JP2013230986A - Novel hydantoin derivative and medicinal agent comprising the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which has a potent AMPK activation activity and exhibits an advantageous effect that comes from the AMPK activation activity in vivo.SOLUTION: It has been found out that 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 has an excellent human AMPK activation activity, and shows excellent blood sugar decrease action and lipopenic action in vivo.

Description

The present invention relates to a hydantoin derivative and an addition salt thereof effective as a human AMPK activator for treating lipid metabolism disorders, diabetes and the like, and a pharmaceutical composition containing these compounds.

In recent years, due to lifestyle changes, the obese population has increased, and accompanying this, patients with so-called metabolic syndrome (metabolic syndrome) who have hyperlipidemia, hyperglycemia (diabetes), and lifestyle-related diseases represented by hypertension 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, stroke, etc., and in patients with metabolic syndrome that develop these symptoms, arteriosclerosis It is because it makes it easy to develop and develop. Possible causes of the disease include visceral fat obesity, abnormal lipid metabolism, abnormal glucose metabolism, abnormal blood pressure, etc. (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, a combination of drugs for controlling blood glucose level and blood lipid concentration is used for pharmacological treatment of diabetic patients and hyperglycemic patients with hyperlipidemia. As drugs for controlling blood glucose levels, sulfonylurea drugs, thiazolidine drugs, and biguanide drugs are widely used. However, side effects such as hypoglycemia, cardiac hypertrophy, edema, and lactic acidosis have been reported in the use of these drugs. As drugs for controlling blood lipid levels, fibrates and statins are widely used, but side effects such as gastrointestinal disorders, liver dysfunction, and renal dysfunction have been reported. Furthermore, in combination therapy, there is a problem of side effects due to the results 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, studies on energy metabolism, obesity, and diabetes onset mechanisms have 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 that is widely present in living bodies such as muscle and liver, and functions as a “metabolic sensor” that promotes metabolism and promotes ATP synthesis in situations where intracellular ATP levels decrease. 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 that it is an intracellular mediator of activated fatty acid oxidation and glucose utilization promoting action that is activated. For example, AMPK is known to affect mitochondrial fatty acid oxidation through activity control on acetyl-CoA carboxylase (ACC).

Thus, AMPK is not only activated under intracellular energy deficiency, but is thought to play an important role in the energy metabolism and nutrient metabolism of the living body. Therefore, activation of AMPK leads to improvement of abnormal sugar metabolism and abnormal lipid metabolism, and can be said to be a suitable molecular target in the prevention of obesity and the treatment of diabetes.

As compounds that activate AMPK, in addition to the aforementioned adipocyte-derived hormone, metformin (non-patent document 5) and AICAR (aminoimidazole carboxamide ribonucleotide), which are antidiabetics, are 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 and lactic acidosis have been reported, and there are problems in therapeutic effect and safety.

On the other hand, compounds having formulas (A) to (Q) described in Table 1 are known as compounds that have been reported to have an AMPK activating action, but none of them have a benzylhydantoin structure, and Differ in structure.

  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 compound of the present invention.

Patent Document 24 discloses a general formula (S) having an anticancer activity.

[Wherein 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 heteromonocyclic or a heterobicyclic ring. D represents a phenyl group or a 6-membered or 5-membered heterocyclic group, E represents a phenyl group, a pyridyl group or a pyrimidyl group, 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)

(Wherein R4 independently represents a hydrogen atom, an alkyl group, etc.)] is disclosed. 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.

Patent Document 25 discloses a general formula (U) having a factor Xa inhibitory action.

[Wherein, D and D ′ represent a hydrogen atom, a cyano group, R ¹ represents a hydrogen atom, a halogen atom, etc., R ² represents a hydrogen atom, ═O, a C _1-4 alkyl group, etc. 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 ′} represent hydrogen, C _1-4 alkyl group, benzyl group, phenyl group, etc. Z represents a bond or C _1-4 alkylene, A represents a C _3-10 hydrocarbon ring optionally substituted by 0-2 R ⁶ , B represents XY, CONR ³ represents R ^{3 ′,} etc., X represents —C (O) NR ³ —, —NR ³ C (O) —, etc., and Y is substituted with 0-2 R ⁶ of C _3-10 represent like hydrocarbon ring which may C _3-10, R ⁶ is (CH _{2) n} OR ^3, represents and ^{(CH2) r R 3 R 3} ', R 10 represents a hydrogen atom, a halogen atom] The compounds represented are disclosed. However, there is no hydantoin derivative in the compounds described in the specification, and there is no description about the AMPK activation action.

WO2004 / 034960 pamphlet WO2004 / 043957 pamphlet US2005038068 pamphlet WO2006 / 071095 pamphlet WO2007 / 002461 pamphlet WO2007 / 005785 pamphlet WO2007 / 062568 pamphlet EP1754483 pamphlet WO2008 / 006432 pamphlet WO2008 / 016278 pamphlet WO2008 / 133441 pamphlet WO2008 / 083124 pamphlet WO2009 / 076631 pamphlet WO2009 / 065131 pamphlet WO2009 / 019445 pamphlet WO2009 / 019446 pamphlet WO2009 / 028891 pamphlet WO2009 / 100130 pamphlet WO2010 / 073011 pamphlet WO2010 / 036613 pamphlet WO2010 / 047982 pamphlet WO2010 / 051206 pamphlet WO2010 / 051176 pamphlet WO2004 / 060305 pamphlet WO1997 / 038984 pamphlet

The Medical Journal of Australia, Vol.185, No.8, pp445-449, 2006. Molecular Medicine, Vol.39, No.4, pp398-407, 2002 Nature, Vol.415, pp339-343, 2002 Nature, Vol.423, pp762-769, 2003 J. Clin. Invest., Vol.108, pp1167-1174, 2001 237th American Chemical Society National Meeting (March 22-26, Salt Lake City) 2009, Abstract MEDI 196

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 focused on the specific role of human AMPK in energy metabolism for the purpose of creating a new 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 first invention is represented by the general formula (1)

[Wherein R ¹ may have 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. a good C ₆ -C ₁₀ aryl group, an optionally substituted C ₇ -C ₁₂ aralkyl group, an aromatic heterocyclic group or substituent 5- may have a substituent or 6-membered Represents an optionally fused heterocyclic group,
X is C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene, C ₂ -C ₄ alkynylene or general formula (2)

(Wherein T represents a single bond, C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene or C ₂ -C ₄ alkynylene;
U is 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 may have a substituent) -C ₆ alkyl group, C ₇ -C ₁₂ aralkyl group which may have a substituent, C ₆ -C ₁₀ aryl group which may have a substituent, C ₁ -C which may have a substituent 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), general formula (3)

(Wherein L ¹ represents a single bond, an oxygen atom or —NR ⁵ —, and R ⁵ represents the same meaning as described above) or general formula (4)

(Wherein L ² represents a single bond or an oxygen atom, R ⁵ represents the same meaning as described above),
Y is a single bond, C ₁ -C ₄ alkylene or general 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, optionally having a substituent C ₁ to 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, an optionally substituted C ₁ -C ₆ alkylsulfonyl group may have an aromatic heterocyclic group, or a substituent 5- or 6-membered and may have a substituent Represents a condensed heterocyclic group) or a carbonyl group, and h and j are the same or different and represent an integer of 0 to 2),
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, an optionally substituted C _{1 to} C ₆ alkoxy group, C _{3 to} C ₆ cycloalkyloxy group optionally having substituent, hydroxyl group, nitro group, cyano group, amino group optionally having substituent, having substituent which may C ₆ -C ₁₀ aryl group, 5-membered and may have a substituent or 6-membered aromatic heterocyclic group which may have a substituent fused heterocyclic group, which may have a substituent Good C ₇ -C ₁₂ aralkyl group, C ₆ -C ₁₀ aryloxy group which may have a substituent, C ₇ -C ₁₂ aralkyloxy group which may have a substituent, may have a substituent good C ₁ -C ₆ alkylthio group, represents an C ₇ -C ₁₂ aralkylthio group optionally having an optionally substituted C ₆ -C ₁₀ arylthio group or a substituted group,
Ring A and Ring B are the same or different and which may have a substituent C ₃ -C ₆ cycloalkyl group, 5-membered and may have a substituent or 6-membered saturated heterocyclic group, a substituted which may have a group C ₆ -C ₁₀ aryl group, a substituted condensed heterocyclic group which may have an aromatic heterocyclic group, or a substituent 5- or 6-membered and may have a substituent,
R ² and R ³ are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group that may have a substituent, a C ₃ -C ₆ cycloalkyl group that may have a substituent, a substituted Represents a C _{6 to} C ₁₀ aryl group which may have a group or a C _{7 to} C ₁₂ aralkyl group which may have a substituent, or R ² and R ³ are bonded, and R ² and R ³ General formula (6) together with the bonding carbon atom

(Wherein Q ² is a single bond, methylene, oxygen atom, —S (O) _r — (r represents an integer selected from 0 to 2), —NR ⁷ — (R ⁷ is a hydrogen atom, a substituent) which may have C ₁ -C ₆ alkyl group, an optionally substituted C ₇ -C ₁₂ aralkyl group, an optionally substituted C ₆ -C ₁₀ aryl group, substituted which may be C ₁ -C ₆ aliphatic acyl group, an optionally substituted C ₁ -C ₆ alkylsulfonyl group, an aromatic heterocyclic group having 5-membered and may have a substituent or 6-membered, or Represents a condensed heterocyclic group which may have a substituent, and m and n are the same or different and represent 1 or 2)]
Or a pharmacologically acceptable salt thereof or a hydrate thereof.

