44h) (Step 22-C) can be performed by the same method as in Step 12-C.

Among the compounds represented by the general formula (44), the compound represented by the general formula (44i) can also be synthesized by the synthesis method shown in Production Method 23.

[Production Method 23]

In the formula, J ^a , W ³ , Y, Z, Ring A, Ring B, r, and t have the same meaning as described above.

The conversion from general formula (46b) and general formula (40) to general formula (44i) (step 23-A) can be performed by the same method as in step 13-A.

In the present specification, among the compounds represented by the general formula (27), the compound represented by the general formula (27b) can also be synthesized by the synthesis method shown in the production method 24.

[Production Method 24]

In the formula, R ¹ , R ² , R ³ , R ⁴ , U, U ^a and Z have the same meaning as described above.

The conversion from the compound represented by the general formula (33) and the compound represented by the general formula (50) to the compound represented by the general formula (27b) (step 24-A) is the same as step 7-A. It can be synthesized by the method.

Among the compounds represented by the general formula (27b), the compound represented by the general formula (27e) can also be synthesized by the synthesis method shown in Production Method 25.

[Production Method 25]

In the formula, R ¹ , R ² , R ³ , U, and Z are as defined above.

Conversion of the compound represented by the general formula (51) to the compound represented by the general formula (27e) (Step 25-A) is carried out by using a suitable solvent such as methanol, ethanol, tetrahydrofuran, ethyl acetate or N, N -Performed by reacting a compound represented by the general formula (51) with hydrogen at 0 to 80 ° C for 1 to 24 hours under a metal catalyst such as palladium carbon, Raney nickel or platinum oxide in dimethylformamide or a mixture thereof. be able to.

In addition, in the absence of a solvent or a suitable solvent such as tetrahydrofuran, 1,4-dioxane, methanol or ethanol, or a mixture thereof, a general formula is used using a metal such as reduced iron or zinc in the presence of an acid such as hydrochloric acid or acetic acid. It can also be carried out by reacting the compound represented by (51) at 0 to 150 ° C. for 0.5 to 12 hours.

In the present specification, the compounds represented by the general formulas (31), (34), (36) and (51) are included in the compound represented by (56) and are also synthesized by the synthesis method shown in Production Method 26. it can.

[Production Method 26]

In the formula, J ^c represents PG ¹ —A ^a —U—, R ^a OOC—U—, O ₂ N—U—, R ^a O (R ^b O) CH—U ^a —, and A ^a , R ¹ , R ^a , R ^b , R ² , R ³ , U, U ^a , W ¹ , Z, PG ¹ have the same meaning as described above.

The conversion from the compound represented by the general formula (52) and the compound represented by the general formula (17) to the compound represented by the general formula (53) (step 26-A) is the same as in step 1-B. It can be done by a method.

Conversion of the compound represented by the general formula (54) and the compound represented by the general formula (14) into the compound represented by the general formula (53) (step 26-B) is the same as in step 1-A. It can be done by a method.

The conversion from the compound represented by the general formula (53) to the compound represented by the general formula (55) (step 26-C) can be performed by the same method as in step 1-C.

The conversion from the compound represented by the general formula (55) to the compound represented by the general formula (56) (step 26-D) can be performed by the same method as in step 1-D.

Conversion of the compound represented by the general formula (52) and the compound represented by the general formula (21) into the general formula (57) (step 26-E) can be performed by the same method as in step 2-B. it can.

Conversion of the compound represented by the general formula (54) and the compound represented by the general formula (19) into the general formula (57) (step 26-F) can be performed by the same method as in step 2-A. it can.

The conversion from the compound represented by the general formula (57) to the compound represented by the general formula (58) (step 26-G) can be performed by the same method as in step 2-C.

The conversion from the compound represented by the general formula (58) to the compound represented by the general formula (56) (step 26-H) can be performed by the same method as in step 2-D.

Each optical isomer of the compound represented by the general formula (1) can be synthesized by the above-described production methods 1 to 26 using an optically active raw material compound.

In addition, the diastereomeric compound obtained by reacting the racemate represented by the general formula (1) with fractional recrystallization using an optically active acid or base, or an optically active alcohol derivative or an optically active oxazolidinone derivative. An ester derivative or an oxazolidinone derivative can also be synthesized by separating it by fractional crystallization or chromatographic techniques and then hydrolyzing it.

It can also be produced by a chromatographic technique using a chiral support.

The present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples.

<Reference Example 1>
5-Formyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

Triethylamine (35.3 mL, 253 mmol) and ethyl chloroformate (25.4 mL, 266 mmol) were added to a solution of 5-formyl-2-methoxybenzoic acid (45.6 g, 253 mmol) in N, N-dimethylformamide (500 mL) with stirring under ice cooling. ) And stirred for 10 minutes under the same conditions. Next, [4- (4-fluorophenoxy) phenylmethyl] amine hydrochloride (70.6 g, 278 mmol) was added to the reaction mixture, and the mixture was stirred for 20 minutes under the same conditions. The reaction mixture was poured into ice water, 1N hydrochloric acid was added to adjust to pH 4, and the crystallized crystals were collected by filtration. The residue was triturated (hexane / ethyl acetate = 1/2) to give the title compound (76.7 g, 80%) as colorless powder crystals.

Melting point: 132-133 ° C
IR (ATR): 3341.3, 1690.7, 1638.3, 1536.1, 1495.0 cm ⁻¹ .

¹ H-NMR (CDCl ₃ , 400 MHz) δ 4.04 (3H, s), 4.67 (2H, d, J = 5.5 Hz), 6.92-7.06 (6H, m), 7.13 (1H, d, J = 8.6 Hz), 7.33 (2H, d, J = 8.6 Hz), 8.00 (1H, brs), 8.04 (1H, dd, J = 8.6) 2.4 Hz), 8.75 (1 H, d, J = 2.4 Hz), 9.99 (1 H, s).

ESIMS (+): 380.1 [M + H] ⁺ .
HRESIMS _(+): 380.12954 (calculated value 380.12981 as C ₂₂ H 19 FNO _4).

[Example 1]
5- (2,4-Dioxo-5,5-dimethylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

First Step 2- [3-[[4- (4-Fluorophenoxy) phenylmethyl] carbamoyl] -4-methoxyphenylmethyl] amino-2-methylpropionate methyl

To a methylene chloride solution (5.3 mL) of methyl 2-amino-2-methylpropionate (242 mg, 1.58 mmol), triethylamine (0.22 mL, 1.58 mmol) and the compound of Reference Example 1 (400 mg, 1.05 mmol), sodium triacetoxyborohydride (334 mg, 1.58 mmol) and acetic acid (90.2 μL, 1.58 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil 25 g; hexane: ethyl acetate) to obtain the title compound (514 mg, quant.) As colorless powder crystals.

Colorless powdery crystal IR (ATR): 3410.1, 2949.4, 177.2, 1647.3, 1532.7, 1498.6, 1458.7, 1365.6, 1292.0, 1245.5, 1218 .4, 1138.2, 1109.9 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.36 (6H, s), 3.61 (2H, s), 3.75 (3H, s), 3.92 (3H, s), 4.64 ( 2H, d, J = 5.5 Hz), 6.90-7.06 (7H, m), 7.32 (2H, d, J = 9.2 Hz), 7.45 (1H, dd, J = 8) .3, 2.1 Hz), 8.15-8.20 (2H, m).
ESIMS (+): 481.2 [M + H] ⁺ .
HRESIMS _(+): 481.21418 (calculated value 481.21387 as _{_{_{C 27 H 30 FN 2 O 5}}} ).

Second Step 5- (2,4-Dioxo-5,5-dimethylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

Potassium cyanate (95.4 mg, 1.18 mmol) was added to an acetic acid solution (5 mL) of the compound in the first step (471 mg, 0.98 mmol), stirred at room temperature for 1 hour, and stirred at 100 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil 25 g; hexane: ethyl acetate) to obtain the title compound (308 mg, 64%) as colorless powder crystals.

Colorless powder crystalline melting point: 155-156 ° C
IR (ATR): 3395.9, 3199.4, 2974.4, 1768.5, 1713.9, 1662.9, 1609.7, 1532.7, 1493.9, 1428.0, 1298.3, 1247 .4, 1209.3, 1135.9, 1023.6 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 1.17 (6H, s), 3.86 (3H, s), 4.41 (2H, s), 4.45 (2H, d, J = 5) .5Hz), 6.95 (2H, d, J = 8.6 Hz), 7.00-7.12 (2H, m), 7.33 (2H, d, J = 8.6 Hz), 7.16 -7.27 (2H, m), 7.32 (2H, d, J = 8.6 Hz), 7.44 (1H, dd, J = 8.6, 2.4 Hz), 7.75 (1H, d, J = 2.4 Hz), 8.68 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
ESIMS (+): 492.2 [M + H] ⁺ .
HRESIMS _(+): 492.19368 (calculated value 492.19347 as _{_{_{C 27 H 27 FN 3 O 5}}} ).
Elemental analysis: Measured value C 65.96%, H 5.61%, N 8.37%, calculated as C ₂₇ H ₂₆ FN ₃ O ₅ C 65.98%, H 5.33%, N 8.55 %.

<Examples 2 to 5>
According to the method of Example 1, the reaction was carried out using the compound of Reference Example 1 and the corresponding amino acid ester to obtain the compounds shown in the following formula and Table 2.

[Example 2]
(S) -5- (2,4-Dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 65-67 ° C
IR (ATR): 3383.8, 3170.8, 2959.6, 1769.3, 173.3, 1638.1, 1529.8, 1494.5 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 0.74 (3H, t, J = 7.3 Hz), 0.95-1.22 (2H, m), 1.58-1.68 (2H, m), 3.85-3.90 (1H, m), 3.87 (3H, s), 4.23 (1H, d, J = 15.3 Hz), 4.46 (2H, d, J = 6.1 Hz), 4.57 (1H, d, J = 15.3 Hz), 6.95 (2H, d, J = 8.6 Hz), 7.08-7.06 (2H, m), 7. 11 (1H, d, J = 8.6 Hz), 7.16-7.24 (2H, m), 7.33 (2H, d, J = 8.6 Hz), 7.40 (1H, dd, J = 8.6, 2.4 Hz), 7.68 (1H, d, J = 2.4 Hz), 8.68 (1H, t, J = 6.1 Hz), 10.8 (1H, s).
ESIMS (+): 506.2 [M + H] ⁺ .
HRESIMS (+): 506.20894 (calculated as C ₂₈ H ₂₉ FN ₃ O ₅ 506.20912).
Elemental analysis: Found _{C 65.67%, H 5.76%,} N 8.00%, C 28 H 28 FN 3 O 5 · 0.4H Calculated C 65.59% as ₂ O, H 5.66 %, N 8.20%.

[Example 3]
(R) -5- (2,4-Dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 65-68 ° C
IR (ATR): 3391.0, 3169.9, 2959.6, 1769.8, 1714.4, 1638.5, 1530.6, 1494.4 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 0.74 (3H, t, J = 7.3 Hz), 0.95-1.22 (2H, m), 1.58-1.68 (2H, m), 3.85-3.90 (1H, m), 3.87 (3H, s), 4.23 (1H, d, J = 15.3 Hz), 4.46 (2H, d, J = 6.1 Hz), 4.57 (1H, d, J = 15.3 Hz), 6.95 (2H, d, J = 8.6 Hz), 7.08-7.06 (2H, m), 7. 11 (1H, d, J = 8.6 Hz), 7.16-7.24 (2H, m), 7.33 (2H, d, J = 8.6 Hz), 7.40 (1H, dd, J = 8.6, 2.4 Hz), 7.68 (1H, d, J = 2.4 Hz), 8.68 (1H, t, J = 6.1 Hz), 10.8 (1H, s).
ESIMS (+): 506.2 [M + H] ⁺ .
HRESIMS (+): 506.20945 (calculated as C ₂₈ H ₂₉ FN ₃ O ₅ 506.20912).
Elemental analysis: Calculated values C 66.25%, H 5.76%, N 8.13%, C ₂₈ H ₂₈ FN ₃ O ₅ calculated values C 66.52%, H 5.58%, N 8.31 %.

