WO2007026962A1

WO2007026962A1 - Phenylene derivative

Info

Publication number: WO2007026962A1
Application number: PCT/JP2006/317708
Authority: WO
Inventors: Kiyoshi Kurokawa; Toshio Miyata; Hiroaki Yanagisawa
Original assignee: Daiichi Sankyo Company, Limited; Renascience Co., Ltd.
Priority date: 2005-08-31
Filing date: 2006-08-31
Publication date: 2007-03-08
Also published as: JPWO2007026962A1; TW200720261A

Abstract

It is intended to provide a novel phenylene derivative represented by the following general formula (I), which is useful as a remedy or a preventive for renal disorders (nephritis, nephropathy, nephrosclerosis, renal failure and so on), diabetic complications (nephropathy, neuropathy, retinopathy, cataract, microangiopathy, skin damage and so on), cardiovascular diseases (myocardial infarction, heart enlargement, heart failure, arteriosclerosis, coronary diseases, peripheral circulatory disturbance, cerebrovascular disorder, hypertension, systolic hypertension, restenosis after angiogenesis and so on), cerebral metabolic impairment (Alzheimer’s disease, Parkinson’s disease and so on), dialysis-related amyloidosis that is a complication of dialysis, peritoneal sclerosis observed in a patient under peritoneal dialysis, rheumatoid arthritis, solar elastosis, aging, senile cataract and so on: (I) wherein A is a group represented by the following general formula (A1), (A2), (A3) or (A4): (A1) (A2) (A3) (A4) and other symbols have each the same meaning as defined in the description; and a pharmacologically acceptable salt and ester thereof.

Description

Specification

Phenylene derivative

Technical field

The present invention relates to a novel phenylene derivative and a pharmacologically acceptable salt thereof.

The present invention also relates to a furene derivative having an advanced glycation end products (AGEs) bioinhibitory action and the like, a pharmacologically acceptable salt thereof and a pharmacologically acceptable salt thereof. Regarding esters.

Furthermore, the present invention comprises nephropathy (nephritis, nephropathy, nephrosclerosis, renal failure, etc.) containing as an active ingredient a phenylene derivative and a pharmacologically acceptable salt thereof and a pharmacologically acceptable ester thereof. Diabetes complications (nephropathy, neuropathy, retinopathy, cataract, microvascular disorder, skin disorder, etc.), cardiovascular disease (myocardial infarction, cardiac hypertrophy, heart failure, arteriosclerosis, coronary artery disease, peripheral circulation) Disorders, cerebrovascular disorders, hypertension, systolic hypertension, angioplasty-restenosis after surgery, etc.), cerebral metabolic disorders (Alzheimer's disease, Parkinson's disease, etc.), dialysis amyloidosis, which is a dialysis complication, peritoneum It relates to a therapeutic or preventive agent for abdominal fll ^ dermatitis, rheumatoid arthritis, photoelastic fibrosis, senile cataract, aging, etc. in dialysis patients.

Furthermore, the present invention provides a preventive or therapeutic agent for the above-mentioned diseases containing the above compound as an active ingredient, a medicament, a progenitor for preventing or treating the above-mentioned disease containing the above compound as an active ingredient, Use of the compound for the manufacture of a medicament for treatment, or a method for preventing or treating the disease, wherein a pharmacologically effective amount of the compound is administered to a warm-blooded animal (preferably a human). .

Background art

AG Es is known to be formed by modifying a protein with a reactive force compound formed mainly with hyperglycemia and oxidative stress in diabetic nephropathy lesions. Diseases involving AGEs include 1) Diabetes complications nephropathy, neuropathy, retinopathy, cataract, microvascular disorder and skin disorder,

2) Cardiovascular diseases such as myocardial infarction, cardiac hypertrophy, heart failure, arteriosclerosis, coronary artery disease, peripheral circulation disorder, cerebrovascular disorder, hypertension, systolic hypertension, and restenosis after angioplasty (especially Restenosis after PTCA)

3) Dialysis complications in dialysis amyloidosis and peritoneal dialysis patients

4) Alzheimer's disease, Parkinson's disease,

5) rheumatoid arthritis,

6) sunlight elastic fibrosis,

7) Aging,

8) Senile cataract,

9) Renal disorders such as renal failure, nephritis, nephropathy and nephrosclerosis are known.