In the second invention, in the general formula (1), X is C ₁ -C ₄ alkylene or the general formula (2a).

Wherein 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 ) — (wherein R ^5a is a hydrogen atom or a C ₁ -C ₆ alkyl group or substituent which may have a substituent) Represents a C _{7 to} C ₁₂ aralkyl group which may have a general formula (3a)

(Wherein L ^1a represents a single bond or —NR ^5a —, R ^5a represents the same meaning as described above) or a general formula (4a)

(Wherein R ^5a represents the same meaning as described above)), and a pharmacologically acceptable salt thereof or a hydrate thereof.

In the third invention, X is the general formula (2b) in the general formula (1).

Wherein T ¹ represents a single bond or C ₁ -C ₄ alkylene,
A ² is the general formula (3b)

(In the formula, 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 is as described above. The same meaning as the above) or general formula (4a)

(Wherein R ^5a represents the same meaning as described above))
Or a pharmacologically acceptable salt thereof or a hydrate thereof according to the first or second invention.

Further, the fourth invention is the above general formula (1), wherein Z is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkoxy group which may have a substituent, or a C _3- which may have a substituent. C ₆ cycloalkyloxy group, nitro group, cyano group, optionally substituted amino group, optionally substituted C _{6 to} C ₁₀ aryloxy group, optionally substituted C _{7 to} C ₁₂ Aralkyloxy group, C _{1 to} C ₆ alkylthio group which may have a substituent, C _{6 to} C ₁₀ arylthio group which may have a substituent or C ₇ which may have a substituent -C ₁₂ about hydantoin derivative or pharmacologically acceptable salt thereof or a hydrate thereof according to any one of the first to third aspects of the invention represented by the aralkylthio group.

The fifth invention, in the general formula (1), Ring A and Ring B are the same or different and may have a substituent group C ₃ -C ₆ cycloalkyl group, substituted good C ₆ -C ₁₀ aryl group, a saturated heterocyclic group of 5- or 6-membered and may have a substituent, an aromatic heterocyclic group having 5-membered or 6-membered and may have a substituent or The present invention relates to a hydantoin derivative or a pharmacologically acceptable salt thereof or a hydrate thereof according to any one of the first to fourth inventions represented by a condensed heterocyclic group which may have a substituent.

In the sixth invention, Ring A is represented by the general formula (7) in the general formula (1).

(In the formula, V ¹ , V ² , V ³ and V ⁴ are the same or different and are a nitrogen atom or CR ⁸ (R ⁸ is a hydrogen atom, a halogen atom or a C ₁ -C which may have a substituent) ₆ alkyl group, C ₃ -C ₆ cycloalkyl group optionally having substituent (s), C ₁ -C ₆ alkoxy group optionally having substituent (s), C ₃ -C ₆ optionally having substituent (s) cycloalkyloxy group, a hydroxyl group, a nitro group, a cyano group, hydroxy group, C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted C ₆ -C ₁₀ An aryloxy group, an optionally substituted C _{7 to} C ₁₂ aralkyloxy group, an optionally substituted C _{1 to} C ₆ alkylthio group, and an optionally substituted C _{6 to} C ₁₀ It represents an arylthio group or a C _{7 to} C ₁₂ aralkylthio group which may have a substituent)), and is described in any one of the first to fifth inventions The above-mentioned hydantoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof.

The seventh invention provides a general formula (1a)

[Wherein R ^1a may have 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. have a good C ₆ -C ₁₀ aryl group or a substituted group represents an C ₇ -C ₁₂ aralkyl group,
X ^a is the general formula (2c)

(Wherein T ² represents a single bond or methylene,
A ³ is the general formula (3c)

(Wherein R ^5b and R ^{5b ′} are the same or different and represent a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a substituent) or the general formula (4b)

(Wherein R ^5b represents the same meaning as described above),
Y ^a represents a single bond, a methylene, an oxygen atom, a 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 -C ₆ alkoxy group which may have a an optionally substituted C ₃ -C ₆ cycloalkyl group or a substituent C ₆ It represents -C ₁₀ aryloxy group,
Ring A ^a represents an aromatic heterocyclic group members 5 may have an optionally substituted C ₆ -C ₁₀ aryl group or a substituent or 6-membered,
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 represents ₁₀ aryl group or 5-membered may have a substituent or 6-membered aromatic heterocyclic group,
R ^2a and R ^3a are the same or different and are 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. Represents a C _{6 to} 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.

(Wherein 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)]
Or a pharmacologically acceptable salt thereof or a hydrate thereof.

The eighth invention relates to the general formula (1b) in the general formula (1a).

[Wherein R ^1b is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a general formula (8)

(Wherein R ⁹ represents a hydroxyl group, a C _{7 to} C ₁₂ aralkyloxy group or a 3 to 6-membered cyclic amino group, v represents an integer of 1 to 6),
X ^b is the general formula (9)

General formula (10)

Or general formula (11)

Represents
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
(1) C ₃ ~C ₆ cycloalkyl group,
(2) C ₁ ~C ₆ alkyl group, C ₁ -C ₆ aliphatic acyl group, or a C ₂ -C ₇ alkoxycarbonyl piperidinyl group optionally substituted with a group, or
(3) a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₂ -C ₇ alkoxycarbonyl group, a cyano group, optionally substituted with one or two C ₁ -C ₆ alkyl group Represents an optionally substituted amino group, a hydroxycarbonyl group or an aminocarbonyl group optionally substituted C ₆ -C ₁₀ aryl group,
R ^2b and R ^3b are the same or different and are each a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group, a general formula (12)

(Wherein R ¹⁰ represents a hydroxycarbonyl group or a C _{8 to} C ₁₃ aralkyloxycarbonyl group, w represents an integer of 1 to 6), or R ^2b and R ^3b are bonded, R ^2b and General formula (6b) together with the carbon atom to which R ^3b is attached

(Wherein, m and n are as defined above)
The hydantoin derivative of 7th invention represented by these, its pharmacologically acceptable salt, or those hydrates.

The ninth invention relates to the general formula (1c) in the general formula (1a).

[Wherein 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, R ^1b , R ^2b , R ^3b and Z ^b are as defined above.]
Or a pharmacologically acceptable salt thereof or a hydrate thereof according to the seventh or eighth aspect of the invention.

In the tenth invention, 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
The hydantoin derivative according to the first invention which is 5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-cyanophenoxy) phenylmethyl] benzamide or a pharmacologically thereof It relates to acceptable salts or their hydrates.

The eleventh invention also relates to a pharmaceutical comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of the first invention to the tenth invention, or an active ingredient thereof.

The twelfth invention is an AMPK activation comprising as an active ingredient one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of the first invention to the tenth invention, or a hydrate thereof. Regarding drugs.

The thirteenth invention is a lipid lowering agent comprising as an active ingredient one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of the first to tenth inventions or hydrates thereof. About.

The 14th invention is an arteriosclerosis comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of the 1st to 10th inventions or hydrates thereof as an active ingredient. It relates to preventive or therapeutic drugs.

Further, the fifteenth aspect of the invention is the prevention of diabetes comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts or hydrates thereof according to any one of the first to tenth aspects of the invention. Or it relates to a therapeutic drug.

The sixteenth aspect of the invention is an obesity prevention comprising one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of the first aspect to the tenth aspect of the invention or hydrates thereof as an active ingredient. Or it relates to a therapeutic drug.

In addition, the seventeenth aspect of the present invention is a cancer therapeutic agent comprising as an active ingredient one or more of the hydantoin derivatives or pharmacologically acceptable salts thereof according to any one of the first to tenth aspects of the present invention or hydrates thereof. About.

The novel hydantoin derivatives and addition salts thereof of the present invention have an excellent AMPK activating action, and exhibit 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 a blood glucose uptake promoting agent in the liver and a lipid-lowering agent.

  The definition in the formula of the compound represented by this invention is demonstrated below.

  “Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom.

“C ₁ -C ₆ alkyl group” means, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, n-pentyl group or n-hexyl group, etc. And a straight or branched hydrocarbon group 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.

“C ₁ -C ₆ alkoxy group” means, for example, 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.

“C ₁ -C ₆ alkylthio group” means, for example, methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, t-butylthio group, n-pentylthio group or 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.

“3- to 6-membered cyclic amino group” is a 3- to 6-membered saturated ring group containing one or more nitrogen atoms, for example, aziridyl group, azetidyl group, pyrrolidyl group, piperidyl group, piperazyl group, morpholyl Group or thiomorpholyl group.

  The “5-membered or 6-membered saturated heterocyclic group” is a 5-membered or 6-membered saturated ring group containing one or more nitrogen, oxygen and / or sulfur atoms. For example, pyrrolidyl group, piperidyl group, piperazyl A group, a morpholyl group, a thiomorpholyl group, a tetrahydrofuranyl group or a 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. For example, 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, pyridadyl 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 fused ring group composed of a 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, pyrazolopyridyl group or imidazopyrimidyl group.