[Example 4]
(R) -5- (2,4-Dioxo-5-phenylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 83-85 ℃
IR (ATR): 3388.4, 3063.5, 1771.2, 1713.2, 1639.0, 1530.1, 1493.8, 1411.9, 1297.7, 1246.1, 1209.0, 1188 .6,1104.3,1014.9,938.4 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.77 (1H, d, J = 15.9 Hz), 3.85 (3H, s), 4.45 (2H, d, J = 5.5 Hz) , 4.73 (1H, d, J = 15.3 Hz), 4.91 (1H, s), 6.96 (2H, d, J = 8.6 Hz), 7.00-7.07 (3H, m), 7.15-7.25 (5H, m), 7.10-7.41 (5H, m), 7.49 (1H, d, J = 2.4 Hz), 8.66 (1H, t, J = 5.8 Hz), 11.4 (1H, s).
ESIMS (+): 540.2 [M + H] ⁺ .
HRESIMS (+): 540.19365 (calculated value 540.19347 as C ₃₁ H ₂₇ FN ₃ O ₅ ).
Elemental analysis: Measured value C 68.66%, H 4.99%, N 7.64%, calculated as C ₃₁ H ₂₆ FN ₃ O ₅ C 69.01%, H 4.86%, N 7.79 %.

[Example 5]
(R) -3- [1- [3-[[4- (4-Fluorophenoxy) phenylmethyl] carbamoyl] -4-methoxyphenylmethyl] -2,4-dioxoimidazolidin-5-yl] propionic acid Benzyl colorless powdery melting point: 50-52 ° C
IR (ATR): 3389.7, 3063.5, 1769.9, 1717.7, 1639.2, 1531.1, 1494.4, 1439.1, 1291.1, 1246.3, 1209.1, 1188 .7,1106.8,1014.3 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 1.91-2.06 (2H, m), 2.20-2.35 (2H, m), 3.85 (3H, s), 3.94 (1H, dd, J = 6.1, 4.3 Hz), 4.22 (1H, d, J = 15.3 Hz), 4.45 (2H, d, J = 6.1 Hz), 4.55 ( 1H, d, J = 15.9 Hz), 5.02 (2H, s), 6.94 (2H, d, J = 8.6 Hz), 6.98-7.05 (2H, m), 7. 09 (1H, d, J = 8.6 Hz), 7.16-7.23 (2H, m), 7.27-7.40 (8H, m), 7.67 (1H, d, J = 2) .4 Hz), 8.67 (1 H, t, J = 5.8 Hz), 11.0 (1 H, s).
ESIMS (+): 626.2 [M + H] ⁺ .
HRESIMS _(+): 626.23043 (calcd 626.23025 as _{_{_{C 35 H 33 FN 3 O 7}}} ).

[Example 6]
(R) -3- [1- [3-[[4- (4-Fluorophenoxy) phenylmethyl] carbamoyl] -4-methoxyphenylmethyl] -2,4-dioxoimidazolidin-5-yl] propionic acid

10% Palladium carbon (15.5 mg) was added to an ethanol (3 mL) solution of the compound of Example 5 (155 mg, 0.25 mmol) in an argon atmosphere, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. The insoluble material in the reaction mixture was removed by filtration through celite, and the filtrate was evaporated under reduced pressure to give the title compound (128 mg, 96%) as colorless powder crystals.

Melting point: 87-89 ° C
IR (ATR): 3387.9, 3062.7, 1768.8, 1707.5, 1631.7, 1534.9, 1494.8, l 1438.5, 1301.6, 1246.8, 1209.3 1189.0, 1107.9, 1015.0, 942.6 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 1.83-2.00 (2H, m), 2.05-2.22 (2H, m), 3.86 (3H, s), 3.91 (1H, dd, J = 6.1, 3.7 Hz), 4.21 (1H, d, J = 15.3 Hz), 4.46 (2H, d, J = 6.1 Hz), 4.59 ( 1H, d, J = 15.3 Hz), 6.95 (2H, d, J = 8.6 Hz), 7.00-7.07 (2H, m), 7.11 (1H, d, J = 8) .6 Hz), 7.17-7.23 (2 H, m), 7.33 (2 H, d, J = 8.6 Hz), 7.39 (1 H, dd, J = 8.6, 2.4 Hz) 7.66 (1H, d, J = 2.4 Hz), 8.67 (1H, t, J = 6.1 Hz), 11.0 (1H, s), 12.2 (1H, brs).
ESIMS (+): 536.2 [M + H] ⁺ .
HRESIMS (+): 536.18369 (calculated as C ₂₈ H ₂₇ FN ₃ O ₇ 536.18330).
Elemental analysis: Calculated as C 62.49%, H 4.81%, N 7.68%, C ₂₈ H ₂₆ FN ₃ O ₇ C 62.80%, H 4.89%, N 7.85 %.

<Reference Example 2>
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxybenzoic acid first step 5-[(carbamoylmethyl) aminomethyl] -2-methoxybenzoic acid methyl

To a methanol solution (100 mL) of methyl 5-formyl-2-methoxybenzoate (4.00 g, 20.6 mmol), glycinamide hydrochloride (5.47 g, 49.4 mmol) and sodium triacetoxyborohydride (8. 73 g, 41.2 mmol) was added and stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate solution (150 mL) was added to the reaction mixture, and the mixture was extracted with chloroform / methanol = 10/1 (100 mL × 7). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Si60N, ethyl acetate: methanol = 10: 1) to give the title compound (3.40 g, 65%) as colorless powder crystals.

IR (ATR): 3365.5, 3181.6, 1725.3, 1645.4, 1500.5, 1432.9 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 2.36 (1H, brs), 3.31 (2H, s), 3.76 (2H, s), 3.89 (3H, s), 3.90 ( 2H, s), 5.67 (1H, brs), 6.92-7.00 (2H, m), 7.40 (1H, dd, J = 8.5, 2.4 Hz), 7.74 ( 1H, d, J = 2.4 Hz).
CIMS (+): 253.1 [M + H] ⁺ .
HRCIMS _(+): 253.1189 (calcd 253.1188 as _{_{_{C 12 H 17 N 2 O 4}}} ).

Second Step 5- [N- (carbamoylmethyl) methoxycarbonylaminomethyl] -2-methoxybenzoic acid methyl ester

Triethylamine (2.56 mL, 18.3 mmol) and methyl chloroformate (1.21 mL, 15.7 mmol) were added to a tetrahydrofuran solution (66 mL) of the compound of the first step (3.30 g, 13.1 mmol) with stirring under ice cooling. The mixture was stirred for 30 minutes under the same conditions. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated to give the title compound (3.06 g, 75%) as colorless powder crystals.

IR (ATR): 3373.3, 1696.1, 1676.6, 1615.2, 1480.1 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.74-3.86 (5H, m), 3.89 (3H, s), 3.90 (3H, s), 4.52 (2H, s), 5.50-6.10 (2H, m), 6.95 (1H, d, J = 8.5 Hz), 7.30-7.48 (1H, m), 7.68 (1H, brs).
CIMS (+): 311.1 [M + H] ⁺ .
HRCIMS _(+): 311.1215 (calcd 311.1243 as _{_{_{C 14 H 19 N 2 O 6}}} ).

Third Step 5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxybenzoate methyl

Sodium methoxide (1.31 g, 24.3 mmol) was added to a methanol solution (50 mL) of the compound in the second step (3.01 g, 9.70 mmol), and the mixture was heated to reflux for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Si60N, ethyl acetate) to give the title compound (2.09 g, 77%) as colorless powder crystals.

Colorless powdery crystal IR (ATR): 3052.0, 1763.4, 1715.4, 1688.8, 1614.8, 1500.5 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.76 (3H, s), 3.78-3.83 (5H, m), 4.38 (2H, s), 7.12 (1H, d , J = 8.5 Hz), 7.43 (1H, dd, J = 8.5, 2.4 Hz), 7.53 (1H, d, J = 2.4 Hz), 10.8 (1H, s) .
EIMS (+): 278.1 [M] ⁺ .
HREIMS _(+): 278.0940 (calcd 278.0903 as _{_{_{C 13 H 14 N 2 O 5}}} ).

Fourth step 5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxybenzoic acid

2N sodium hydroxide aqueous solution (7 mL) was added to a methanol solution (35 mL) of the compound of the third step (2.06 g, 7.40 mmol), and the mixture was heated to reflux for 3 hours. 2N Hydrochloric acid was added to the reaction mixture to adjust to pH = 3, and the crystallized crystals were collected by filtration to give the title compound (1.75 g, 90%) as colorless powder crystals.

Melting point: 214-215 ° C
IR (ATR): 3056.2, 1770.8, 1690.6, 1576.8, 1463.4 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.79 (5H, s), 4.37 (2H, 2), 7.09 (1H, d, J = 8.5 Hz), 7.39 (1H , Dd, J = 8.5, 1.8 Hz), 7.52 (1H, d, J = 1.8 Hz), 10.8 (1H, s), 12.6 (1H, s).
EIMS (+): 264.1 [M] ⁺ .
HREIMS _(+): 264.0739 (calcd 264.0746 as _{_{_{C 12 H 12 N 2 O 5}}} ).

<Reference Example 3>
3- (2,4-Dioxoimidazolidin-1-yl) methylbenzoic acid first step 3- (carbamoylmethyl) aminomethylbenzoic acid benzyl

According to the first step method of Reference Example 2, the reaction was carried out using benzyl 3-formylbenzoate (200 mg, 0.83 mmol) and glycinamide hydrochloride (734 mg, 6.64 mmol) to give the title compound 2 (198 mg, 80% ) Was obtained as colorless powdery crystals.

IR (ATR): 3376.6, 3188.8, 176.2, 1644.6, 1443.2, 1408.9, 1382.1, 1270.9, 1188.5, 1098.8 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.31 (3H, s), 3.85 (2H, s), 5.37 (2H, s), 5.54 (1H, brs), 6.96 ( 1H, brs), 7.31-7.54 (7H, m), 7.96-8.04 (2H, m).
CIMS (+): 299.1 [M + H] ⁺ .
HRCIMS _(+): 299.1366 (calcd 299.1396 as _{_{_{C 17 H 19 N 2 O 3}}} ).

Second Step 3- [N- (carbamoylmethyl) methoxycarbonylaminomethyl] benzyl benzoate

In accordance with the second step method of Reference Example 2, the reaction was carried out using the compound of the first step (139 mg, 0.47 mmol) and methyl chloroformate (43.3 μL, 0.56 mmol) to give the title compound (170 mg, quant.). Was obtained as a colorless oil.

IR (ATR): 3376.7, 3205.2, 2955.3, 1703.6, 1667.2, 1472.0, 1411.9, 1276.1, 1185.5, 1103.1 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.79 (3H, s), 3.85 (2H, s), 4.62 (2H, s), 5.37 (3H, s), 7.31- 7.50 (7H, m), 7.95 (1H, s), 8.01 (1H, d, J = 7.3 Hz).
CIMS (+): 357.1 [M + H] ⁺ .
HRCIMS _(+): 357.1426 (calcd 357.1450 as _{_{_{C 19 H 21 N 2 O 5}}} ).