In addition, in the case of diabetes, it has been reported that vascular dilation derived from vascular endothelium is impaired by AGEs, and that AGEs promotes renal cirrhosis (for example, Drugs (New Zealand)). 64-5, 459-70 (2004), JP 2004-300 1 53 and International Publication 02/083 127 pamphlet).

On the other hand, drugs that have nephroprotective effects (proteinuria suppression 'inhibition of decreased renal function) have been used in the treatment of diabetic nephropathy, and such drugs have shown efficacy in large-scale clinical trials. Only angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE I), which are antihypertensive drugs (for example, New 'England' Jananore ■ Ob 'Medicine (New En gland J ourna 1 of Me dicine) (UK) Vol. 329, pl 456-1462 (1 993)). However, because ARB and ACEI have antihypertensive effects, their usefulness in patients without hypertension has not been elucidated. It is considered difficult to suppress the development of diabetic nephropathy using only the drug in the shape of a drug. Therefore, the development of a powerful nephroprotective drug that does not have an antihypertensive action is now strongly desired.

In recent years, it has been proved that several drugs in ARB and ACE I inhibit the production of AGEs, and that the renal protective effect of ARB and ACE I is exerted independently of the antihypertensive effect. Furthermore, it has become clear that renal damage is dependent on renal tissue AGE s rather than blood pressure, and that administration of ARB significantly reduces AGEs as well as renal protection.

Thus, in diabetic nephropathy, it forces et amount tissue AGE _S obtain Ri Do indicative of the leading disorders, specifically inhibit drug AGE s production, potent renoprotective drugs without antihypertensive It is thought that it becomes.

Some compounds having a partial structure in common with the phenylene derivative of the present invention and exhibiting an AGE s production inhibitory action have been disclosed (for example, see WO 02/083 127). However, these compounds differ from the compounds of the present invention in that —CH ₂ —A is not bonded to phenylene through a single bond or a C ₆ — ₁₀ arylene group.

Further, some compounds having a partial structure in common with the fuerene derivative of the present invention and exhibiting nephritis inhibitory action are disclosed (for example, JP-A-10-310524, JP-A-7-5355). (See publication No. 1). However, these compounds, (corresponding to group A in the compounds of the present invention) differ from the compounds of the present invention is group linked via a single bond or a C ₆ _ ₁₀ Ariren groups and methylene in phenylene There is also no suggestion that it has an AG Es production-inhibiting action like the compound of the present invention.

In addition, there are compounds that have a partial structure in common with that of Tomei Akira's phenylene derivatives and have been disclosed for use in inhibiting the production of AGEs (see, for example, International Publication No. 2005/0 3073 Panflate). ) And power, and, of these compounds, group linked via a single bond or a C ₆ _ ₁₀ Ariren groups and methylene in phenylene is different from the compounds of the present invention (in group A in the compounds of the present invention Corresponding). The present inventors have conducted extensive research for the purpose of developing a prophylactic or therapeutic agent for diabetic complications (particularly nephropathy) that has no antihypertensive action and few side effects. The present invention has been completed by finding that it has an AG Es production inhibitory effect and a renal protective action, and improves diabetic complications (particularly nephropathy), cardiovascular diseases, cerebral metabolic disorders and the like.

That is, the present invention relates to nephropathy (nephritis, nephropathy, nephrosclerosis, renal failure, etc.), diabetic complications (nephropathy, neuropathy, retinopathy, cataract, microvascular disorder, skin disorder, etc.), cardiovascular system Disease (myocardial infarction, cardiac hypertrophy, heart failure, arteriosclerosis, coronary artery disease, peripheral circulation disorder, cerebral vascular disorder, hypertension, systolic hypertension, restenosis after angioplasty), cerebral metabolic disorder (Alzheimer) Disease, Parkinson's disease, etc.) Dialysis complications such as dialysis amyloidosis, abdominal dysfunction in patients with peritoneal dialysis, rheumatoid arthritis, photoelastic fibrosis, aging, senile cataract, etc. Provided are novel derivatives of phenylene, and pharmacologically acceptable salts and esters thereof.

Disclosure of the invention

The present invention is as follows.