“C ₁ -C ₆ alkyl group optionally having substituent (s)”, “C ₃ -C ₆ cycloalkyl group optionally having substituent (s)”, “C ₆ -C optionally having substituent (s)” ₁₀ aryl group ”,“ C ₇ -C ₁₂ aralkyl group which may have a substituent ”, C ₁ -C ₆ alkoxy group which may have a substituent”, “C which may have a substituent” _{3 to} C ₆ cycloalkyloxy group ”,“ C _{6 to} C ₁₀ aryloxy group which may have a substituent ”,“ C _{7 to} C ₁₂ aralkyloxy group which may have a substituent ”,“ Substitution ” 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 ”,“ optionally substituted C ₆ -C ₁₀ arylthio group ”,“ optionally substituted C ₇ -C ₁₂ aralkylthio group ”,“ optionally substituted ” good C ₁ ~C ₆ Alkylsulfonyl group "," optionally substituted C ₆ -C ₁₀ arylsulfonyl group "," optionally substituted C ₁ -C ₆ alkylsulfonyloxy group "has" substituent C ₆ -C ₁₀ arylsulfonyloxy group ”,“ C ₁ -C ₆ aliphatic acyl group optionally having substituent ”,“ C ₇ -C ₁₂ aromatic optionally having substituent ” "Acyl group", "optionally substituted 3- to 6-membered cyclic amino group", "optionally substituted 5-membered or 6-membered saturated heterocyclic group", "with substituent The “substituent” in the “optionally 5-membered or 6-membered aromatic heterocyclic group” and the “fused heterocyclic group optionally having a substituent” is, for example, a halogen atom, 1 to 3 halogen atoms in optionally substituted C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group, one to three C ₁ may be substituted with a halogen atom -C ₆ alkoxycarbonyl Shi 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, a hydroxyl group, a nitro group, one or two C ₁ -C ₆ alkyl amino group which may be substituted with a group, 3- to 6-membered cyclic amino group, cyano group, hydroxy group, Examples include formyl group and aminocarbonyl group.

The “amino group optionally having a substituent” includes, for example, an amino group which may be substituted with 1 or 2 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 the “C ₁ -C ₄ alkylene” include linear or branched alkylene having 1 to 4 carbon atoms such as methylene, ethylene, trimethylene, methylethylene, dimethylmethylene and the like.
Examples of the “C ₂ -C ₄ alkenylene” include linear or branched alkenylene having 1 to 4 carbon atoms such as vinylene, propenylene, methyl ethenylene and the like.
Examples of “C ₂ -C ₄ alkynylene” include linear or branched alkynylene having 1 to 4 carbon atoms such as ethynylene, propynylene, and 3-methylpropynylene.

The compounds of the present invention is excellent in order to represent the AMPK activating effect was, R1 is a hydrogen atom, an optionally substituted C ₁ -C ₆ alkyl group, optionally C ₃ may have a substituent -C ₆ cycloalkyl group or C ₇ -C ₁₂ aralkyl group which may have a substituent, more preferably a hydrogen atom, C ₁ -C ₆ alkyl group, or C ₃ -C _6, more preferably a cycloalkyl group, hydrogen Particularly preferred are atoms, C ₁ -C ₆ alkyl groups, or C ₃ -C ₆ cycloalkyl groups.
X is particularly preferably a structure represented by —CH ₂ NHCO—.
Y is particularly preferably an oxygen atom.
Z is preferably optionally C ₃ -C ₆ cycloalkyloxy group which may have a good C ₁ -C ₆ alkoxy group or a substituted group may have a substituent, C ₁ -C ₆ alkoxy or C ₃ -C more preferably ₆ cycloalkyloxy group, C ₁ -C ₆ alkoxy groups are particularly preferred.

Ring A is a saturated heterocyclic group of 5- may have a substituent or 6-membered, 5-membered may have an optionally substituted C ₆ -C ₁₀ aryl group or a substituent or 6 preferably an aromatic heterocyclic group of members, more preferably 5-membered or 6-membered saturated heterocyclic group, C ₆ -C ₁₀ aromatic heterocyclic group an aryl group or a 5- or 6-membered, C ₆ -C ₁₀ aryl The group is particularly preferred.
Ring B is preferably a C ₆ -C ₁₀ aryl group which may have a substituent, and may be substituted by a halogen atom, a C ₁ -C ₆ alkyl group or 1 or 2 C ₁ -C ₆ alkyl groups A C ₆ -C ₁₀ aryl group which may be substituted with any of the good amino groups is more preferred, and a C ₆ -C ₁₀ aryl group which may be substituted with 1 to 3 halogen atoms is particularly preferred.

  The compound of the present invention can be converted into a pharmacologically acceptable salt as 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 a pharmacologically acceptable salt thereof may be an inner salt, an anhydride, a hydrate or a 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 medicament of the present invention can be administered orally or by parenteral means such as 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 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]

[Wherein W ¹ represents a leaving group, R ^a represents an optionally substituted C ₁ -C ₆ alkyl group or an optionally substituted C ₇ -C ₁₂ aralkyl group, R ¹ , R ² , R ³ , X, Y, Z, Ring A, and Ring B are as defined above]
Here, the leaving group represented by W ¹ includes a halogen atom, a C _{1 to} C ₆ alkylsulfonyloxy group which may have a substituent, a phenylsulfonyloxy group or a p-tolylsulfonyloxy group. such as C ₁ -C ₆ alkyl C ₆ optionally substituted by a group -C ₁₀ arylsulfonyloxy group.

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

  Conversion from the compound represented by the general formula (16) and the compound represented by the general formula (17) to the compound represented by the general formula (15) (Step 1-B) is carried out using an appropriate solvent such as toluene, Sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogenation in 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, N, N-dimethylformamide, N-methylpyrrolidinone, or a mixture thereof In the presence of a base such as sodium, triethylamine, diisopropylethylamine or pyridine, the compound represented by the general formula (16) and the compound represented by the general formula (17) are reacted at −78 ° C. to 120 ° C. for 10 minutes to 100 hours. Can be done.

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, N, N-dimethyl. In a formamide 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 optionally added in the presence of a base such as pyridine or triethylamine. The reaction can be carried out at 150 ° C. for 5 minutes to 48 hours.

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

Conversion from 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 a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide or the like. In these mixed liquids, 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 as necessary, or In the presence of an acid such as hydrochloric acid or acetic acid, the compound represented by the general formula (18) can be reacted at 0 to 130 ° C. for 5 minutes to 12 hours.

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]

[Wherein 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 the general formula (13) and the compound represented by the general formula (19) to the compound represented by the general formula (20) (step 2-A) is the same as in step 1-A. It can be done by a method.

Conversion from the compound represented by the general formula (16) and the compound represented by the general formula (21) to the compound represented by the general formula (20) (step 2-B) is the same as 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) into the compound represented by the general formula (23) (Step 2-C) is carried out by using an appropriate solvent such as toluene, Sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogenation in 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, N, N-dimethylformamide, N-methylpyrrolidinone, or a mixture thereof In the presence of a base such as sodium, triethylamine, diisopropylethylamine or pyridine, the compound represented by the general formula (20) and the compound represented by the general formula (22) are reacted at −78 ° C. to 120 ° C. for 10 minutes to 100 hours. Can be done.

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 a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, A base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine in methanol, ethanol, or a mixture thereof. In the presence, 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.

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]

[Wherein R ¹ , R ² , R ³ , W ¹ , X, Y, Z, Ring A, and Ring B are as defined above]
Conversion from the compound represented by the general formula (24) and the compound represented by the general formula (25) to the compound represented by the general formula (1) (Step 3-A) is carried out by using an appropriate solvent such as toluene, Sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogenation in 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidinone, or mixtures thereof In the presence of a base such as sodium, triethylamine, diisopropylethylamine or pyridine, the compound represented by the general formula (24) and the compound represented by the general formula (25) are reacted at −78 ° C. to 120 ° C. for 10 minutes to 100 hours. Can be done.

Among the compounds represented by the general formula (1) which 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]

[Wherein, 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 -C ₁₀ aryl group, an optionally substituted C ₇ -C ₁₂ aralkyl group may have an aromatic heterocyclic group or substituent 5- may have a substituent or 6-membered Represents a condensed 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. such substituted C ₆ which may be -C ₁₀ arylsulfonyloxy group with an alkyl group.

In the conversion from 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 representing, it can be carried out by the same method as in Step 3-A.

When W ² represents boric acid, pyridine, triethylamine, 4- (dimethylamino) in a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, N, N-dimethylformamide or a mixture thereof. ) Bases such as pyridine, sodium carbonate, or cesium carbonate; metals such as copper acetate; and compounds represented by general formula (1d) in the presence of ligands such as pyridine, triethylamine, and 2,2-bipyridine as required It can carry out by making it react with the compound represented by Formula (26) at 0-150 degreeC for 30 minutes-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]

[Wherein, 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, a trimethylsilyl group, a silyl group such as t-butyldimethylsilyl which may have a substituent such as a group, 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, In hexane, tetrahydrofuran, diethyl ether, dichloromethane, N, N-dimethylformamide, N-methylpyrrolidine, dimethyl sulfoxide, 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 t-butoxide, pyridine, triethylamine or N, N-dimethylaniline, an appropriate iodide salt, such as sodium iodide, potassium iodide or tetrabutylammonium iodide, as necessary And a compound represented by the general formula (27) and a compound represented by the general formula (28) It can be carried out by reacting 1 to 100 hours and things at -15~120 ℃.

  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, benzene or the like. In a mixture, etc., using a halogenating agent such as thionyl chloride, phosphorus oxychloride or thionyl bromide, the compound represented by the general formula (27a) is reacted at −20 to 80 ° C. for 0.5 to 6 hours, or appropriate In a solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide or a mixture thereof, in the presence of a base such as triethylamine or pyridine, an appropriate sulfonylating agent such as methanesulfonyl chloride or trifluoromethanesulfonic acid anhydride is used. It 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. That.