Third Step 3- (2,4-Dioxoimidazolidin-1-yl) methylbenzoate

According to the third step method of Reference Example 2, the reaction was performed using the compound of the second step (170 mg, 0.47 mmol) to obtain the title compound (107 mg, 92%) as colorless powder crystals.

IR (ATR): 3186.8, 3063.1, 1692.2, 1469.1, 1420.2, 1280.2, 1203.4, 1081.7, 1001.0 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.85 (5H, s), 4.50 (2H, s), 7.47-7.59 (2H, m), 7.80-7.91 (2H, m), 10.9 (1H, s).
EIMS (+): 248.1 [M] ⁺ .
HREIMS _(+): 248.0801 (calcd 248.0797 as _{_{_{C 12 H 12 N 2 O 4}}} ).

Fourth Step 3- (2,4-Dioxoimidazolidin-1-yl) methylbenzoic acid

According to the fourth step method of Reference Example 2, the reaction was performed using the compound of the third step (97.9 mg, 0.39 mmol) to obtain the title compound (73.0 mg, 80%) as colorless powder crystals.

IR (ATR): 3171.1, 3055.5, 1760.6, 1696.8, 1591.4, 1459.6, 1419.2, 1300.6, 1232.0, 1183.6, 1109.0 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.84 (2H, s), 4.49 (2H, s), 7.44-7.55 (2H, m), 7.79-7.88 (2H, m), 10.9 (1H, s), 13.0 (1H, s).
CIMS (+): 235.1 [M + H] ⁺ .
HRCIMS _(+): 235.0710 (calcd 235.0719 as _{_{_{C 11 H 11 N 2 O 4}}} ).

[Example 7]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

A solution of the compound of Reference Example 2 (300 mg, 1.14 mmol) in N, N′-dimethylformamide (7 mL) was stirred with ice cooling and triethylamine (0.32 mL, 2.28 mmol), diethylphosphorocyanidate (0.21 mL, 1.25 mmol) was added and stirred for 10 minutes under the same conditions. To the reaction mixture was added [4- (4-fluorophenoxy) phenylmethyl] amine (248 mg, 1.14 mmol) in N, N′-dimethylformamide (3 mL). In addition, the mixture was stirred for 30 minutes under the same conditions.

Water was added to the reaction mixture, followed by extraction with chloroform / methanol = 10/1 (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Si60N, ethyl acetate) and recrystallized (hexane: ethyl acetate = 1: 1) to give the title compound (491 mg, 93%) as colorless powder crystals.

Melting point: 140-141 ° C
IR (ATR): 3380.0, 3062.1, 1718.6, 1633.6, 1535.5, 1498.3 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.79 (2H, s), 3.87 (3H, s), 4.39 (2H, s), 4.46 (2H, d, J = 6) .1 Hz), 6.95 (2H, d, J = 8.5 Hz), 6.98-7.07 (2H, m), 7.12 (1H, d, J = 8.5 Hz), 7.15 −7.25 (2H, m), 7.33 (2H, d, J = 8.5 Hz), 7.36 (1H, dd, J = 8.5, 2.4 Hz), 7.62 (1H, d, J = 2.4 Hz), 8.69 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
ESIMS (+): 464.2 [M + H] ⁺ .
HRESIMS _(+): 464.16260 (calculated value 464.16217 as _{_{_{C 25 H 23 FN 3 O 5}}} ).
Elemental analysis: Calculated value C 64.72%, H 4.84%, N 9.05%, C ₂₅ H ₂₂ FN ₃ O ₅ calculated value C 64.79%, H 4.78%, N 9.07 %.

<Reference Example 4>
4- [4- (Aminomethyl) phenoxy] -N, N-dimethylaniline first step 4- [4- (dimethylamino) phenoxy] benzonitrile

To a methanol solution (9.5 mL) of 4- (4-aminophenoxy) benzonitrile (1.00 g, 4.76 mmol), 37% aqueous formalin solution (3.86 mL, 47.6 mmol) and acetic acid (0. 82 mL, 14.3 mmol) and sodium cyanoborohydride (897 mg, 14.3 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give the title compound (1.15 g, quant.) As colorless powder crystals.

IR (ATR): 2893.9, 2223.4, 1599.1, 1514.9, 1492.6, 1350.7, 1252.5 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 2.98 (6H, s), 6.73-6.79 (2H, m), 6.93-7.01 (4H, m), 7.54-7 .59 (2H, m).
EIMS (+): 238 [M] ⁺ .
HREIMS _(+): 238.1116 (calcd 238.1106 as _{_{C 15 H 14 N 2 O)}} .

Second Step 4- [4- (Aminomethyl) phenoxy] -N, N-dimethylaniline

Lithium aluminum hydride (2.61 g, 68.8 mmol) was added to a tetrahydrofuran solution (98 mL) of the compound in the first step (8.20 g, 34.4 mmol) under ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. Water (2.61 mL), 15% aqueous sodium hydroxide solution (2.61 mL) and water (7.83 mL) were added to the reaction mixture, and the mixture was stirred for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The compound (8.29 g, 99%) was obtained as pale yellow powdery crystals.

IR (ATR): 3354.6, 2836.9, 1788.9, 1604.4, 1498.9, 1230.9, 1159.9 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.50 (2H, brs), 2.93 (6H, s), 3.81 (2H, s), 6.73 (2H, dt, J = 6.4) , 3.9 Hz), 6.90 (2H, dt, J = 5.7, 3.3 Hz), 6.95 (2H, dd, J = 6.7, 2.4 Hz), 7.21 (2H, d, J = 8.6 Hz).
EIMS (+): 242 [M] ⁺ .
_{HREIMS (+): 242.1396 (C} 15 H 18 N 2 O Calculated 242.1419).

<Reference Example 5>
4- [4- (Aminomethyl) phenoxy] benzoic acid ethyl hydrochloride

Concentrated hydrochloric acid (2.76 mL) was added to a methanol solution (63 mL) of ethyl 4- (4-cyanophenoxy) benzoate (5.91 g, 22.1 mmol), and 10% palladium hydroxide carbon (2. 591 mg) was added, and the mixture was stirred at room temperature for 10 hours under a hydrogen atmosphere. The insoluble material in the reaction solution was filtered off using celite, the filtrate was evaporated under reduced pressure, and the residue was triturated with ether to give the title compound (6.02 g, 89%) as colorless powder crystals.

IR (ATR): 2965.1, 1715.6, 1599.5, 1499.8, 1277.0, 1250.5, 1161.8, 1096.3, 1012.9 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 1.29 (3H, t, J = 7.0 Hz), 4.01 (2H, s), 4.28 (2H, q, J = 7.1 Hz) 7.04 (2H, d, J = 8.5 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.97 ( 2H, d, J = 8.5 Hz), 8.53 (3H, brs).
EIMS (+): 271 [M] ⁺ .
HREIMS (+): 271.1192 (calculated value 271.1208 as C ₁₆ H ₁₇ NO ₃ ).

<Examples 8 to 21>
According to the method of Example 7, the reaction was carried out using the compound of Reference Example 2 or Reference Example 3 and the corresponding amine to obtain the compounds of Table 3.

[Example 8]
3- (2,4-Dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 193-195 ° C.
IR (ATR): 3302.0, 2953.4, 2732.1, 1756.7, 1719.7, 1632.6, 1543.4, 1494.4, 1458.9, 1348.0, 1311.8, 1250 .3, 1211.2, 1188.0, 1115.2 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.85 (2H, s), 4.45 (2H, d, J = 6.1 Hz), 4.48 (2H, s), 6.94 (2H , D, J = 8.5 Hz), 6.98-7.06 (2H, m), 7.20 (2H, t, J = 8.8 Hz), 7.32 (2H, d, J = 7. 9 Hz), 7.40-7.49 (2 H, m), 7.75 (1 H, s), 7.80 (1 H, d, J = 6.7 Hz), 9.05 (1 H, t, J = 6.1 Hz), 10.9 (1 H, s).
ESIMS (−): 432.1 [M−H] ⁺ .
HRESIMS _(-): 432.13579 (calculated value 432.13596 as _{_{_{C 24 H 19 FN 3 O 4}}} ).

[Example 9]
3- (2,4-Dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenyl] benzamide colorless powdery crystalline melting point: 224-226 ° C.
IR (ATR): 3265.1, 3049.7, 1761.5, 1708.3, 1649.5, 1528.6, 1496.6, 1466.0, 1407.2, 1320.2, 1211.0, 1098 .9,1011.6 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.88 (2H, s), 4.52 (2H, s), 6.98-7.07 (4H, m), 7.21 (2H, t , J = 8.8 Hz), 7.45-7.54 (2H, m), 7.75 (2H, d, J = 9.1 Hz), 7.80 (1H, s), 7.86 (1H) , D, J = 7.3 Hz), 10.3 (1H, s), 10.9 (1H, s).
ESIMS (−): 418.1 [M−H] ⁺ .
HRESIMS _(-): 418.12037 (calculated value 418.12031 as _{_{_{C 23 H 17 FN 3 O 4}}} ).

[Example 10]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenyl] benzamide colorless powdery crystalline melting point: 202-204 ° C.
IR (ATR): 3346.4, 3179.3, 3070.9, 1770.2, 1712.8, 1638.0, 1537.5, 1496.7, 1468.4, 1425.1, 1320.4, 1248 5, 1209.1, 1097.3, 1021.6, 935.2, 873.4, 828.1, 746.7, 710.0, 621.2, 514.6, 487.6, 416.1 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.82 (2H, s), 3.88 (3H, s), 4.41 (2H, s), 6.96-7.05 (4H, m ), 7.13-7.24 (3H, m), 7.39 (1H, dd, J = 8.6, 1.8 Hz), 7.51 (1H, d, J = 1.8 Hz), 7 .72 (2H, d, J = 8.6 Hz), 10.1 (1H, s), 10.9 (1H, s).
ESIMS (+): 450.1 [M + H] ⁺ .
HRESIMS _(+): 450.14709 (calculated value 450.14652 as _{_{_{C 24 H 21 FN 3 O 5}}} ).

[Example 11]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- (4-phenoxyphenylmethyl) benzamide colorless powdery crystalline melting point: 115-117 ° C.
IR (ATR): 3334.9, 3142.0, 3061.9, 1770.6, 1711.4, 1622.6, 1539.7, 1488.5, 1425.2, 1315.9, 1230.6, 1164 0.0, 1097.4, 1023.0, 951.9, 870.5, 815.0, 761.9, 691.8, 637.8, 595.2, 512.7, 416.2 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.79 (2H, s), 3.87 (3H, s), 4.39 (2H, s), 4.47 (2H, d, J = 6) .1Hz), 6.95-7.00 (4H, m), 7.07-7.15 (2H, m), 7.32-7.40 (5H, m), 7.63 (1H, d) , J = 2.4 Hz), 8.70 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
ESIMS (+): 446.2 [M + H] ⁺ .
HRESIMS _(+): 446.17172 (calculated value 446.17160 as _{_{_{C 25 H 24 N 3 O 5}}} ).

[Example 12]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-toluyloxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 122-124 ° C.
IR (ATR): 3586.8, 3380.6, 3166.3, 3063.0, 2921.0, 2731.7, 1765.7, 1708.5, 1645.8, 1545.9, 1497.9, 1464 3,1430.2,1342.3,1302.7,1234.6,1167.8,1102.4,1010.0,946.2,876.9,809.9,753.1,690.7 , 606.8, 498.0 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 2.27 (3H, s), 3.79 (2H, s), 3.86 (3H, s), 4.39 (2H, s), 4. 45 (2H, d, J = 6.1 Hz), 6.88 (2H, d, J = 8.6 Hz), 6.93 (2H, d, J = 9.2 Hz), 7.12 (1H, d , J = 8.6 Hz), 7.16 (2H, d, J = 7.9 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 8. 6, 2.4 Hz), 7.62 (1 H, d, J = 2.4 Hz), 8.69 (1 H, t, J = 6.1 Hz), 10.9 (1 H, s).
ESIMS (+): 460.2 [M + H] ⁺ .
HRESIMS _(+): 460.18656 (calculated value 460.18725 as _{_{_{C 26 H 26 N 3 O 5}}} ).