[1] General formula (I):

(I)

During,

A is the following general formula (A l), (A 2), (A 3) or (A 4)

(Al) (A3) (A4)

A group represented by: B represents a 1H-tetrazol-5-yl group or a 2,4-dioxo-1,3-thiozolidine-5-yl group;

X represents a single bond or a C ₆ - shows a ₁₀ Ariren group;

Y ¹ represents carbonyl, sulfonyl or a single bond;

Y ² represents an alkylene group or a single bond;

Y ³ represents methylene, carbonyl or a single bond;

Y ⁴ represents a methine or nitrogen atom;

Y ⁵ represents methylene, carbonyl or a single bond;

R ¹ is

An alkyl group (the alkyl group is a group selected from the following substituent group α)

1 to 3 may be substituted)

C ₆ - ₁₄ Ariru group (the 〇 ₆ _ ₁₄ Ariru group may be one to five substituted with a group selected from the following substituent group] 3),

C ₆ - ₄ Ariru - C _i-6 alkyl group (the C ₆ - ₄ Ariru - C _i-6 alkyl group may be one to five substituted with a group selected from the following substituent group),

4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is selected from the following substituent group) 3 1 to 5 of these groups may be substituted)

A 4- to 10-membered heterocycle containing from 1 to 3 heteroatoms identical or different selected from nitrogen, oxygen and sulfur atoms. ₆ alkyl group (said heterocyclic one C _x _ ₆ alkyl group may be one to five substituted with a group selected from the following substituent group),

C ₃ _ ₇ cycloalkyl group (said C ₃ - ₇ cycloalkyl groups, may be one to five substituents by a group selected from the following substituent group i3),

C ₃ - ₇ cycloalkyl - CI- ₆ alkyl group (the C ₃ - ₇ cycloalkyl one C - ₆ § alkyl group, it may also optionally be one to five substituted with a group selected from the following substituent group β I) C ₆ — ₄ alkyl group C! _ ₆ alkyl group (wherein the C ₆ — i ₄ vector force rubo C — ₆ alkyl group is a group selected from the following substituent group β: 1 to 5 may be substituted with

Aliphatic acyl group (this aliphatic acyl group may be substituted with 1 to 5 groups selected from the following substituent group | 3)

Indicates;

R ² represents a hydrogen atom, a group selected from the following substituent group: 3, a carboxyl group, or a group represented by 1 C (O) NR ¹³ R ¹⁴ ;

R ³ ,

Hydrogen atom,

C ₁₈ alkyl group (the —8 alkyl group is a group selected from the following substituent group)

1 to 3 may be substituted)

〇 ₆ _ ₁₄ Ariru group (said C ₆ - ₁₄ Ariru group may be one to five substituted with a group selected the following substituent group / 3 forces), or

4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (the heterocyclic group is selected from the following substituent group j3) 1 to 5 may be substituted with a group)

R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or _{A 4-} aryl group (wherein the C _{6 —} ₁₄ aryl group may be substituted with 1 to 5 groups selected from the following substituent group β);

R ⁶ and R ^7, the force to form the connexion C ₃ _ ₇ cycloalkane such together, or the same or different connexion each a hydrogen atom or a C _ ₈ alkyl group (said C i one ₈ alkyl groups, the following substituents 1 to 3 groups may be substituted with a group selected from the group);

R ⁸ and R ^9, the same or different and each represents a hydrogen atom, a group selected from the following substituent group] 3, a carboxyl group or a C (O) group represented by NR ¹³ R ^14; R ¹⁰ is , Hydrogen atom,

_ ₈ alkyl group (the alkyl group has 1 to may be three substituted with a group selected from the following substituent group monument), '

C ₆ _ ₁₄ Ariru group (said C ₆ one ₁₄ Ariru group, Substituent Group | may be one to five substituted by a group selected from 3), or

A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms which are the same or different and are selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is a group selected from the following substituent group j3) 1 to 5 may be substituted with

R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a group selected from the following substituent group] 3, a carboxyl group, or a group represented by 1 C (O) NR ¹³ R ¹⁴ ;

R ¹³ and R ¹⁴ together represent a 4- to 10-membered nitrogen-containing heterocycle (the nitrogen-containing heterocycle may be substituted with 1 to 5 groups selected from the following substituent group J3). power \ or the same or different and each represent a hydrogen atom or C ₈ alkyl group form formed (the - ₈ alkyl group has 1 to may be three substituted with a group selected from the following substituent group alpha) the Show.