  In addition, in a suitable solvent such as dichloromethane, chloroform, tetrahydrolane or a mixed solution thereof, in the presence of triphenylphosphine, carbon tetrabromide, carbon tetrachloride or iodine is used, and the compound represented by the general formula (27a) is obtained. 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) to the compound represented by the general formula (1f) (Step 5-C) is carried out by using an appropriate solvent such as toluene, Sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, hydrogenation in 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, N, N-dimethylformamide, N-methylpyrrolidinone, or a mixture thereof In the presence of a base such as sodium, triethylamine, diisopropylethylamine or pyridine, the compound represented by the general formula (29) and the compound represented by the general formula (30) are reacted at -78 ° C to 120 ° C for 10 minutes to 100 hours. Can be done.

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 Wily and Sons (1999)). It can be carried out by deprotection according to the method described in)).

For example, a method using an acid, a base, ultraviolet light, hydrazine, tetrabutylammonium fluoride, trimethylsilyl iodide, or the like, or a reduction method can be used.

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]

[Wherein Ring A ¹ has 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. Represents a good condensed heterocyclic group, and U, Y, Z, R ^1d , R ² , R ³ , and Ring B are as defined above.

Conversion of the compound represented by the general formula (27a) and the compound represented by the general formula (30a) to 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 organic phosphorus compound such as triphenylphosphine or tributylphosphine in hexane, tetrahydrofuran, or a mixture thereof, an electrophilic agent such as diethyl azodicarboxylate, diisopropyl azodicarboxylate or dipiperidine azodicarboxylate is used, and the general formula ( The compound represented by 27a) and the compound represented by the general formula (30a) are reacted at 0 to 60 ° C. for 3 to 24 hours, or an appropriate solvent such as toluene, benzene, hexane, tetrahydrofuran, or a mixture thereof. Use phospholane compounds such as cyanomethylenetributylphosphorane or cyanomethylenetrimethylphosphorane , The compound represented by the general formula (27a) and the general formula and a compound represented by (30a) can be carried out by reacting 1 to 24 hours at room temperature to 120 ° C..

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

  [Production method 7]

[Wherein, R ^a and R ^b represent 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 represents a linear alkylene constituted C ₂ -C ₄ together, T ^a is a single bond, C ₁ -C ₃ represents alkylene, a C ₂ -C ₃ alkenylene or C ₂ -C ₃ alkynylene, U ^a as 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, is Ring B described above Represents the same meaning]

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

  Conversion of the compound represented by general formula (33) and the compound represented by general formula (30b) into the compound represented by general formula (1h) (step 7-B) is the same as step 7-A. It can be done by a method.

Conversion of 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 (published by John Wily and Sons (1999)). This can be done by deprotection according to the above method.

For example, 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, an acid such as hydrochloric acid, sulfuric acid or nitric acid is used. ) Can be performed by hydrolyzing at 0 to 100 ° C. for 1 to 48 hours.

Or a metal catalyst 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 hydrogen under normal pressure to 0.5 MPa.

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

  [Production method 8]

[Wherein R ¹ , R ² , R ³ , R ⁵ , R ^a , T, U, Y, Z, Ring A, and Ring B are as defined 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, chloroform, etc. , Tetrahydrofuran, diethyl ether, N, N-dimethylformamide or a mixture thereof, such as pyridine, triethylamine, N-methylmorpholine or 4- (dimethylamino) pyridine, N-hydroxybenzotriazole, N- Dicyclohexylcarbodiimide, 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide in the presence of a reaction aid such as hydroxysuccinimide or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine Using a condensing agent such as hydrochloride, diethyl cyanophosphate, diphenyl phosphate azide, or carbonyldiimidazole, the general formula (3 The reaction can be carried out by reacting the compound represented by 5) with the compound represented by the general formula (30c) at -15 to 120 ° C for 0.5 to 24 hours.

  In addition, the compound represented by the general formula (35) may be used in the absence of a solvent or in an appropriate solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixed solution thereof, if necessary, such as pyridine or triethylamine. In the presence of a base, thionyl chloride, thionyl bromide, acetic anhydride or ethyl chlorocarbonate is used to react the compound represented by the general formula (35) at -15 to 50 ° C. for 5 minutes to 6 hours to form a carboxyl group. After forming a reactive derivative group such as acid chloride, acid bromide or acid anhydride, pyridine, triethylamine or 4-in a suitable solvent such as toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide or a mixture thereof. Reacted with a compound represented by the general formula (30c) in the presence of a base such as (dimethylamino) pyridine at −78 to 50 ° C. for 15 minutes to 12 hours. It can also be carried out by Rukoto.

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 an appropriate solvent such as water, acetic acid, methanol, ethanol, dichloromethane. , Tetrahydrofuran, 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. It can carry out by hydrolyzing the compound represented by General formula (36) at 0-150 degreeC for 0.5 to 100 hours using.

In addition, a metal catalyst 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. It 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 hydrogen at atmospheric 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]

[Wherein R ¹ , R ² , R ³ , R ⁵ , T, U, Y, Z, Ring A, and Ring B are as defined above]

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 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 are as defined above. Represent]

  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, In tetrahydrofuran, dichloromethane, N, N-dimethylformamide or a mixture thereof, the compound represented by the general formula (27c) and the general formula using carbonyldiimidazole in the presence of a base such as pyridine or triethylamine as necessary. It can be performed by reacting the compound represented by (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 such as toluene. , Tetrahydrofuran, dichloromethane, N, N-dimethylformamide, or a mixture thereof, and in the presence of a base such as pyridine or triethylamine as necessary, the compound represented by the general formula (27c) and the general formula (38) It can also be carried out by reacting with a compound 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 A ^b is —NH—, the production of the compound represented by the general formula (1k) (step 10-C) is performed using 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. The reaction can also be performed 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]

[Wherein R ¹ , R ² , R ³ , R ⁵ , T, U, Y, Z, Ring A, and Ring B are as defined above]

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

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

  [Production method 12]

Wherein 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, and k represents 2, 3 or 4. R ^1d , R ² , R ³ , Y, Z, Ring A, and Ring B are as defined 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). 1-78 to 120 ° C. using an organophosphorus compound such as triphenylphosphine or triethyl phosphite in a suitable solvent, such as toluene, tetrahydrofuran, benzene, or a mixture thereof. After reacting for 12 hours, sodium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide or potassium t-butoxide in a suitable solvent such as toluene, tetrahydrofuran, diethyl ether, dimethyl sulfoxide or a mixture thereof The reaction is carried out by reacting the compound represented by the general formula (32a) at −78 to 120 ° C. for 1 to 12 hours in the presence of Door can be.

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

Conversion of the compound represented by the general formula (1m) to the compound represented by the general formula (1n) (Step 12-C) is carried out by using a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 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 mixture thereof, in a hydrogen atmosphere of normal pressure to 0.5 MPa, the general formula (1 m) It can be carried out by reducing the represented compound 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]

[Wherein R ^1d , R ² , R ³ , W ³ , Y, Z, Ring A, Ring B, r, and t are as defined above]

Conversion of the compound represented by the general formula (29aa) and the compound represented by the general formula (40) to 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 in tetrahydrofuran, diethyl ether, dimethyl sulfoxide, hexamethylphosphoric triamide or a mixture thereof, an appropriate iodide salt as necessary, For example, sodium iodide, copper (I) iodide, tetrabutylammonium iodide or the like is added, and the compound represented by the general formula (29aa) and the compound represented by the general formula (40) are -78 to 120. The reaction can be carried out at 1 ° 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]

[Wherein, 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 are as defined 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-dimethylsulfide complex, lithium aluminum hydride or diisobutylaluminum hydride in ethanol, dichloromethane or a mixture thereof. The reaction can be performed 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) can be carried out by using an appropriate solvent such as tetrahydrofuran, diethyl ether, methanol, ethanol, 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 from the compound represented by the general formula (25a) to the compound represented by the general formula (13) (Step 14-C) can be carried out by using a suitable solvent such as toluene, dichloromethane, chloroform, acetonitrile, dimethyl sulfoxide, acetone or The mixture is reacted with a compound represented by the general formula (25a) for 1 to 48 hours at −78 to 80 ° C. with an oxidizing agent such as Jones reagent, PCC, PDC, manganese dioxide or oxalic chloride (Swern oxidation). Can be done.

  Conversion from 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. The compound represented by the general formula (13) is added with 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 from the compound represented by the general formula (25a) to the compound represented by the general formula (16) (Step 14-F) can be carried out by using a suitable 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, 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, tetrahydrofuran or a mixture thereof, etc. Medium, acid, base or hydrazine, etc., 0-100 ° C It can be carried out by reacting 1 to 24 hours.

  Conversion from the compound represented by the general formula (13) to the compound represented by the general formula (16) (Step 14-G) can be carried out in an appropriate solvent such as methanol, ethanol, dichloromethane, chloroform or a mixture thereof. , Lithium borohydride, sodium borohydride, sodium cyanoborohydride or triacetoxyhydrogen 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 appropriate After reacting the compound represented by the general formula (13) with hydroxylamine or the like at 0 to 60 ° C. for 0.5 to 24 hours using a reducing agent such as sodium borohydride, for example, dichloromethane, tetrahydrofuran, In ethanol or a mixture of these, in the presence of a metal catalyst such as iron, palladium, or zinc, acetic acid or a salt as necessary. Presence of acid, such as, under 0 to 80 ° C. a hydrogen stream can be carried out by reacting 1 to 24 hours.