[Example 13]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-cyanophenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 182-184 ° C
IR (ATR): 3371.0, 3058.2, 2226.2, 1770.1, 1691.7, 1648.1, 1528.3, 1497.2, 1416.8, 1287.0, 1255.3, 1167 7, 1121.9, 1012.8, 953.0, 876.4, 851.1, 830.9, 768.9, 702.3, 627.0, 546.9, 511.9, 430.5 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.79 (2H, s), 3.88 (3H, s), 4.39 (2H, s), 4.50 (2H, d, J = 6) .1Hz), 7.03-7.15 (5H, m), 7.34-7.44 (3H, m), 7.63 (1H, d, J = 2.4 Hz), 7.81 (2H) , D, J = 9.2 Hz), 8.75 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
ESIMS (+): 471.2 [M + H] ⁺ .
HRESIMS _(+): 471.16622 (calculated value 471.16684 as _{_{_{C 26 H 23 N 4 O 5}}} ).

[Example 14]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- [4- (dimethylamino) phenoxy] phenylmethyl] benzamide pale yellow powdery crystalline melting point: 139-140 ℃
IR (ATR): 3347.0, 3146.1, 2937.9, 1770.1, 1709.9, 1622.5, 1499.3, 1468.4, 1422.6, 1314.4, 1228.1, 1161 8, 1097.3, 1023.8, 947.8, 872.0, 815.7, 762.1, 685.6, 635.9, 596.4, 501.3, 416.0 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 2.85 (6H, s), 3.78 (2H, s), 3.86 (3H, s), 4.38 (2H, s), 4. 42 (2H, d, J = 5.5 Hz), 6.74 (2H, d, J = 9.2 Hz), 6.84 (2H, d, J = 8.6 Hz), 6.89 (2H, d , J = 9.2 Hz), 7.11 (1H, d, J = 9.2 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 8. 6, 2.4 Hz), 7.61 (1 H, d, J = 2.4 Hz), 8.65 (1 H, t, J = 5.5 Hz), 10.9 (1 H, s).
ESIMS (+): 489.2 [M + H] ⁺ .
HRESIMS _(+): 489.21409 (calculated value 489.21379 as _{_{_{C 27 H 29 N 4 O 5}}} ).
Elemental analysis: measured C 66.32%, H 5.87%, N 11.27%, calculated as C ₂₇ H ₂₈ N ₄ O ₅ C 66.38%, H 5.78%, N 11.47 %.

[Example 15]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-methoxyphenoxy) phenylmethyl] benzamide colorless powdery crystalline melting point: 139-140 ° C.
IR (ATR): 3352.9, 3140.4, 2942.7, 2837.3, 1770.0, 1709.8, 1624.5, 1536.9, 1498.0, 1470.0, 1426.2, 1311 7, 1224.2, 1163.8, 1098.2, 1024.5, 953.7, 875.6, 840.7, 762.4, 684.2, 636.0, 596.8, 504.0 , 417.3 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.73 (3H, s), 3.78 (2H, s), 3.86 (3H, s), 4.38 (2H, s), 4. 44 (2H, d, J = 6.1 Hz), 6.88 (2H, d, J = 8.6 Hz), 6.92-6.99 (4H, m), 7.11 (1H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.36 (1H, dd, J = 8.6, 2.4 Hz), 7.62 (1H, d, J = 2.4 Hz), 8.67 (1 H, t, J = 6.1 Hz), 10.9 (1 H, s).
ESIMS (+): 476.2 [M + H] ⁺ .
HRESIMS (+): 476.18309 (calculated as C ₂₆ H ₂₆ N ₃ O ₆ 476.18216).
Elemental analysis: measured value C 65.83%, H 5.35%, N 8.94%, calculated as C ₂₆ H ₂₆ N ₃ O ₆ C 65.67%, H 5.30%, N 8.84 %.

[Example 16]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-tert-butoxycarbonylpiperidin-1-yloxy) phenylmethyl] benzamide white solid IR (ATR) : 3395.6, 312.11.7, 2946.2, 1763.7, 1712.4, 1693.9, 1634.6, 1597.8, 1510.1 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 1.39 (9H, s), 1.44 to 1.52 (2H, m), 1.84 to 1.89 (2H, m), 3.16 (2H, s), 3.60-3.66 (2H, m), 3.78 (2H, s), 3.86 (3H, s), 4.38-4.41 (4H, m), 4.48-4.52 (1H, m), 6.92 (2H, d, J = 8.5 Hz), 7.11 (1H, d, J = 8.7 Hz), 7.23 (2H, d , J = 8.5 Hz), 7.36 (1H, dd, J = 2.4, 8.7 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.62 (1H, t, J = 6.1 Hz), 10.85 (1H, s).
ESIMS (+): 553.3 [M + H] ⁺ .
HRESIMS (+): 553.26644 (calculated as C ₂₉ H ₃₇ N ₄ O ₇ 553.26622).
Elemental analysis: Found C 62.62%, H 6.55%, N 10.10%, C 29 H 36 N 4 O 7 · 0.2H Calculated C 63.03% as ₂ O, H 6.57 %, N 10.14%.

[Example 17]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenylthio) phenylmethyl] benzamide colorless powdery crystalline melting point: 149-150 ° C.
IR (ATR): 3142, 1710, 1625, 1544, 1467, 1422, 1252, 1222, 1098, 1029, 815, 627, 416 cm ⁻¹ .
¹ HNMR (CDCl ₃ , 400 MHz): δ 3.78 (2H, s), 3.94 (3H, s), 4.52 (2H, s), 4.64 (2H, d, J = 6.1 Hz) 6.90-7.05 (3H, m), 7.24-7.27 (4H, m), 7.32-7.43 (3H, m), 7.68 (1H, br), 8 .12 (1H, d, J = 2.4 Hz), 8.19 (1H, t, J = 5.5 Hz).
ESIMS (+): 480 [M + H] ⁺
HRESIMS _(+): 480.1392 (calcd 480.1393 as _{_{_{C 25 H 23 FN 3 O 4}}} S).

[Example 18]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N-[[6- (4-fluorophenoxy) pyridin-3-yl] methyl] benzamide colorless powder crystal IR (ATR ): 3591, 3398, 3162, 3070, 1765, 1712, 1642, 1537, 1505 cm ⁻¹ .
¹ HNMR (CDCl ₃ , 400 MHz): δ 3.78 (2H, s), 3.95 (3H, s), 4.53 (2H, s), 4.62 (2H, d, J = 6.1 Hz) ), 6.89 (1H, d, J = 8.5 Hz), 7.00 (1H, d, J = 8.5 Hz), 7.07-7.09 (4H, m), 7.40 (1H) , Brs), 7.42 (1H, dd, J = 8.5, 2.4 Hz), 7.75 (1H, dd, J = 8.5, 2.4 Hz), 8.12 (2H, d, J = 2.4 Hz), 8.15 (1H, d, J = 2.4 Hz), 8.21 (1H, t, J = 6.1 Hz).
ESIMS (+): 465.2 [M + H] ⁺
HRESIMS (+): 465.15781 (calculated value as C ₂₄ H ₂₂ FN ₄ O ₅ 465.15742).

[Example 19]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N-[[5- (4-fluorophenoxy) pyridin-2-yl] methyl] benzamide colorless powder crystal IR (ATR ): 3571, 3517, 3125, 3054, 2734, 1762, 1708, 1625, 1532 cm ⁻¹ .
¹ HNMR (CDCl ₃ , 400 MHz): δ 3.78 (2H, s), 4.01 (3H, s), 4.53 (2H, s), 4.77 (2H, d, J = 5.4 Hz) ), 6.98-7.08 (5H, m), 7.25 (1H, dd, J = 8.5, 2.4 Hz), 7.34 (1H, d, J = 8.5 Hz), 7 .40 (1H, brs), 7.41 (1H, dd, J = 8.5, 2.4 Hz), 8.13 (1H, d, J = 2.4 Hz), 8.33 (1H, d, J = 2.4 Hz), 8.90 (1H, t, J = 5.4 Hz).
ESIMS (+): 465.2 [M + H] ⁺
HRESIMS (+): 465.15784 (calculated as C ₂₄ H ₂₂ FN ₄ O ₅ 465.15742).

[Example 20]
4- [4-[[5-[(2,4-Dioxoimidazolidin-1-yl) methyl] -2-methoxybenzamido] methyl] phenoxy] ethyl benzoate colorless powder crystals IR (ATR): 3335. 0, 3137.7, 3065.9, 1769.9, 1710.3, 1598.9, 1499.3, 1469.1, 1425.1, 1308.7, 1279.0, 1246.5, 1163.5, 1098.3, 1015.2, 952.5, 874.4, 843.8, 764.1, 638.5, 596.2, 498.4, 417.1 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.38 (3H, t, J = 7.3 Hz), 3.79 (2H, s), 3.97 (3H, s), 4.36 (2H, q , J = 7.3 Hz), 4.54 (2H, s), 4.69 (2H, d, J = 5.5 Hz), 6.95-7.07 (5H, m), 7.37 (2H) , D, J = 8.6 Hz), 7.42 (1H, dd, J = 8.6, 2.4 Hz), 7.73 (1H, brs), 8.01 (2H, d, J = 9. 2 Hz), 8.15 (1 H, d, J = 2.4 Hz), 8.24 (1 H, t, J = 5.5 Hz).
ESIMS (+): 518.2 [M + H] ⁺ .
HRESIMS (+): 518.19243 (calculated value 518.19272 as C ₂₈ H ₂₈ N ₃ O ₇ ).

[Example 21]
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (cyclohexyloxy) phenylmethyl] benzamide white solid IR (ATR): 3341.5, 3121.5, 2932.2, 2856.4, 1796.4, 1710.4, 1623.0, 1546.4 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ1.25-1.40 (5H, m), 1.49-1.54 (1H, m), 1.66-1.70 (2H, m) , 1.87-1.90 (2H, m), 3.31 (3H, m), 3.78 (2H, s), 3.86 (3H, s), 4.25-4.30 (1H M), 4.38-4.40 (4H, m), 6.87 (2H, d, J = 8.8 Hz), 7.11 (1H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.36 (1H, dd, J = 2.4, 8.5 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.60 ( 1H, t, J = 6.1 Hz), 10.85 (1H, s).
ESIMS (+): 452.2 [M + H] ⁺ .
HRESIMS _(+): 452.21918 (calculated value 452.21855 as _{_{_{C 25 H 30 N 3 O 5}}} ).
Elemental analysis: Measured value C 66.34%, H 6.44%, N 9.29%, calculated as C ₂₅ H ₂₉ N ₃ O ₅ C 66.50%, H 6.47%, N 9.31 %.

[Example 22]
5- (2,4-Dioxo-3-butylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

Potassium carbonate (135 mg, 0.98 mmol) and iodobutane (88.8 μL, 0.78 mmol) were added to an N, N′-dimethylformamide solution (6.5 mL) of the compound of Example 7 (300 mg, 0.65 mmol) at room temperature. Stirred for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3).

The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to obtain the title compound (330 mg, 97%) as colorless powder crystals.