However,

(1) When R ¹ is a Ci—s alkyl group and Y ¹ is a single bond, B is a 2,4 1-doxo1,3 _thiazolidine-5-yl group,

(2) When Y ² is methylene, both R ⁶ and R ⁷ are not hydrogen atoms,

(3) When R ¹ is an unsubstituted C ₈ alkyl group, Y ¹ is not carbonyl,

(4) When R ¹ is an unsubstituted —6 aliphatic acyl group, Y ¹ is not a single bond.

(Substituent group α)

Halogen atom, C ^ s alkylthio group, C ₆ aliphatic acyl group, ₆ alkyl sulfonyl group, Ci-e alkoxy group, Cyano group and nitro group.

(Substituent group) 3)

Halogen atom, ₆ alkyl group, halo Ci-6 alkyl group, alkoxy group, Flip alkylthio group, Ji ₆ alkylsulfonyl group, C - ₆ aliphatic Ashiru group, O Kiso group, Shiano group, a nitro group, c ₃ - ₇ cycloalkyl group, c ₆ - ₁₄ Ariru group, C - ₆ Arukokishiimino group , C ₆ _ ₁₄ Ariru one carbonyl group, and a nitrogen atom, 4 to 10-membered heterocyclic group containing the same or different ivy 1 to 3 of the terrorist atoms selected from oxygen radicals and sulfur atom. ]

Or a pharmacologically acceptable salt or ester thereof.

[2] General formula (I):

(I)

[Where

A is the following general formula (A1) (A2), (A3) or (A4)

A group represented by (Al) (A2) (A3) (A4);

B represents a 1H-tetrazole-5-yl group or a 2,4-dioxo-3-thiozolidine-5-yl group;

X represents a single bond or a C ₆ _ ₁₀ Ariren group;

Y ¹ represents carbonyl, sulfonyl or a single bond;

Y ² represents an alkylene group or a single bond;

Y ³ represents methylene, carbonyl or a single bond;

Y ⁴ represents a methine or nitrogen atom;

Y ⁵ represents methylene, carbonyl or a single bond;

R ¹ is C丄one ₈ alkyl group (said C i one ₈ alkyl group may be 1 to 3 substituted with a group selected from the following substituent group alpha),

C _{6 —} ₁₄ 7 reel group (the same _{6 —} ₁₄ aryl group may be substituted with 1 to 5 groups selected from the following substituent group J3),

C ₆ - ₁₄ Ariru one ₆ alkyl group (the C ₆ - ₁₄ § Li one Roux 0 ^ ₆ alkyl group may be one to five substituted with a group selected from the following substituent group), a nitrogen atom A 4- to 10-membered heterocyclic group containing the same or different 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom (the heterocyclic group is selected from the following substituent group) 1 to 5 of these groups may be substituted)

Nitrogen atom, 4 to 1 0-membered heterocycle 10 ₂ _ ₆ alkyl group include the same or different 1 to terrorist atom 3 of the selected from oxygen atom and sulfur atom (the heterocyclic ring - C - ₆ alkyl The group may be substituted with 1 to 5 groups selected from the following substituent group β):

C ₃ one ₇ cycloalkyl group,

C ₃ - ₇ cycloalkyl one C - 6 alkyl group or

C ₆ - ₄ Ariru - Power Ruponiru - C - ₆ alkyl group (the C ₆ _ ₄ Ariru - force Lupo two Le one C i - ₆ alkyl groups, one to five groups selected from the following substituent group β Which may be substituted);

R ² represents a hydrogen atom, a group selected from the following substituent group / 3, a carboxyl group or a group represented by —C (O) NR ¹³ R ¹⁴ ;

R ³ is

Hydrogen atom,

A C ^ s alkyl group (the Ci-s alkyl group may be substituted by 1 to 3 groups selected from the following substituent group α);

C ₆ one ₁₄ Ariru group (said C ₆ - ₁₄ Ariru group may be one to five substituted with a group selected from the following substituent group] 3), or A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms identical or different selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is selected from the following substituent group) 1 to 5 may be substituted with a group)

R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C 6 ^ ₄ aryl group (the C _{6 —} i ₄ aryl group is a group selected from the following Substituent Group 3; May be converted);