  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, ethanol or a mixture thereof, etc. It can also be carried out by reacting with an acid or a base at 0 to 80 ° C. for 1 to 24 hours.

  Conversion from the compound represented by the general formula (25) to the compound represented by the general formula (16) (Step 14-H) can be carried out by using a suitable solvent such as chlorobenzene, acetonitrile, ethylene glycol, N, N-dimethyl. Bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine are present in formamide, dimethyl sulfoxide, hexamethylphosphate triamide or a mixture thereof. Below, 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 an appropriate solvent such as methanol, ethanol, tetrahydrofuran, or a mixture thereof, Use acid, base, hydrazine, etc. It can be carried out by reacting 24 hours.

  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, tetrahydrofuran or a mixture thereof. It 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 or the like under a metal catalyst such as palladium carbon, Raney nickel or platinum oxide. Can do.

  In addition, in an appropriate solvent such as water, ethanol, tetrahydrofuran, 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), from a compound in which 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 no 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, nitric acid, etc. The compound represented by the general formula (41) is hydrolyzed at 0 to 100 ° C. for 1 to 48 hours using a base acid such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. Can be done.

Conversion (14-J) from the compound represented by the general formula (43) to the compound represented by the general formula (42) can be carried out by using a suitable solvent such as water, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene or a mixture thereof, triphenylphosphine, tolylphosphine, 2-dicyclohexylphosphino-2 ', 6 In the presence of a ligand such as' -dimethoxybiphenyl or diphenylphosphinoferrocene, a base such as sodium carbonate, cesium carbonate, or triethylamine, and a metal catalyst such as tetrakistriphenylphosphine, trisdibenzylideneacetone palladium, palladium acetate, or copper iodide. Under, cyan zinc, potassium ferricyanide or cyanide It can be carried out by reacting at 0 to 250 ° C. for 1 to 48 hours using a cyanating agent such as sodium.

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 Production Method 15.

[Production method 15]

[Wherein J ^a represents a formyl group, a cyano group, COOR ^a , and A ^a , R ^a , T, U, W ¹ , Y, Z, Ring A, Ring B have the same meaning 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 step 5-A Can be performed.

  Conversion of 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.

Of 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]

[Wherein, J ^a , U, Y, Z, Ring A ¹ , and Ring B have the same meaning as described above]

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

Of 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 , and R ⁴ , R ^a , T, T ^a , U, U ^a , Y, Z, Ring A, and Ring B represent the same meaning as described above.]

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

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

Of 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]

[Wherein, J ^a , R ⁵ , T, U, Y, Z, Ring A, and Ring B are as defined above]

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

Of 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]

[Wherein, J ^a , R ⁵ , T, U, Y, Z, Ring A, and Ring B represent the same meaning as described above.]

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

Of 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 meanings as defined above]

  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 (38c) 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.

Of 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 Production Method 21.

[Production method 21]

[Wherein, J ^a , R ⁵ , T, U, Y, Z, Ring A, and Ring B represent the same meaning as described above.]

Conversion of the compound represented by general formula (45b) and the compound represented by general formula (30d) into the compound represented by general formula (44f) (step 21-A) is the same method as 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 Production Method 22.

  [Production method 22]

[Wherein J ^b , W ³ , Y, Z, Ring A, Ring B, r, t, and k have the same meaning as described above]

  Conversion from the compound represented by the general formula (46a) and the compound represented by the general formula (32a) to 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 general formula (47a) and the compound represented by general formula (39) into the compound represented by general formula (44g) (step 22-B) is the same method as 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.

Of 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]

[Wherein, J ^a , W ³ , Y, Z, Ring A, Ring B, r, and t are as defined above]

The conversion from the general formula (46b) and the general formula (40) to the 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 Production Method 24.

[Production method 24]

[Wherein R ¹ , R ² , R ³ , R ⁴ , U, U ^a , and Z are as defined above]

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

Of 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]

[Wherein 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, N, N- It is carried out by reacting the 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. Can do.

Further, in a solvent-free or suitable solvent such as tetrahydrofuran, 1,4-dioxane, methanol, ethanol or a mixture thereof, a general formula (reduced iron or zinc) is used 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]

[Wherein J ^c represents PG ¹ -A ^a -U-, R ^a OOC-U-, O ₂ NU-, 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, and PG ¹ are as defined above.

  Conversion of the compound represented by the general formula (52) and the compound represented by the general formula (17) into 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 from the compound represented by the general formula (54) and the compound represented by the general formula (14) to 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 from the compound represented by the general formula (52) and the compound represented by the general formula (21) to the general formula (57) (step 26-E) can be performed by the same method as in step 2-B. it can.

Conversion from the compound represented by the general formula (54) and the compound represented by the general formula (19) to 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 racemate represented by the general formula (1) can be obtained by fractional recrystallization using an optically active acid or base, or by reacting with an optically active alcohol derivative or optically active oxazolidinone derivative. It can also be synthesized by separating an ester derivative or an oxazolidinone derivative by fractional crystallization or a chromatographic technique followed by hydrolysis.

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

EXAMPLES The present invention will be specifically described by 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

To a solution of 5-formyl-2-methoxybenzoic acid (45.6 g, 253 mmol) in N, N-dimethylformamide (500 mL) under ice-cooling, triethylamine (35.3 mL, 253 mmol) and ethyl chloroformate (25.4 mL, 266 mmol) 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 ^o C
IR (ATR): 3341.3, 1690.7, 1638.3, 1536.1, 1495.0 cm ^-1 .
¹ H-NMR (CDCl ₃ , 400 MHz) δ4.04 (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 (1H, d, J = 2.4 Hz), 9.99 ( 1H, s).
ESIMS (+): 380.1 [M + H] ⁺ .
HRESIMS (+): 380.12954 (calculated as C ₂₂ H ₁₉ FNO ₄ 380.12981).

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

Triethylamine (0.22 mL, 1.58 mmol) with methylene chloride solution (5.3 mL) in methyl 2-amino-2-methylpropionate (242 mg, 1.58 mmol) and ice-cooled stirring (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. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 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 (Biotarge; SNAP Cartridge KP-Sil 25 g; hexane: ethyl acetate) to obtain the title compound (514 mg, quant.) As colorless powder crystals.

Colorless powdery crystals
IR (ATR): 3410.1, 2949.4, 1717.2, 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) δ1.36 (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 as C ₂₇ H ₃₀ FN ₂ O ₅ 481.21387).

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

To a solution of the compound of the first step (471 mg, 0.98 mmol) in acetic acid (5 mL) was added potassium cyanate (95.4 mg, 1.18 mmol), and the mixture was 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 x 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 (Biotarge; SNAP Cartridge KP-Sil 25 g; hexane: ethyl acetate) to give the title compound (308 mg, 64%) as colorless powder crystals.

Colorless powder crystalline melting point: 155-156 ^o 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) δ1.17 (6H, s), 3.86 (3H, s), 4.41 (2H, s), 4.45 (2H, d, J = 5.5 Hz), 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 as C ₂₇ H ₂₇ FN ₃ O ₅ 492.19347).
Elemental analysis: Calculated as C 65.96%, H 5.61%, N 8.37%, 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 of Table 2.

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

Colorless powder crystalline melting point: 65-67 ^o C
IR (ATR): 3383.8, 3170.8, 2959.6, 1769.3, 1713.3, 1638.1, 1529.8, 1494.5 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ0.74 (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: Calculated value as C 65.67%, H 5.76%, N 8.00%, C ₂₈ H ₂₈ FN ₃ O ₅・ 0.4H ₂ O C 65.59%, H 5.66%, N 8.20%.

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

Colorless powder crystalline melting point: 65-68 ^o 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) δ0.74 (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: measured C 66.25%, H 5.76%, N 8.13%, calculated as C ₂₈ H ₂₈ FN ₃ O ₅ C 66.52%, H 5.58%, N 8.31%.

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

Colorless powder crystalline melting point: 83-85 ^o C
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) δ3.77 (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 as C ₃₁ H ₂₇ FN ₃ O ₅ 540.19347).
Elemental analysis: measured 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%.

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

Colorless powder crystalline melting point: 50-52 ^o 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) δ1.91-2.06 (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 (1H, t, J = 5.8 Hz), 11.0 (1H, s).
ESIMS (+): 626.2 [M + H] ⁺ .
HRESIMS (+): 626.23043 (calculated as C ₃₅ H ₃₃ FN ₃ O ₇ 626.23025).

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

To a solution of the compound of Example 5 (155 mg, 0.25 mmol) in ethanol (3 mL) was added 10% palladium carbon (15.5 mg) under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble material in the reaction mixture was filtered off using 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 ^o 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) δ1.83-2.00 (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 (2H, m), 7.33 (2H, d, J = 8.6 Hz), 7.39 (1H, 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: measured C 62.49%, H 4.81%, N 7.68%, calculated as 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
Methyl 5-[(carbamoylmethyl) aminomethyl] -2-methoxybenzoate

Methyl 5-formyl-2-methoxybenzoate (4.00 g, 20.6 mmol) in methanol (100 mL) was added to glycinamide hydrochloride (5.47 g, 49.4 mol), sodium triacetoxyborohydride (8.73 g, 41.2 mol). ) And stirred at room temperature for 2.5 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (150 mL), 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 (calculated as C ₁₂ H ₁₇ N ₂ O ₄ 253.1188).