Melting point: 37-38 ° C
IR (ATR): 3397.2, 2934.4, 1768.1, 1702.3, 1649.1, 1494.2, 1461.3, 1245.3, 1209.1 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 0.94 (3H, t, J = 7.3 Hz), 1.28-1.40 (2H, m), 1.56-1.66 (2H, m) , 3.52 (2H, t, J = 7.3 Hz), ... (2H, s), 3.94 (3H, s), 4.55 (2H, s), 4.64 (2H , D, J = 5.5 Hz), 6.91-7.06 (7H, m), 7.32 (2H, d, J = 8.6 Hz), 7.38 (1H, dd, J = 8. 6, 2.4 Hz), 8.13 (1H, d, J = 2.4 Hz), 8.17 (1H, t, J = 5.5 Hz).
ESIMS (+): 520.2 [M + H] ⁺ .
HRESIMS (+): 520.22438 (calculated value 520.22477 as C ₂₉ H ₃₁ FN ₃ O ₅ ).
Elemental analysis: Calculated value C as measured C 66.91%, H 6.05%, N 8.06%, C ₂₉ H ₃₀ FN ₃ O ₅ C 67.09%, H 5.82%, N 8.09 %.

[Example 23]
5- (2,4-Dioxo-3- (2-benzyloxyethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

The reaction was performed according to Example 22 using the compound of Example 7 (150 mg, 0.32 mmol) and benzyl 2-bromoethyl ether (75.9 μL, 0.48 mmol) to give the title compound (180 mg, 94%) as colorless. Obtained as powdery crystals.

IR (ATR): 3408.2, 2948.6, 1761.5, 1698.3, 1644.6, 1608.3, 1527.7, 1496.4, 1469.7, 1447.8, 1358.8, 1299 7, 1247.5, 1211.5 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.67-3.73 (4H, m), 3.78 (2H, t, J = 5.5 Hz), 3.92 (3H, s), 4.54 (4H, s), 4.64 (2H, d, J = 5.5 Hz), 6.89-7.06 (7H, m), 7.25-7.38 (8H, m), 8.13 (1H, d, J = 2.4 Hz), 8.17 (1H, t, J = 5.5 Hz).
ESIMS (+): 598.2 [M + H] ⁺ .
HRESIMS _(+): 598.23497 (calculated value 598.23534 as _{_{_{C 34 H 33 FN 3 O 6}}} ).

[Example 24]
5- (2,4-Dioxo-3- (2-morpholinoethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

To a solution of the compound of Example 7 (193 mg, 0.42 mmol) in N, N′-dimethylformamide (4 mL), potassium carbonate (174 mg, 1.26 mmol), N- (2-chloroethyl) morpholine hydrochloride (117 mg,. 63 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated.

The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-NH; hexane: ethyl acetate) to obtain the title compound (222 mg, 92%) as colorless powder crystals.

Melting point: 37-38 ° C
IR (ATR): 3397.6, 2948.4, 1767.8, 1704.2, 1650.3, 1609.4, 1528.0, 1495.0, 1462.7, 1424.2, 1357.6, 1297 .3,1246.3,1209.7 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 2.50 (4H, brs), 2.59 (2H, t, J = 6.4 Hz), 3.62-3.70 (6H, m), 3.72 (2H, s), 3.94 (3H, s), 4.56 (2H, s), 4.64 (2H, d, J = 5.5 Hz), 6.91-7.06 (6H, m ), 7.32 (2H, d, J = 8.6 Hz), 7.39 (1H, dd, J = 8.6, 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz) , 8.18 (1H, t, J = 5.5 Hz).
ESIMS (+): 577.2 [M + H] ⁺ .
HRESIMS _(+): 577.24601 (calculated value 577.24624 as _{_{_{C 31 H 34 FN 4 O 6}}} ).
Elemental analysis: Calculated value C as measured C 66.91%, H 6.05%, N 8.06%, C ₂₉ H ₃₀ FN ₃ O ₅ C 67.09%, H 5.82%, N 8.09 %.

[Example 25]
5- (2,4-Dioxo-3-cyclopropylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

To a 1,2-dichloroethane solution (5 mL) of the compound of Example 7 (250 mg, 0.54 mmol), cyclopropylboric acid (92.8 mg, 1.08 mmol), sodium carbonate (114 mg, 1.08 mmol), copper acetate ( 98.1 mg, 0.54 mmol) and 2,2′-bipyridyl (84.3 mg, 0.54 mmol) were added, and the mixture was stirred at 70 ° C. for 3 hours.

A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to obtain the title compound (206 mg, 76%) as colorless powder crystals.

Melting point: 50-52 ° C
IR (ATR): 3395.3, 2933.5, 1769.2, 1708.1, 1649.0, 1528.1, 1494.7, 1459.1, 1359.7, 1299.6, 1244.9, 1209 0.0, 1188.4 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 0.92-1.00 (4H, m), 2.57-2.65 (1H, m), 3.65 (2H, s), 3.94 (3H , S), 4.53 (2H, s), 4.64 (2H, d, J = 5.5 Hz), 6.91-7.06 (7H, m), 7.32 (2H, d, J = 8.6 Hz), 7.39 (1 H, dd, J = 8.6, 2.4 Hz), 8.12 (1 H, d, J = 2.4 Hz), 8.18 (1 H, t, J = 5.5 Hz).
ESIMS (+): 504.2 [M + H] ⁺ .
HRESIMS (+): 504.19423 (calculated as C ₂₈ H ₂₇ FN ₃ O ₅ 504.19347).
Elemental analysis: Calculated value C as measured C 66.91%, H 6.05%, N 8.06%, C ₂₉ H ₃₀ FN ₃ O ₅ C 67.09%, H 5.82%, N 8.09 %.

[Example 26]
5- (2,4-Dioxo-3- (2-hydroxyethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

To a methanol / tetrahydrofuran = 1/1 solution (3 mL) of the compound of Example 23 (159 mg, 0.27 mmol), 10% palladium carbon (15.9 Mg) was added under an argon atmosphere, and at room temperature under a hydrogen atmosphere. Stir for 11 hours. The insoluble material in the reaction solution was filtered off using Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; ethyl acetate: methanol) to give the title compound (132 mg , 96%) was obtained as colorless powdery crystals.

Melting point: 101-102 ° C
IR (ATR): 3383.2, 2933.1, 1757.3, 1693.8, 1645.8, 1606.1, 1526.0, 1495.9, 1460.5, 1416.1, 1389.4, 1296 .1,1246.3,1209.8,1184.9 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 2.80 (1H, t, J = 5.8 Hz), 3.73-3.80 (4H, m), 3.81-3.88 (2H, m) 3.95 (3H, s), 4.57 (2H, s), 4.64 (2H, d, J = 5.5 Hz), 6.91-7.06 (7H, m), 7.31. (2H, d, J = 8.6 Hz), 7.39 (1H, dd, J = 8.6, 2.4 Hz), 8.11 (1H, d, J = 2.4 Hz), 8.19 ( 1H, t, J = 5.5 Hz).
ESIMS (+): 508.2 [M + H] ⁺ .
HRESIMS (+): 508.18835 (calculated as C ₂₇ H ₂₇ FN ₃ O ₆ 508.18839).
Elemental analysis: Measured value C 63.79%, H 5.30%, N 8.23%, calculated as C ₂₇ H ₂₆ FN ₃ O ₆ C 63.90%, H 5.16%, N 8.28 %.

[Example 27]
4- [4- [5- (2,4-Dioxo-3-cyclopropylimidazolidin-1-yl) methyl-2-methoxybenzamidomethyl] phenoxy] ethyl benzoate

To a 1,2-dichloroethane solution (11.5 mL) of the compound of Example 20 (1.19 g, 2.30 mmol), cyclopropylboric acid (395 mg, 4.60 mmol), sodium carbonate (488 mg, 4.60 mmol), acetic acid. Copper (418 mg, 2.30 mmol) and 2,2′-bipyridyl (359 mg, 2.30 mmol) were added and stirred at 70 ° C. for 6 hours.

A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to obtain the title compound (517 mg, 40%) as colorless powder crystals.

IR (ATR): 3395.2, 2981.0, 1769.3, 1704.9, 1650.0, 1597.4, 1497.7, 1460.5, 1430.7, 1365.4, 1274.7, 1235 0.0, 1161.1, 1098.8, 1015.2, 947.8, 871.8, 821.1, 749.8, 648.4, 595.1, 501.6, 435.5 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 0.93-1.00 (4H, m), 1.38 (3H, t, J = 7.3 Hz), 2.57-2.65 (1H, m) , 3.65 (2H, s), 3.96 (3H, s), 4.36 (2H, q, J = 7.3 Hz), 4.53 (2H, s), 4.68 (2H, d) , J = 5.4 Hz), 6.95-7.01 (3H, m), 7.03 (2H, d, J = 8.5 Hz), 7.35-7.43 (3H, m), 7 97-8.03 (2H, m), 8.13 (1H, d, J = 2.4 Hz), 8.22 (1H, t, J = 5.4 Hz).
ESIMS (+): 558.2 [M + H] ⁺ .
HRESIMS (+): 558.222357 (calculated as C ₃₁ H ₃₂ N ₃ O ₇ 558.22402).

[Example 28]
4- [4- [5- (2,4-Dioxo-3-cyclopropylimidazolidin-1-yl) methyl-2-methoxybenzamidomethyl] phenoxy] benzoic acid

1N sodium hydroxide aqueous solution (1.73 mL) was added to an ethanol solution (2 mL) of the compound of Example 27 (483 mg, 0.87 mmol), and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture to adjust to pH = 3, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; ethyl acetate: methanol) to obtain the title compound (280 mg, 61%) as colorless powder crystals.

Melting point: 77-79 ° C
IR (ATR): 3383.5, 2928.0, 1768.7, 1705.4, 1596.3, 1498.1, 1429.4, 1304.2, 1233.1, 1158.5, 1110.1, 1015 0.0, 945.8, 874.1, 819.9, 772.1, 750.0, 596.0, 499.5, 438.1 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 0.78-0.84 (4H, m), 2.48-2.56 (1H, m), 3.73 (2H, s), 3.87 (3H, s), 4.41 (2H, s), 4.50 (2H, d, J = 5.5 Hz), 6.99 (2H, d, J = 8.6 Hz), 7.06-7 .15 (3H, m), 7.35-7.43 (3H, m), 7.64 (1H, d, J = 2.4 Hz), 7.92 (2H, d, J = 8.6 Hz) , 8.74 (1H, t, J = 5.5 Hz), 12.8 (1H, brs).
EIMS (+): 530.2 [M] ⁺ .
HREIMS (+): 530.19283 (calculated value 530.19272 as C ₂₉ H ₂₈ N ₃ O ₇ ).

[Example 29]
4- [4- [5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxybenzamidomethyl] phenoxy] benzoic acid

1N sodium hydroxide aqueous solution (2.38 mL) was added to an ethanol solution (4 mL) of the compound of Example 20 (615 mg, 1.19 mmol), and the mixture was heated and stirred at room temperature for 3 hours and at 80 ° C. for 4 hours. 1N Hydrochloric acid was added to the reaction mixture to adjust to pH = 3, and the precipitated crystals were collected by filtration, and the residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; chloroform: methanol) to give the title compound (355 mg). 61%) was obtained as colorless powdery crystals.