Second step
Methyl 5- [N- (carbamoylmethyl) methoxycarbonylaminomethyl] -2-methoxybenzoate

Triethylamine (2.56 mL, 18.3 mol) and methyl chloroformate (1.21 mL, 15.7 mol) were added to a tetrahydrofuran solution (66 mL) of the compound of the first step (3.30 g, 13.1 mmol) under ice-cooling and stirring for 30 minutes under the same conditions. Stir. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 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) δ3.74-3.86 (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 (Calculated as C ₁₄ H ₁₉ N ₂ O ₆ 311.1243).

Third process
Methyl 5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxybenzoate

Sodium methoxide (1.31 g, 24.3 mol) was added to a methanol solution (50 mL) of the compound of the second step (3.01 g, 9.70 mmol), and the mixture was refluxed for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 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 crystals

IR (ATR): 3052.0, 1763.4, 1715.4, 1688.8, 1614.8, 1500.5 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ3.76 (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 (calculated value as C ₁₃ H ₁₄ N ₂ O ₅ 278.0903).

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

To a methanol solution (35 mL) of the compound in the third step (2.06 g, 7.40 mmol) was added 2N aqueous sodium hydroxide solution (7 mL), 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 ^o C

IR (ATR): 3056.2, 1770.8, 1690.6, 1576.8, 1463.4 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ3.79 (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 (calculated as C ₁₂ H ₁₂ N ₂ O ₅ 264.0746).

<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 %) As colorless powdery crystals.

IR (ATR): 3376.6, 3188.8, 1716.2, 1644.6, 1443.2, 1408.9, 1382.1, 1270.9, 1188.5, 1098.8 cm ^-1 .
¹ H-NMR (CDCl ₃ , 400 MHz) δ3.31 (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 (calculated value 299.1396 as C ₁₇ H ₁₉ N ₂ O ₃ ).

Second step
3- [N- (Carbamoylmethyl) methoxycarbonylaminomethyl] benzoic acid Benzyl

According to 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.). Obtained as a colorless oil.

IR (ATR): 3396.7, 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) δ3.79 (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 (calculated as C ₁₉ H ₂₁ N ₂ O ₅ 357.1450).

Third process
Methyl 3- (2,4-dioxoimidazolidin-1-yl) methylbenzoate

The reaction was performed using the compound of the second step (170 mg, 0.47 mmol) according to the third step method of Reference Example 2 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) δ3.85 (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 (calculated as C ₁₂ H ₁₂ N ₂ O ₄ 248.0797).

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

The reaction was performed using the compound of the third step (97.9 mg, 0.39 mmol) according to the fourth step method of Reference Example 2, and the title compound (73.0 mg, 80%) was obtained 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) δ3.84 (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} ).

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

Triethylamine (0.32 mL, 2.28 mmol) and diethylphosphorocyanidate (0.21 mL, 1.25 mmol) in an N, N'-dimethylformamide solution (7 mL) of the compound of Reference Example 2 (300 mg, 1.14 mmol) under ice-cooling and stirring. ) And stirred for 10 minutes under the same conditions.To the reaction mixture was added a solution of [4- (4-fluorophenoxy) phenylmethyl] amine (248 mg, 1.14 mmol) in N, N'-dimethylformamide (3 mL). Stir for 30 minutes under 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 ^o 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) δ3.79 (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 as C ₂₅ H ₂₃ FN ₃ O ₅ 464.16217).
Elemental analysis: Measured value C 64.72%, H 4.84%, N 9.05%, C ₂₅ H ₂₂ Calculated as FN ₃ O ₅ 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% formalin aqueous solution (3.86 mL, 47.6 mmol), acetic acid (0.82 mL, 14.3 mmol) under ice-cooling and stirring, Sodium cyanoborohydride (897 mg, 14.3 mmol) was added and 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) δ2.98 (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 (calculated as C ₁₅ H ₁₄ N ₂ O 238.1106).

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 of 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, the filtrate was concentrated, and the title 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) δ1.50 (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 (calculated as C ₁₅ H ₁₈ N ₂ O 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 (591 mg) under an argon atmosphere. ) And stirred at room temperature for 10 hours under a hydrogen atmosphere. The insoluble material in the reaction mixture 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.

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

Colorless powder crystalline melting point: 193-195 ^o 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 (2H, m), 7.75 (1H, s ), 7.80 (1H, d, J = 6.7 Hz), 9.05 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
ESIMS (-): 432.1 [MH] ⁺ .
HRESIMS (-): 432.13579 (calculated as C ₂₄ H ₁₉ FN ₃ O ₄ 432.13596).

3- (2,4-Dioxoimidazolidin-1-yl) methyl-N- [4- (4-fluorophenoxy) phenyl] benzamide

Colorless powder crystalline melting point: 224-226 ^o 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 [MH] ⁺ .
HRESIMS (-): 418.12037 (calculated as C ₂₃ H ₁₇ FN ₃ O ₄ 418.12031).

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

Colorless powder crystalline melting point: 202-204 ^o 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) δ3.82 (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 as C ₂₄ H ₂₁ FN ₃ O ₅ 450.14652).

5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- (4-phenoxyphenylmethyl) benzamide

Colorless powder crystalline melting point: 115-117 ^o 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, 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) δ3.79 (2H, s), 3.87 (3H, s), 4.39 (2H, s), 4.47 (2H, d, J = 6.1 Hz), 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 as C ₂₅ H ₂₄ N ₃ O ₅ 446.17160).

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

Colorless powdery melting point: 122-124 ^o 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) δ2.27 (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 (1H, d, J = 2.4 Hz), 8.69 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
ESIMS (+): 460.2 [M + H] ⁺ .
HRESIMS (+): 460.18656 (calculated as C ₂₆ H ₂₆ N ₃ O ₅ 460.18725).

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

Colorless powder crystalline melting point: 182-184 ^o 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) δ3.79 (2H, s), 3.88 (3H, s), 4.39 (2H, s), 4.50 (2H, d, J = 6.1 Hz), 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 as C ₂₆ H ₂₃ N ₄ O ₅ 471.16684).

5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- [4- (dimethylamino) phenoxy] phenylmethyl] benzamide

Pale yellow powdery crystalline melting point: 139-140 ^o C
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) δ2.85 (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 (1H, d, J = 2.4 Hz), 8.65 (1H, t, J = 5.5 Hz), 10.9 (1H, s).
ESIMS (+): 489.2 [M + H] ⁺ .
HRESIMS (+): 489.21409 (calculated value 489.21379 as C ₂₇ H ₂₉ N ₄ O ₅ ).
Elemental analysis: Calculated as C 66.32%, H 5.87%, N 11.27%, C ₂₇ H ₂₈ N ₄ O ₅ C 66.38%, H 5.78%, N 11.47%.

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

Colorless powder crystalline melting point: 139-140 ^o 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) δ3.73 (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 (1H, t, J = 6.1 Hz), 10.9 (1H, s).
ESIMS (+): 476.2 [M + H] ⁺ .
HRESIMS (+): 476.18309 (calculated as C ₂₆ H ₂₆ N ₃ O ₆ 476.18216).
Elemental analysis: Calculated as C 65.83%, H 5.35%, N 8.94%, C ₂₆ H ₂₆ N ₃ O ₆ C 65.67%, H 5.30%, N 8.84%.

5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-tert-butoxycarbonylpiperidin-1-yloxy) phenylmethyl] benzamide

White solid
IR (ATR): 3395.6, 3121.7, 2946.2, 1763.7, 1712.4, 1693.9, 1634.6, 1597.8, 1510.1 cm ^-1 .
¹ H-NMR (DMSO-d ₆ , 400 MHz) δ1.39 (9H, s), 1.44-1.52 (2H, m), 1.84-1.89 (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: Calculated value as C 62.62%, H 6.55%, N 10.10%, C ₂₉ H ₃₆ N ₄ O ₇ , 0.2H ₂ O C 63.03%, H 6.57%, N 10.14%.

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

Colorless powder crystalline melting point: 149-150 ^o C
IR (ATR): 3142, 1710, 1625, 1544, 1467, 1422, 1252, 1222, 1098, 1029, 815, 627, 416 cm ^-1 .
¹ H NMR (CDCl ₃ , 400 MHz): δ3.78 (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 (calculated as C ₂₅ H ₂₃ FN ₃ O ₄ S 480.1393).

5- (2,4-Dioxoimidazolidin-1-yl) methyl-2-methoxy-N-[[6- (4-fluorophenoxy) pyridin-3-yl] methyl] benzamide

Colorless powdery crystals
IR (ATR): 3591, 3398, 3162, 3070, 1765, 1712, 1642, 1537, 1505 cm ^-1 .
¹ H NMR (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 as C ₂₄ H ₂₂ FN ₄ O ₅ 465.15742).

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

Colorless powdery crystals
IR (ATR): 3571, 3517, 3125, 3054, 2734, 1762, 1708, 1625, 1532 cm ^-1 .
¹ H NMR (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).

4- [4-[[5-[(2,4-Dioxoimidazolidin-1-yl) methyl] -2-methoxybenzamido] methyl] phenoxy] ethyl benzoate

Colorless powdery 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) δ1.38 (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 (1H, d, J = 2.4 Hz), 8.24 (1H, t, J = 5.5 Hz).
ESIMS (+): 518.2 [M + H] ⁺ .
HRESIMS (+): 518.19243 (calculated as C ₂₈ H ₂₈ N ₃ O ₇ 518.19272).

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 as C ₂₅ H ₃₀ N ₃ O ₅ 452.21855).
Elemental analysis: Calculated as C 66.34%, H 6.44%, N 9.29%, C ₂₅ H ₂₉ N ₃ O ₅ C 66.50%, H 6.47%, N 9.31%.