Melting point: 120-122 ° C
IR (ATR): 3386.7, 3059.6, 1764.2, 1705.7, 1636.6, 1596.4, 1535.0, 1498.3, 1462.2, 1415.7, 1305.8, 1231 1, 1159.7, 1103.0, 1015.1, 953.1, 846.6, 816.4, 750.2, 692.0, 631.5, 597.0, 500.1, 415.4 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.79 (2H, s), 3.88 (3H, s), 4.39 (2H, s), 4.50 (2H, d, J = 6) .1 Hz), 6.99 (2H, d, J = 9.2 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.12 (1H, d, J = 8.6 Hz), 7 .35-7.43 (3H, m), 7.64 (1H, d, J = 2.4 Hz), 7.92 (2H, d, J = 9.2 Hz), 8.75 (1H, t, J = 6.1 Hz), 10.9 (1H, s), 12.8 (1H, brs).
EIMS (+): 490.2 [M] ⁺ .
HREIMS _(+): 490.16167 (calculated value 490.16142 as _{_{_{C 26 H 24 N 3 O 7}}} ).

[Example 30]
4- [4- [5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxybenzamidomethyl] phenoxy] benzamide

To a N, N′-dimethylformamide solution (2 mL) of the compound of Example 29 (351 mg, 0.72 mmol), triethylamine (0.22 mL, 1.58 mmol), diethylphosphorocyanidate (0.13 mL, 0.79 mmol) was added, and the mixture was stirred for 10 minutes under the same conditions. To the reaction mixture was added 0.5 M ammonia / 1,4-dioxane solution (2.88 mg, 1.44 mmol), and the mixture was stirred at room temperature for 3 hours.

1N hydrochloric acid was added to the reaction mixture to adjust the pH to 3, followed by extraction with chloroform / methanol = 10/1 (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; chloroform: methanol) to obtain the title compound (88.1 mg, 25%) as colorless powder crystals.

Melting point: 208-210 ° C
IR (ATR): 3379.2, 3247.7, 2985.8, 2739.7, 1763.4, 1709.0, 1638.5, 1609.9, 1503.9, 1460.5, 1414.8, 1345 6, 1246.9, 1231.0, 1171.7, 1103.7, 1014.4, 940.9, 850.4, 764.5, 686.9, 597.9, 530.4, 416.2 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.79 (2H, s), 3.87 (3H, s), 4.39 (2H, s), 4.49 (2H, d, J = 6) .1 Hz), 6.97 (2H, d, J = 8.5 Hz), 7.05 (2H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7 .27 (1H, brs), 7.34-7.40 (3H, m), 7.64 (1H, d, J = 2.4 Hz), 7.84-7.93 (3H, m), 8 .73 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
EIMS (+): 489.2 [M] ⁺ .
HREIMS _(+): 489.17765 (calculated value 489.17741 as _{_{_{C 26 H 25 N 4 O 6}}} ).

[Example 31]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-piperidyloxy) phenylmethyl] benzamide hydrochloride

To a methanol solution (12.6 mL) of Example 16 (1.40 g, 2.53 mmol) was added 4N hydrogen chloride-ethyl acetate solution (12.6 mL), and the mixture was stirred at room temperature for 7.5 hours. Under ice-cooling, 5N aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 6-7, and ethyl acetate and methanol were distilled off under reduced pressure, followed by extraction twice with a chloroform-methanol mixed solvent (5: 1). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Purification by trituration (diisopropyl ether: ethyl acetate: methanol = 3: 3: 1) gave the title compound (1.186 g, 2.43 mmol, 96%) as a white solid.

White solid IR (ATR): 3409.2, 3157.6, 2939.9, 2720.9, 2480.2, 1757.8, 1713.4, 1643.4, 1608.3 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 1.70-1.79 (2H, m), 2.00-2.07 (2H, m), 2.96-3.02 (2H, m) 3.16-3.21 (2H, m), 3.78 (2H, s), 3.86 (3H, s), 4.38-4.41 (4H, m), 4.54-4 .59 (1H, m), 6.94 (2H, d, J = 8.9 Hz), 7.12 (1H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8. 9 Hz), 7.36 (1 H, dd, J = 2.4, 8.6 Hz), 7.61 (1 H, d, J = 2.4 Hz), 8.64 (1 H, t, J = 6.1 Hz) ).
ESIMS (+): 453.2 [M + H] ⁺ .
HRESIMS _(+): 453.21432 (calculated value 453.21379 as _{_{_{C 24 H 29 N 4 O 5}}} ).

[Example 32]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (N-acetyl-4-piperidyloxy) phenylmethyl] benzamide

Acetic anhydride (0.150 mL) and triethylamine (0.092 mL, 0.663 mmol) were added to a tetrahydrofuran solution (6.64 mL) of the compound of Example 31 (300 mg, 0.613 mmol), and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted 5 times with ethyl acetate.

The ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Purification by an automatic column chromatograph system (Biotage, 11 g of KP-NH, hexane: ethyl acetate) gave the title compound (265 mg, 0.536 mmol, 87%) as a colorless amorphous substance.

Colorless amorphous IR (ATR): 3389.5, 2931.9, 1765.6, 1718.6, 1635.3, 1507.9 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.75-1.96 (4H, m), 2.12 (3H, s), 3.37-3.43 (1H, m), 3.62- 3.76 (3H, m), 3.78 (2H, s), 3.94 (3H, s), 4.53 (3H, s), 4.61 (2H, d, J = 5.5 Hz) , 6.89 (2H, d, J = 8.6 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz), 7.40 ( 1H, dd, J = 2.4, 7.9 Hz), 7.60 (1H, s), 8.14-8.17 (2H, m).
ESIMS (+): 495.2 [M + H] ⁺ .
HRESIMS _(+): 495.22485 (calculated value 495.22436 as _{_{_{C 26 H 31 N 4 O 6}}} ).
Elemental analysis: Found C 61.51%, H 6.17%, N 10.87%, C 26 H 30 N 4 O 6 · 0.7H Calculated C 61.58% as ₂ O, H 6.24 %, N 11.05%.

[Example 33]
5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (N-methyl-4-piperidyloxy) phenylmethyl] benzamide

To a dichloromethane-tetrahydrofuran solution (6.64 mL) of the compound of Example 31 (300 mg, 0.613 mmol) was added 37% aqueous formaldehyde solution (0.059 mL, 0.729 mmol) and triethylamine (0.092 mL, 0.663 mmol). Stir at room temperature for 1 hour. Sodium (triacetoxy) borohydride (183 mg, 0.862 mmol) was added and stirred at room temperature for 7 hours.

37% formaldehyde aqueous solution (0.059 mL, 0.729 mmol) and hydrogenated (triacetoxy) sodium borohydride (183 mg, 0.862 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the organic solvent was distilled off under reduced pressure, and the resulting insoluble material was removed by filtration. The filtrate was extracted twice with ethyl acetate. The ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.

The obtained residue and the collected solid were combined and purified by an automatic column chromatograph system (Biotage, KP-sil 25 g, chloroform: methanol, Biotage, KP-NH 11 g, ethyl acetate: methanol), colorless amorphous One title compound (92 mg, 0.197 mmol, 32%) was obtained.

Colorless amorphous IR (ATR): 3388.2, 2939.8, 2799.5, 1765.1, 1715.8, 1643.3, 1530.3, 1507.9 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.80-1.88 (2H, m), 1.98-2.03 (2H, m), 2.30 (5H, m), 2.69 (2H , S), 3.78 (2H, s), 3.93 (3H, s), 4.30 (1H, s), 4.53 (2H, s), 4.61 (2H, d, J = 5.5 Hz), 6.89 (2H, d, J = 5.5 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.40 (1H, dd, J = 2.4, 8.6 Hz), 8.11-8.14 (2H, m).
ESIMS (+): 467.2 [M + H] ⁺ .
HRESIMS (+): 467.22893 (calculated as C ₂₅ H ₃₁ N ₄ O ₅ 467.22944).
Elemental analysis: Found C 62.55%, H 6.55%, N 11.62%, C 25 H 30 N 4 O 5 · 0.7H Calculated C 62.67% as ₂ O, H 6.61 %, N 11.69%.

[Example 34]
3- (2,4-Dioxoimidazolidin-1-yl) methyl-4-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide first step 3-formyl-4-methoxy-N- [4- (4-Fluorophenoxy) phenylmethyl] benzamide

To a solution of 3-formyl-4-methoxybenzoic acid (784 mg, 4.35 mmol) in N, N-dimethylformamide (12 mL) under ice-cooling, triethylamine (0.61 mL, 4.35 mmol) and ethyl chloroformate (0.44 mL) were added. 4.57 mmol) and stirred for 10 minutes under the same conditions.

Next, [4- (4-fluorophenoxy) phenylmethyl] amine hydrochloride (1.21 g, 4.79 mmol) was added to the reaction mixture, and the mixture was stirred for 20 minutes under the same conditions. The reaction mixture was poured into ice water, and 1N hydrochloric acid was added to adjust to pH 4, followed by extraction with ethyl acetate (40 mL × 3).

The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to obtain the title compound (1.29 g, 78%) as colorless powder crystals.

IR (ATR): 3313.4, 3071.8, 2869.1, 1882.9, 1681.7, 1635.3, 1604.0, 1542.9, 1491.1, 1415.7, 1315.9, 1246 0.0, 1208.8, 1188.7, 1105.4, 1015.3, 920.3, 827.2, 762.7, 691.4, 648.3, 564.2, 523.8, 502.1 cm ^-1 .
¹ H-NMR (CDCl ₃ , 400 MHz) δ4.00 (3H, s), 4.59 (2H, d, J = 5.4 Hz), 6.67 (1H, t, J = 5.4 Hz), 6 .92-7.05 (6H, m), 7.08 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.23 (1H, dd, J = 8.5, 2.4 Hz), 10.4 (1H, s).
EIMS (+): 379 [M] ⁺ .
HREIMS (+): 379.1205 (calculated value 379.1220 as C ₂₂ H ₁₈ FNO ₄ ).

Second Step 2- [5-[[4- (4-Fluorophenoxy) phenylmethyl] carbamoyl] -2-methoxyphenylmethyl] aminoacetic acid methyl

To a methylene chloride solution (9.4 mL) of glycine methyl ester hydrochloride (620 mg, 4.94 mmol), triethylamine (0.69 mL, 4.94 mmol) and the compound of the first step (1.25 g, 3.29 mmol) were stirred with ice cooling. ), Sodium triacetoxyborohydride (1.05 g, 4.94 mmol) and acetic acid (0.28 mL, 4.94 mmol) were added, and the mixture was stirred at room temperature for 1 hour.

A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil 25 g; ethyl acetate: methanol) to obtain the title compound (1.22 g, 82%) as a colorless oil.

IR (ATR): 3315.2, 2950.4, 2840.2, 1738.1, 1634.2, 1607.9, 1494.6, 1436.9, 1316.4, 1249.9, 1209.6, 1145 8, 1025.6, 909.0, 876.6, 827.6, 729.4, 627.5, 502. cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 3.42 (2H, s), 3.70 (3H, s), 3.82 (2H, s), 3.88 (2H, s), 4.60 ( 2H, d, J = 5.4 Hz), 6.38 (1H, t, J = 5.4 Hz), 6.90 (1H, d, J = 8.5 Hz), 6.92-7.06 (6H M), 7.32 (2H, d, J = 8.5 Hz), 7.68 (1H, d, J = 2.4 Hz), 7.78 (1H, dd, J = 8.5, 2.. 4 Hz.
ESIMS (+): 453.2 [M + H] ⁺ .
HRESIMS _(+): 453.18298 (calculated value 453.18257 as _{_{_{C 25 H 26 FN 2 O 5}}} ).

Third Step 3- (2,4-Dioxoimidazolidin-1-yl) methyl-4-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

Potassium cyanate (260 mg, 3.21 mmol) was added to an acetic acid solution (7.6 mL) of the compound in the second step (1.21 g, 2.67 mmol), and the mixture was stirred at room temperature for 30 minutes and then at 100 ° C. for 1.5 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated.

The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; hexane: ethyl acetate) and then triturated (hexane / ethyl acetate = 1/1) to give the title compound (1.08 g, 87%) as colorless. Obtained as powdery crystals.