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) for 3 hours at room temperature. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 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 (Biotarge; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to obtain the title compound (330 mg, 97%) as colorless powder crystals.
Melting point: 37-38 ^o 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) δ0.94 (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), 3.70 (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 as C ₂₉ H ₃₁ FN ₃ O ₅ 520.22477).
Elemental analysis: measured C 66.91%, H 6.05%, N 8.06%, calculated as C ₂₉ H ₃₀ FN ₃ O ₅ C 67.09%, H 5.82%, N 8.09%.

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

According to Example 22, the reaction was carried out 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 a colorless powder. Obtained as a crystal.

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) δ3.67-3.73 (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 as C ₃₄ H ₃₃ FN ₃ O ₆ 598.23534).

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, 0.63 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 x 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 (Biotarge; SNAP Cartridge KP-NH; hexane: ethyl acetate) to give the title compound (222 mg, 92%) as colorless powder crystals.

Melting point: 37-38 ^o 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) δ2.50 (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: measured C 66.91%, H 6.05%, N 8.06%, calculated as C ₂₉ H ₃₀ FN ₃ O ₅ C 67.09%, H 5.82%, N 8.09%.

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 x 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 (Biotarge; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to obtain the title compound (206 mg, 76%) as colorless powder crystals.

Melting point: 50-52 ^o 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, 1188.4 cm ^-1 .
¹ H-NMR (CDCl ₃ , 400 MHz) δ0.92-1.00 (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 (1H, dd, J = 8.6, 2.4 Hz), 8.12 (1H, d, J = 2.4 Hz), 8.18 (1H, 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: measured C 66.91%, H 6.05%, N 8.06%, calculated as C ₂₉ H ₃₀ FN ₃ O ₅ C 67.09%, H 5.82%, N 8.09%.

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, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Biotarge; SNAP Cartridge KP-Sil; ethyl acetate: methanol) to give the title compound (132 mg, 96%) was obtained as colorless powder crystals.

Melting point: 101-102 ^o 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) δ2.80 (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%, C ₂₇ H ₂₆ Calculated as FN ₃ O ₆ C 63.90%, H 5.16%, N 8.28%.

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), copper acetate (418 mg, 2.30 mmol) and 2,2′-bipyridyl (359 mg, 2.30 mmol) were added, and the mixture was stirred at 70 ^° C. for 6 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 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 (Biotarge; 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, 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) δ0.93-1.00 (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 (+): 558.22357 (calculated as C ₃₁ H ₃₂ N ₃ O ₇ 558.22402).

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

To an ethanol solution (2 mL) of the compound of Example 27 (483 mg, 0.87 mmol) was added 1N aqueous sodium hydroxide solution (1.73 mL), 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 x 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 (Biotarge; SNAP Cartridge KP-Sil; ethyl acetate: methanol) to obtain the title compound (280 mg, 61%) as colorless powder crystals.

Melting point: 77-79 ^o 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, 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) δ0.78-0.84 (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 as C ₂₉ H ₂₈ N ₃ O ₇ 530.19272).

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

A 1N aqueous sodium hydroxide 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. The residue was purified by silica gel column chromatography (Biotarge; SNAP Cartridge KP-Sil; chloroform: methanol) to give the title compound (355 mg, 61%) was obtained as colorless powder crystals.

Melting point: 120-122 ^o 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) δ3.79 (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 as 490.16142 as C ₂₆ H ₂₄ N ₃ O ₇ ).

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

To a solution of the compound of Example 29 (351 mg, 0.72 mmol) in N, N′-dimethylformamide (2 mL), triethylamine (0.22 mL, 1.58 mmol) and diethylphosphorocyanidate (0.13 mL, 0.79 mmol) were stirred with ice cooling. ) Was added and stirred for 10 minutes under the same conditions, 0.5M ammonia / 1,4-dioxane solution (2.88 mg, 1.44 mmol) was added to the reaction mixture, 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, 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 (Biotarge; SNAP Cartridge KP-Sil; chloroform: methanol) to obtain the title compound (88.1 mg, 25%) as colorless powder crystals.

Melting point: 208-210 ^o 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) δ3.79 (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 as C ₂₆ H ₂₅ N ₄ O ₆ 489.17741).

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

A 4N hydrogen chloride-ethyl acetate solution (12.6 mL) was added to a methanol solution (12.6 mL) of Example 16 (1.40 g, 2.53 mmol), 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 mixture to adjust the liquidity to pH 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) δ1.70-1.79 (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 (1H, dd, J = 2.4, 8.6 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.64 (1H, t , J = 6.1 Hz).
ESIMS (+): 453.2 [M + H] ⁺ .
HRESIMS (+): 453.21432 (calculated as C ₂₄ H ₂₉ N ₄ O ₅ 453.221379).

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 the solvent was evaporated under reduced pressure. Purification by an automatic column chromatograph system (Biotage, KP-NH 11 g, 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 as C ₂₆ H ₃₁ N ₄ O ₆ 495.22436).
Elemental analysis: Calculated value as C 61.51%, H 6.17%, N 10.87%, C ₂₆ H ₃₀ N ₄ O ₆ , 0.7H ₂ O C 61.58%, H 6.24%, N 11.05%.

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), and the mixture was stirred at room temperature for 1 hour. did. Hydrogenated (triacetoxy) sodium borohydride (183 mg, 0.862 mmol) was added, and the mixture was stirred at room temperature for 7 hours. A 37% aqueous formaldehyde solution (0.059 mL, 0.729 mmol) and sodium (triacetoxy) 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 evaporated 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), and were colorless and amorphous. The 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) δ1.80-1.88 (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: Calculated value as C 62.55%, H 6.55%, N 11.62%, C ₂₅ H ₃₀ N ₄ O ₅・ 0.7H ₂ O C 62.67%, H 6.61%, N 11.69%.

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), ethyl chloroformate (0.44 mL, 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 layers were 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 (Biotarge; 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, 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 as C ₂₂ H ₁₈ FNO ₄ 379.1220).

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

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), the first step compound (1.25 g, 3.29 mmol), triacetoxyhydrogen with ice-cooling and stirring Sodium borohydride (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 x 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 (Biotarge; 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) δ3.42 (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 as C ₂₅ H ₂₆ FN ₂ O ₅ 453.18257).

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

To the acetic acid solution (7.6 mL) of the compound of the second step (1.21 g, 2.67 mmol) was added potassium cyanate (260 mg, 3.21 mmol), and the mixture was stirred at room temperature for 30 minutes and then stirred at 100 ^° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 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 (Biotarge; 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 a colorless powder Obtained as a crystal.

Melting point: 115-118 ^o 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) δ3.86 (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).

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 methyl 4-carboxylate

4-Methyltetrahydro-2H-pyran-4-carboxylic acid methyl ester hydrochloride (464 mg, 2.37 mmol) in methylene chloride solution (5 mL) was stirred with ice-cooling and triethylamine (0.33 mL, 2.37 mmol). A compound (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 x 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 (Biotarge; SNAP Cartridge KP-Sil; hexane: ethyl acetate) to give 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) δ1.66-1.74 (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 as C ₂₉ H ₃₂ FN ₂ O ₆ 523.22444).

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

Potassium cyanate (150 mg, 1.85 mmol) was added to an acetic acid solution (5 mL) of the compound of the first step (806 mg, 1.54 mmol), stirred at room temperature for 30 minutes, and stirred at 100 ^° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 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 (Biotarge; SNAP Cartridge KP-Sil; hexane: ethyl acetate) and triturated (diisopropyl ether) to give the title compound (686 mg, 83%) as colorless powder crystals.

Melting point: 90-93 ^o 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) δ1.52 (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 (+): 534.20472 (calculated as C ₂₉ H ₂₉ FN ₃ O ₆ 534.20404).

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

<Test Example 1: De novo lipid synthesis ability inhibitory action>
HepG2 cells were cultured in a 12-well plate for 48 hours, then 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 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 repeating a series of extraction operations again, the dried solid was dissolved in methanol, and the radioactivity was measured with a scintillation counter.

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

From the results of this test, the compound of the present application showed a strong inhibitory activity on de novo lipid synthesis.

<Test Example 2: AMPKα and ACC phosphorylation promoting action>
HepG2 cells (6 cm ² culture dish) cultured in Dulbecco's modified Eagle's 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 Bradford method. Then, phosphorylated AMPKα (pThr172) and phosphorylated ACC1 (pSer79) were detected by SDS-PAGE and Western blotting.

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

The test results of ACC (Ser79) phosphorylation are shown in Table 6. In the table, “EC ₅₀ ” represents the concentration of the test compound at 50% of the maximum effect of ACC (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 a result of this test, the compound of the present application showed a 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 with OA-2 diet (CLEA Japan) from 6 weeks of age, and the test was started at 7 weeks of age. In a 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 consecutive days, followed by a 14-day rest. During the administration period and during withdrawal, the same feed as that used for breeding was used. Seven days later, blood was collected from the tail vein, and blood glucose and triglyceride were measured by an enzymatic method.

  The test results are shown in Table 7. 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. Shows the rate of decrease in the mean blood glucose level (or average triglyceride level), 20% <rate of decrease <30%: A, 10% <rate of decrease <20%: B, 1% <rate of decrease <10%: C And

As a result of this test, the present compound was found to have a good mouse blood glucose lowering action and triglyceride lowering action.