Melting point: 115-118 ° C
IR (ATR): 3374.7, 3129.2, 3032.7, 2756.4, 1764.5, 1717.4, 1630.7, 1555.7, 1496.9, 1460.9, 1353.6, 1323 8, 1251.9, 1210.3, 1187.0, 1123.9, 1026.6, 995.5, 851.4, 830.4, 762.5, 693.7, 624.9, 551.7 , 506.8, 419.1 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 3.86 (3H, s), 3.88 (2H, s), 4.41 (2H, s), 4.44 (2H, d, J = 5 .5 Hz), 6.94 (2H, d, J = 8.6 Hz), 6.98-7.06 (2H, m), 7.09 (2H, d, J = 8.6 Hz), 7.15 −7.24 (2H, m), 7.31 (2H, d, J = 8.6 Hz), 7.69 (1H, d, J = 2.4 Hz), 7.88 (1H, dd, J = 8.6, 2.4 Hz), 8.94 (1H, t, J = 5.5 Hz), 10.9 (1H, s).
ESIMS (+): 464.2 [M + H] ⁺ .
HRESIMS (+): 464.16166 (calculated as C ₂₅ H ₂₃ FN ₃ O ₅ 464.16217).

[Example 35]
5- (2,4-Dioxo-8-oxa-1,3-diazaspiro [4.5] decan-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide

First Step 4- [3-[[4- (4-Fluorophenoxy) phenylmethyl] carbamoyl] -4-methoxyphenylmethyl] amino-tetrahydro-2H-pyran 4-methyl carboxylate

To a methylene chloride solution (5 mL) of 4-aminotetrahydro-2H-pyran-4-carboxylic acid methyl ester hydrochloride (464 mg, 2.37 mmol), triethylamine (0.33 mL, 2.37 mmol) with ice-cooling and stirring, Reference Example 1 (600 mg, 1.58 mmol), sodium triacetoxyborohydride (502 mg, 2.37 mmol) and acetic acid (0.14 mL, 2.37 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3).

The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to obtain the title compound (809 mg, 98%) as colorless powder crystals.

IR (ATR): 3401.5, 3325.7, 2959.1, 2853.6, 1727.2, 1644.4, 1535.8, 1498.6, 1420.8, 1362.1, 1279.1, 1246 .9, 1210.0, 1091.5, 1025.8, 980.3, 928.9, 879.7, 825.4, 781.0, 758.3, 688.0, 614.9, 567.5 , 504.5, 466.2 cm ⁻¹ .
¹ H-NMR (CDCl ₃ , 400 MHz) δ 1.66-1.74 (2H, m), 2.03-2.14 (2H, m), 3.56-3.65 (4H, m), 3 .77 (3H, s), 3.88-3.97 (5H, m), 4.65 (2H, d, J = 6.1 Hz), 6.92-7.06 (7H, m), 7 .32 (2H, d, J = 8.6 Hz), 7.45 (1H, dd, J = 8.3, 2.1 Hz), 8.16-8.24 (2H, m).
ESIMS (+): 523.2 [M + H] ⁺ .
HRESIMS _(+): 523.22516 (calculated value 523.22444 as _{_{_{C 29 H 32 FN 2 O 6}}} ).

Second Step 5- (2,4-Dioxo-8-oxa-1,3-diazaspiro [4.5] decan-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenyl Methyl] benzamide

To the acetic acid solution (5 mL) of the compound in the first step (806 mg, 1.54 mmol) was added potassium cyanate (150 mg, 1.85 mmol), and the mixture was stirred at room temperature for 30 minutes and then stirred at 100 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3).

The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (Biotarget; SNAP Cartridge KP-Sil; hexane: ethyl acetate) and then triturated (diisopropyl ether) to give the title compound (686 mg, 83%) as colorless powder crystals.

Melting point: 90-93 ° C
IR (ATR): 2948.0, 1763.5, 1715.5, 1646.0, 1530.7, 1494.9, 1414.4, 1349.0, 1246.6, 1209.9, 1099.6, 1013 6, 933.4, 818.3, 771.0, 714.4, 633.0, 564.5, 504.5, 431.3 cm ⁻¹ .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ 1.52 (2H, d, J = 12.8 Hz), 1.86 (2H, td, J = 13.0, 5.1 Hz), 3.70 ( 2H, dd, J = 11.0, 4.9 Hz), 3.83-3.93 (5H, m), 4.43-4.49 (4H, m), 6.95 (2H, d, J = 9.2 Hz), 7.00-7.05 (2H, m), 7.09 (1H, d, J = 8.6 Hz), 7.16-7.24 (2H, m), 7.33 (2H, d, J = 8.6 Hz), 7.42 (1H, dd, J = 8.6, 2.4 Hz), 7.73 (1H, d, J = 2.4 Hz), 8.69 ( 1H, t, J = 6.1 Hz), 11.0 (1H, s).
ESIMS (+): 534.2 [M + H] ⁺ .
HRESIMS (+): 534.0472 (calculated as C ₂₉ H ₂₉ FN ₃ O ₆ 534.20404).

The usefulness of the compounds of the present invention is shown in Test Examples 1 to 3.

<Test Example 1: De novo lipid synthesis ability inhibiting action>
HepG2 cells were cultured in a 12-well plate for 48 hours, replaced with serum-free medium (FCS free / DMEM), and cultured for 16 hours. Subsequently, HepG2 cells were replaced in serum-free medium containing the test compound, [1- ¹⁴ C] -labeled acetic acid and unlabeled acetic acid, and further incubated for 3 hours.

After the incubation, the reaction was stopped by adding methanol, and then the reaction solution was recovered. Chloroform was added to the reaction solution, and after extraction by shaking, the lower layer (chloroform) was collected and dried. After a series of extraction operations were repeated again, the dried solid was dissolved in methanol, and the radioactivity was measured with a scintillation counter.

Table 4 shows the test results. The “inhibitory activity” in the table represents de novo lipid synthesis inhibitory activity when 30 μM of the test compound was used. Inhibition ratio 81% to 100%: A, inhibition ratio 51% to 80%: B, inhibition ratio 21 % To 50%: C, inhibition ratio 10% to 20%: D

As shown in Table 4, the compounds of the present invention showed a strong inhibitory activity on de novo lipid synthesis.

<Test Example 2: AMPKα and ACC1 phosphorylation promoting action>
HepG2 cells (6 cm ² culture dish) cultured in Dulbecco's modified Eagle medium (FCS / DMEM) containing 10% bovine serum and 1% penicillin / streptomycin were cultured in serum-free medium (FCS free / DMEM) for 16 hours. The medium was replaced with a test compound-containing medium and incubated for 3 hours (37 ° C., 5% carbon dioxide). Three hours later, the cell lysate was collected, and the amount of protein was quantified by the Bradford method. Then, phosphorylated AMPKα (pThr172) and phosphorylated ACC1 (pSer79) were detected by SDS-PAGE and Western blotting.

The test results of AMPKα (Thr172) phosphorylation are shown in Table 5. In the table, “EC ₅₀ ” represents the concentration of the test compound when 50% of the maximum effect of AMPKα (Thr172) phosphorylation ability by the test compound is shown, EC ₅₀ <1 μM: A, 1 μM <EC ₅₀ <5 μM : B, 5 μM <EC ₅₀ : C

The test results of ACC1 (Ser79) phosphorylation are shown in Table 6. In the table, “EC ₅₀ ” represents the concentration of the test compound when showing 50% of the maximum effect of ACC1 (Ser79) phosphorylation ability by the test compound, EC ₅₀ <1 μM: A, 1 μM <EC ₅₀ <5 μM. : B, 5 μM <EC ₅₀ : C

As shown in Tables 5 and 6, the compounds of the present invention were found to have good AMPKα phosphorylation promoting action and ACC phosphorylation promoting action.

<Test Example 3: Mouse blood glucose and triglyceride lowering action>
B6. V-Lep <ob> / J (ob / ob) male mice (Nippon Charles River) were bred from OA-2 diet (CLEA Japan) from 6 weeks of age, and then the test was started from 7 weeks of age. In the satiety state, the test compound (30 mg / kg) was suspended in a 0.1% Tween 80 solution and orally administered once a day for 7 days. Seven days later, blood was collected from the tail vein, and blood glucose and triglyceride were measured by an enzymatic method.

Table 7 shows the test results. The “decrease rate” in the table is a value obtained by subtracting the average blood glucose level (or average triglyceride level) of the test compound administration group from the average blood glucose level (or average triglyceride level) of the vehicle control group. Of 20% <reduction rate <30%: A, 10% <reduction rate <20%: B, 1% <reduction rate <10%: C To do.

As shown in Table 7, the compound of the present invention was found to have a good mouse blood glucose lowering action and triglyceride lowering action.

Although the present invention has been described in detail using specific embodiments, it will be apparent to those skilled in the art that various modifications and variations can be made without departing from the spirit and scope of the invention. This application is based on a Japanese patent application (Japanese Patent Application No. 2010-187713) filed on August 25, 2010, which is incorporated by reference in its entirety.

Since the novel benzylhydantoin derivative and its addition salt of the present invention have an excellent human AMPK activating action, it is useful as an advantageous effect derived from the AMPK activating action, such as a hypoglycemic agent or a lipid lowering agent.

Claims

Hydantoin derivatives represented by the general formula (1) or pharmacologically acceptable salts thereof or hydrates thereof.

[In Formula (1), R 1 has a hydrogen atom, a C 1 -C 6 alkyl group which may have a substituent, a C 3 -C 6 cycloalkyl group which may have a substituent, or a substituent. An optionally substituted C 6 -C 10 aryl group, an optionally substituted C 7 -C 12 aralkyl group, an optionally substituted 5- or 6-membered aromatic heterocyclic group or substituent Represents a condensed heterocyclic group which may have
X represents C 1 -C 4 alkylene, C 2 -C 4 alkenylene, C 2 -C 4 alkynylene or general formula (2),
Y represents a single bond, C 1 -C 4 alkylene or general formula (5),
Z is a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, or an optionally substituted C 1 to C 6 alkoxy group, optionally having C 3 to C 6 cycloalkyloxy group, hydroxyl group, nitro group, cyano group, optionally having amino group and substituent Or a C 6 -C 10 aryl group, a 5- or 6-membered aromatic heterocyclic group which may have a substituent, a condensed heterocyclic group which may have a substituent, or a substituent. Good C 7 -C 12 aralkyl group, optionally substituted C 6 -C 10 aryloxy group, optionally substituted C 7 -C 12 aralkyloxy group, optionally substituted good C 1 ~ C 6 alkylthio group, an optionally substituted C 6 ~ C 10 arylthio group Represents an C 7 ~ C 12 aralkylthio group which may have a substituent,
Ring A and Ring B are the same or different, and may be a C 3 to C 6 cycloalkyl group which may have a substituent, a 5- or 6-membered saturated heterocyclic group which may have a substituent, a substituted A C 6 -C 10 aryl group which may have a group, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent,
R 2 and R 3 are the same or different and are a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group, a substituted group. Represents a C 6 -C 10 aryl group which may have a group or a C 7 -C 12 aralkyl group which may have a substituent, or R 2 and R 3 are bonded to each other, and R 2 and R 3 The general formula (6) is represented together with the carbon atom to be bonded]

[In the formula (2), T represents a single bond, C 1 -C 4 alkylene, C 2 -C 4 alkenylene or C 2 -C 4 alkynylene;
U represents a single bond, C 1 -C 4 alkylene or C 2 -C 4 alkenylene;
A is a carbonyl group, an oxygen atom, —S (O) p — (p represents an integer selected from 0 to 2), —NR 4 — (R 4 is a hydrogen atom, C 1 which may have a substituent) C 6 alkyl group, optionally substituted C 7 to C 12 aralkyl group, optionally substituted C 6 to C 10 aryl group, optionally substituted C 1 to C 6 aliphatic acyl group, optionally substituted C 1 -C 6 alkylsulfonyl group, optionally substituted 5-membered or 6-membered aromatic heterocyclic group or optionally substituted Represents a good condensed heterocyclic group), —N (R 5 ) SO 2 —, —SO 2 N (R 5 ) — (R 5 is a hydrogen atom, a C 1 -C 6 alkyl group optionally having substituent (s). Or a C 7 to C 12 aralkyl group which may have a substituent), a general formula (3) or a general formula (4)]

[In Formula (3), L 1 represents a single bond, an oxygen atom or —NR 5 —, and R 5 represents the same meaning as described above]

[In Formula (4), L 2 represents a single bond or an oxygen atom, and R 5 represents the same meaning as described above.]

[In the formula (5), Q 1 represents an oxygen atom, —S (O) q — (q represents an integer selected from 0 to 2), —NR 6 — (R 6 represents a hydrogen atom, and has a substituent. An optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 7 -C 12 aralkyl group, an optionally substituted C 6 -C 10 aryl group, and an optionally substituted group. Good C 1 -C 6 aliphatic acyl group, optionally substituted C 1 -C 6 alkylsulfonyl group, optionally substituted 5- or 6-membered aromatic heterocyclic group or substituent Or a carbonyl group, and h and j are the same or different and each represents an integer of 0 to 2]

[In the formula (6), Q 2 is a single bond, methylene, oxygen atom, —S (O) r — (r represents an integer selected from 0 to 2) or —NR 7 — (R 7 is a hydrogen atom, An optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 7 -C 12 aralkyl group, an optionally substituted C 6 -C 10 aryl group, a substituent A C 1 -C 6 aliphatic acyl group which may have a substituent, a C 1 -C 6 alkylsulfonyl group which may have a substituent, a 5-membered or 6-membered aromatic complex which may have a substituent Represents a condensed heterocyclic group which may have a cyclic group or a substituent, and m and n are the same or different and represent 1 or 2]
The hydantoin derivative or a pharmacologically acceptable salt thereof or a hydrate thereof according to claim 1, wherein, in the general formula (1), X is C 1 -C 4 alkylene or the general formula (2a).

[In the formula (2a), T 1 represents a single bond or C 1 -C 4 alkylene,
U 1 represents a single bond or C 1 -C 4 alkylene,
A 1 is an oxygen atom, a sulfur atom, —NR 4a —, (R 4a is a hydrogen atom, an optionally substituted C 1 to C 6 alkyl group or an optionally substituted C 7 to C 12. An aralkyl group), —N (R 5a ) SO 2 —, —SO 2 N (R 5a ) — (R 5a is a C 1 -C 6 alkyl group or substituent optionally having a hydrogen atom or a substituent) Represents a C 7 to C 12 aralkyl group which may have a general formula (3a) or a general formula (4a)]

[In Formula (3a), L 1a represents a single bond or —NR 5a —, and R 5a represents the same meaning as described above.]

[In formula (4a), R 5a is as defined above.]
The hydantoin derivative or a pharmacologically acceptable salt thereof or a hydrate thereof according to claim 1 or 2, wherein X in the general formula (1) is represented by the general formula (2b).

[In formula (2b), T 1 represents a single bond or C 1 -C 4 alkylene, and A 2 represents general formula (3b) or general formula (4a)].

[In the formula (3b), R 5a ′ represents a hydrogen atom, a C 1 to C 6 alkyl group which may have a substituent or a C 7 to C 12 aralkyl group which may have a substituent, and R 5a Represents the same meaning as described above]

[In formula (4a), R 5a is as defined above.]
In the general formula (1), Z represents a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkoxy group, an optionally substituted C 3 -C 6 cycloalkyloxy group, Nitro group, cyano group, optionally substituted amino group, optionally substituted C 6 -C 10 aryloxy group, optionally substituted C 7 -C 12 aralkyloxy group A C 1 -C 6 alkylthio group which may have a substituent, a C 6 -C 10 arylthio group which may have a substituent, or a C 7 -C 12 aralkylthio group which may have a substituent. The hydantoin derivative according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, or a hydrate thereof.
In the general formula (1), Ring A and Ring B are the same or different and may have a C 3 -C 6 cycloalkyl group which may have a substituent, or C 6 -C which may have a substituent. A 10- aryl group, a 5- or 6-membered saturated heterocyclic group that may have a substituent, a 5- or 6-membered aromatic heterocyclic group that may have a substituent, or a substituent The hydantoin derivative or a pharmaceutically acceptable salt thereof or a hydrate thereof according to any one of claims 1 to 4, which is represented by a good condensed heterocyclic group.
The hydantoin derivative or a pharmacologically acceptable salt thereof or a hydrate thereof according to any one of claims 1 to 5, wherein Ring A is represented by the general formula (7) in the general formula (1).

[In the formula (7), V 1 , V 2 , V 3 and V 4 are the same or different and each represents a nitrogen atom or C—R 8 (R 8 may have a hydrogen atom, a halogen atom or a substituent. May have a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group which may have a substituent, a C 1 -C 6 alkoxy group which may have a substituent, or a substituent C 3 -C 6 cycloalkyloxy group, hydroxyl group, nitro group, cyano group, hydroxycarbonyl group, C 1 -C 6 alkoxycarbonyl group, amino group which may have a substituent, may have a substituent C 6 -C 10 aryloxy group, optionally substituted C 7 -C 12 aralkyloxy group, optionally substituted C 1 -C 6 alkylthio group, optionally substituted C 6 ~ C 10 arylthio group, or which may C 7 ~ have a substituent Represents a represents) a 12 aralkylthio group]
Hydantoin derivatives represented by the general formula (1a) or pharmacologically acceptable salts thereof or hydrates thereof.

[In Formula (1a), R 1a has a hydrogen atom, a C 1 -C 6 alkyl group which may have a substituent, a C 3 -C 6 cycloalkyl group which may have a substituent, or a substituent. An optionally substituted C 6 -C 10 aryl group or an optionally substituted C 7 -C 12 aralkyl group,
X a represents the general formula (2c),
Y a represents a single bond, methylene, oxygen atom, sulfur atom or —NR 6a — (R 6a represents a hydrogen atom or an optionally substituted C 1 -C 6 alkyl group);
Z a is a hydrogen atom, an optionally substituted C 1 to C 6 alkoxy group, an optionally substituted C 3 to C 6 cycloalkyloxy group, or an optionally substituted C 6. It represents ~ C 10 aryloxy group,
Ring A a represents a C 6 -C 10 aryl group which may have a substituent or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent,
Ring B a is an optionally substituted C 3 ~ C 6 cycloalkyl group, a saturated heterocyclic group of 5- or 6-membered and may have a substituent, an optionally substituted C 6 ~ C 10 represents an aromatic heterocyclic group of the aryl group or 5-membered may have a substituent or 6-membered,
R 2a and R 3a are the same or different and are a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 6 cycloalkyl group or a substituted group. Or a C 6 -C 10 aryl group which may have a group, or R 2a and R 3a are bonded to each other, together with the carbon atom to which R 2a and R 3a are bonded, the general formula (6a)]

[In the formula (2c), T 2 represents a single bond or methylene,
A 3 represents General Formula (3c) or General Formula (4b)]

[In Formula (3c), R 5b and R 5b ′ are the same or different and each represents a hydrogen atom or a C 1 -C 6 alkyl group which may have a substituent]

[In formula (4b), R 5b represents the same meaning as described above]

[In the formula (6a), Q 2a represents a single bond, methylene, oxygen atom, sulfur atom, —NR 7a — (R 7a represents a hydrogen atom or a C 1 -C 6 alkyl group which may have a substituent) M and n are the same or different and represent 1 or 2]
The hydantoin derivative represented by the general formula (1b) or a pharmacologically acceptable salt thereof or a hydrate thereof.

[In the formula (1b), R 1b represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a general formula (8);
Xb represents general formula (9), general formula (10), or general formula (11),
Y b represents an oxygen atom or a sulfur atom,
Z b represents a hydrogen atom or a C 1 -C 6 alkoxy group,
Ring A b represents a C 6 ~ C 10 aryl group or pyridyl group,
Ring B b is (1) a C 3 -C 6 cycloalkyl group,
(2) a piperidinyl group optionally substituted with a C 1 -C 6 alkyl group, a C 1 -C 6 aliphatic acyl group or a C 2 -C 7 alkoxycarbonyl group, or (3) a halogen atom, C 1 -C A 6 alkyl group, a C 1 -C 6 alkoxy group, a C 2 -C 7 alkoxycarbonyl group, a cyano group, an amino group optionally substituted with 1 or 2 C 1 -C 6 alkyl groups, a hydroxycarbonyl group, or Represents a C 6 -C 10 aryl group optionally substituted by an aminocarbonyl group,
R 2b and R 3b are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 6 -C 10 aryl group or general formula (12), or R 2b and R 3b are bonded to each other. , R 2b and R 3b represent the general formula (6b) together with the carbon atom to which they are bonded]

[In the formula (8), R 9 represents a hydroxyl group, a C 7 to C 12 aralkyloxy group or a 3- to 6-membered cyclic amino group, and v represents an integer of 1 to 6]

[In the formula (12), R 10 represents a hydroxycarbonyl group or a C 8 to C 13 aralkyloxycarbonyl group, and w represents an integer of 1 to 6]

[In formula (6b), m and n are as defined above]
The hydantoin derivative of claim 7 or 8, represented by the general formula (1c), a pharmacologically acceptable salt thereof, or a hydrate thereof.

[In the formula (1c), R 11 represents a halogen atom, a C 2 -C 7 alkoxycarbonyl group, a cyano group, or an amino group optionally substituted by 1 or 2 C 1 -C 6 alkyl groups, R 1b , R 2b , R 3b and Z b are as defined above.
The compound represented by the general formula (1) is
(R) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
(S) -5- (2,4-dioxo-5-propylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-5,5-dimethylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
3- (2,4-dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenyl] benzamide,
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-tert-butoxycarbonylpiperidin-1-yloxy) phenylmethyl] benzamide;
5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenylthio) phenylmethyl] benzamide,
5- (2,4-Dioxo-8-oxa-1,3-diazaspiro [4.5] decan-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide ,
5- (2,4-dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-3-butylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide,
5- (2,4-dioxo-3-cyclopropylimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
5- (2,4-dioxo-3- (2-hydroxyethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide;
5- (2,4-dioxo-3- (2-morpholinoethyl) imidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-fluorophenoxy) phenylmethyl] benzamide or 5- (2 , 4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-cyanophenoxy) phenylmethyl] benzamide, or a pharmaceutically acceptable salt thereof Or their hydrates.
A pharmaceutical comprising one or more of the hydantoin derivatives according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient.
An AMPK activator comprising as an active ingredient at least one of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of claims 1 to 10, or a hydrate thereof.
A lipid-lowering agent comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of claims 1 to 10 or hydrates thereof as an active ingredient.
11. A prophylactic or therapeutic agent for arteriosclerosis comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts or hydrates thereof according to any one of claims 1 to 10.
A preventive or therapeutic agent for diabetes comprising the hydantoin derivative according to any one of claims 1 to 10, or a pharmacologically acceptable salt thereof, or one or more hydrates thereof as an active ingredient.
A prophylactic or therapeutic agent for obesity comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of claims 1 to 10.
A cancer therapeutic agent comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof according to any one of claims 1 to 10 as an active ingredient.