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

Claims (17)

General formula (1)

[Wherein R ¹ may have 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. a good C ₆ -C ₁₀ aryl group, an optionally substituted C ₇ -C ₁₂ aralkyl group, an aromatic heterocyclic group or substituent 5- may have a substituent or 6-membered Represents an optionally fused heterocyclic group,
X is C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene, C ₂ -C ₄ alkynylene or general formula (2)

(Wherein T represents a single bond, C ₁ -C ₄ alkylene, C ₂ -C ₄ alkenylene or C ₂ -C ₄ alkynylene;
U is 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 may have a substituent) -C ₆ alkyl group, C ₇ -C ₁₂ aralkyl group which may have a substituent, C ₆ -C ₁₀ aryl group which may have a substituent, C ₁ -C which may have a substituent 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), general formula (3)

(Wherein L ¹ represents a single bond, an oxygen atom or —NR ⁵ —, and R ⁵ represents the same meaning as described above) or general formula (4)

(Wherein L ² represents a single bond or an oxygen atom, R ⁵ represents the same meaning as described above),
Y is a single bond, C ₁ -C ₄ alkylene or general 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, optionally having a substituent C ₁ to 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, an optionally substituted C ₁ -C ₆ alkylsulfonyl group may have an aromatic heterocyclic group, or a substituent 5- or 6-membered and may have a substituent Represents a condensed heterocyclic group) or a carbonyl group, and h and j are the same or different and represent an integer of 0 to 2),
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, an optionally substituted C _{1 to} C ₆ alkoxy group, C _{3 to} C ₆ cycloalkyloxy group optionally having substituent, hydroxyl group, nitro group, cyano group, amino group optionally having substituent, having substituent which may C ₆ -C ₁₀ aryl group, 5-membered and may have a substituent or 6-membered aromatic heterocyclic group which may have a substituent fused heterocyclic group, which may have a substituent Good C ₇ -C ₁₂ aralkyl group, C ₆ -C ₁₀ aryloxy group which may have a substituent, C ₇ -C ₁₂ aralkyloxy group which may have a substituent, may have a substituent good C ₁ -C ₆ alkylthio group, represents an C ₇ -C ₁₂ aralkylthio group optionally having an optionally substituted C ₆ -C ₁₀ arylthio group or a substituted group,
Ring A and Ring B are the same or different and which may have a substituent C ₃ -C ₆ cycloalkyl group, 5-membered and may have a substituent or 6-membered saturated heterocyclic group, a substituted which may have a group C ₆ -C ₁₀ aryl group, a substituted condensed heterocyclic group which may have an aromatic heterocyclic group, or a substituent 5- or 6-membered and may have a substituent,
R ² and R ³ are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group that may have a substituent, a C ₃ -C ₆ cycloalkyl group that may have a substituent, a substituted Represents a C _{6 to} C ₁₀ aryl group which may have a group or a C _{7 to} C ₁₂ aralkyl group which may have a substituent, or R ² and R ³ are bonded, and R ² and R ³ General formula (6) together with the bonding carbon atom

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

Wherein 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 ) — (wherein R ^5a is a hydrogen atom or a C ₁ -C ₆ alkyl group or substituent which may have a substituent) Represents a C _{7 to} C ₁₂ aralkyl group which may have a general formula (3a)

(Wherein L ^1a represents a single bond or —NR ^5a —, R ^5a represents the same meaning as described above) or a general formula (4a)

(Wherein R ^5a represents the same meaning as described above)), or a pharmaceutically acceptable salt thereof or a hydrate thereof. In the general formula (1), X represents the general formula (2b)

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

(In the formula, 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 is as described above. The same meaning as the above) or general formula (4a)

(Wherein R ^5a represents the same meaning as described above))
The hydantoin derivative of Claim 1 or Claim 2 represented by these, its pharmacologically acceptable salt, or those hydrates. In the above formula (1), Z is a hydrogen atom, a halogen atom, an optionally substituted C ₁ -C ₆ alkoxy group, an optionally substituted C ₃ -C ₆ cycloalkyl 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 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 aralkylthio group 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. ₁₀ aryl group, optionally substituted 5- or 6-membered saturated heterocyclic group, optionally substituted 5- or 6-membered aromatic heterocyclic group or substituted The hydantoin derivative according to any one of claims 1 to 4, which is represented by a good condensed heterocyclic group, a pharmacologically acceptable salt thereof, or a hydrate thereof. In the general formula (1), Ring A represents the general formula (7)

(In the formula, V ¹ , V ² , V ³ and V ⁴ are the same or different and are a nitrogen atom or CR ⁸ (R ⁸ is a hydrogen atom, a halogen atom or a C ₁ -C which may have a substituent) ₆ alkyl group, C ₃ -C ₆ cycloalkyl group optionally having substituent (s), C ₁ -C ₆ alkoxy group optionally having substituent (s), C ₃ -C ₆ optionally having substituent (s) cycloalkyloxy group, a hydroxyl group, a nitro group, a cyano group, hydroxy group, C ₁ -C ₆ alkoxycarbonyl group, an optionally substituted amino group, an optionally substituted C ₆ -C ₁₀ An aryloxy group, an optionally substituted C _{7 to} C ₁₂ aralkyloxy group, an optionally substituted C _{1 to} C ₆ alkylthio group, and an optionally substituted C _{6 to} C ₁₀ 6 represents a C ₇ -C ₁₂ aralkylthio group which may have an arylthio group or a substituent. Totoin derivatives or pharmacologically acceptable salts thereof or hydrates thereof. General formula (1a)

[Wherein R ^1a may have 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. have a good C ₆ -C ₁₀ aryl group or a substituted group represents an C ₇ -C ₁₂ aralkyl group,
X ^a is the general formula (2c)

(Wherein T ² represents a single bond or methylene,
A ³ is the general formula (3c)

(Wherein R ^5b and R ^{5b ′} are the same or different and represent a hydrogen atom or a C ₁ -C ₆ alkyl group which may have a substituent) or the general formula (4b)

(Wherein R ^5b represents the same meaning as described above),
Y ^a represents a single bond, a methylene, an oxygen atom, a 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 -C ₆ alkoxy group which may have a an optionally substituted C ₃ -C ₆ cycloalkyl group or a substituent C ₆ It represents -C ₁₀ aryloxy group,
Ring A ^a represents an aromatic heterocyclic group members 5 may have an optionally substituted C ₆ -C ₁₀ aryl group or a substituent or 6-membered,
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 represents ₁₀ aryl group or 5-membered may have a substituent or 6-membered aromatic heterocyclic group,
R ^2a and R ^3a are the same or different and are 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. Represents a C _{6 to} 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.

(Wherein 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)]
Or a pharmacologically acceptable salt thereof or a hydrate thereof. In the general formula (1a), the general formula (1b)

[Wherein R ^1b is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a general formula (8)

(Wherein R ⁹ represents a hydroxyl group, a C _{7 to} C ₁₂ aralkyloxy group or a 3 to 6-membered cyclic amino group, v represents an integer of 1 to 6),
X ^b is the general formula (9)

General formula (10)

Or general formula (11)

Represents
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
(1) C ₃ ~C ₆ cycloalkyl group,
(2) C ₁ ~C ₆ alkyl group, C ₁ -C ₆ aliphatic acyl group, or a C ₂ -C ₇ alkoxycarbonyl piperidinyl group optionally substituted with a group, or
(3) a halogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₂ -C ₇ alkoxycarbonyl group, a cyano group, optionally substituted with one or two C ₁ -C ₆ alkyl group Represents an optionally substituted amino group, a hydroxycarbonyl group or an aminocarbonyl group optionally substituted C ₆ -C ₁₀ aryl group,
R ^2b and R ^3b are the same or different and are each a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group, a general formula (12)

(Wherein R ¹⁰ represents a hydroxycarbonyl group or a C _{8 to} C ₁₃ aralkyloxycarbonyl group, w represents an integer of 1 to 6), or R ^2b and R ^3b are bonded, R ^2b and General formula (6b) together with the carbon atom to which R ^3b is attached

(Wherein, m and n are as defined above)
8. The hydantoin derivative or a pharmacologically acceptable salt thereof according to claim 7 or a hydrate thereof. In the general formula (1a), the general formula (1c)

[Wherein 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, R ^1b , R ^2b , R ^3b and Z ^b are as defined above.]
9. The hydantoin derivative of claim 7 or claim 8, or a pharmacologically acceptable salt thereof, or a hydrate thereof. 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
The hydantoin derivative according to claim 1, which is 5- (2,4-dioxoimidazolidin-1-yl) methyl-2-methoxy-N- [4- (4-cyanophenoxy) phenylmethyl] benzamide or pharmacologically thereof Acceptable salts or hydrates thereof. The pharmaceutical which uses one or more types of the hydantoin derivative of any one of Claims 1-10, its pharmacologically acceptable salt, or those hydrates as an active ingredient. The AMPK activator which uses as an active ingredient one or more types of the hydantoin derivative of any one of Claims 1-10, its pharmacologically acceptable salt, or those hydrates. The lipid lowering agent which uses as an active ingredient one or more types of the hydantoin derivative of any one of Claims 1-10, its pharmacologically acceptable salt, or those hydrates. 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 claims 1 to 10. The prophylactic or therapeutic agent of diabetes which uses as an active ingredient one or more types of the hydantoin derivative of any one of Claims 1-10, its pharmacologically acceptable salt, or those hydrates. 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. The cancer therapeutic agent which uses 1 or more types of the hydantoin derivative of any one of Claims 1-10, its pharmacologically acceptable salt, or those hydrates as an active ingredient.