R ⁶ and R ^7, the force to form a C ₃ _ ₇ cycloalkane together, or the same or different connexion each a hydrogen atom or a C - ₈ alkyl group (said C i _ ₈ alkyl group, the following substituents 1 to 3 groups may be substituted with a group selected from the group);

R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a group selected from the following substituent group, a carboxyl group, or a group represented by 1C (O) NR ¹³ R ¹⁴ ;

R ¹⁰ is

Hydrogen atom,

C ^ s alkyl group (the C _ ₈ alkyl group may be 1 to 3 substituted with a group selected from the following substituent group monument),

C 64 ₄ Ariru group (said C ₆ - ₁₄ Ariru group may be one to five substituted with a group selected from the following substituent group] 3), or

A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms identical or different selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is selected from the following substituent group) 1 to 5 may be substituted with a group)

R ¹³ and R ¹⁴ together are a 4- to 10-membered nitrogen-containing heterocycle (the nitrogen-containing heterocycle may be substituted with 1 to 5 groups selected from the following substituent group / 3) the to shape formed either someヽare the same or different connexion each a hydrogen atom or a C i _ ₈ alkyl group (The Ci- ₈ alkynole group may be substituted with 1 to 3 groups selected from the following substituent group).

However,

(1) When R ¹ is an ₁₈ alkyl group and Y ¹ is a single bond, B is a 2,4-dioxo-1,3-thiazolidine-5-yl group,

(2) When Y ² is methylene, both R ⁶ and R ⁷ are not hydrogen atoms,

(3) When R ¹ is an unsubstituted C ₈ alkyl group, Y ¹ is not carbonyl,

(4) When R ¹ is an unsubstituted aliphatic acyl group, Y ¹ is not a single bond.

(Substituent group a)

A halogen atom, an alkylthio group, an alkylsulfonyl group, an alkoxy group, a cyano group and a utro group;

(Substituent group

Halogen atom, Ci- ₆ alkyl group, halo C- ₆ alkyl group, same ₆ alkoxy group, Ci- ₆ alkylthio group, C ₆ alkylsulfonyl group, aliphatic acyl group, cyan group, nitro group, C ₃ _ ₇ cycloalkyl group, C ₆ - ₁₄ § Li Ichiru group, and a nitrogen atom, 4 to 1 0-membered heterocyclic ring containing 1 to 3 identical or different hetero atoms selected from oxygen atom Contact Yopi sulfur atom Group. ]

Or a pharmacologically acceptable salt or ester thereof.

[3] B is 1H- Tetorazoru 5 I group, and X is C ₆ - ₁₀ Ariren group, [1] or [2] The compound according or a pharmacologically acceptable salt thereof Wakashi Ku is Estenore.

[4] The compound according to [3], wherein X is phenylene, or a pharmacologically acceptable salt or ester thereof.

[5] The compound according to [1] or [2], wherein B is 2,4-dioxothiazolidine-1-5-inole group, and X is a single bond, or a pharmacologically acceptable salt thereof, or Estenore. [6] The compound according to [1] or [2] or a pharmacologically acceptable salt thereof, wherein A is a group represented by the general formula (A1), and R ² is a hydrogen atom or a strong lpoxyl group. Salt or ester.

[7] A is a group represented by the general formula (A2), and R ³ is, was or hydrogen atom C ₆ one ₁₄ Ariru group (said C ₆ one ₁₄ Ariru groups, in claim 1 The compound according to [1] or [2], or a pharmacologically acceptable salt or ester thereof, which may be substituted with 1 to 5 groups selected from the defined substituent group force.

[8] Α is a group represented by the above general formula (A3), Y ³ is a carbonyl or a single bond, and R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom. Or a pharmacologically acceptable salt or esterole thereof according to [1] or [2], wherein is a carboxyl group.

[9] A is a group represented by the above general formula (A4), Y ⁵ is a carbonyl or a single bond, and R ¹¹ and R ¹² are the same or different and are each a hydrogen atom or a carboxyl group. The compound according to [1] or a pharmacologically acceptable salt or ester thereof.

[10] 3— {N- (3-Phenylpropionyl) 1 N— [2, 1 (1H—Tetrazonole 5—Inole) Biphenyl 2-4 1 ^ T Noremethyl] Amino} Benzoic acid (Example 1) ),

3- {N-pentyl-N- [4- (2,4-dioxo-1,3-thiazolidine-1-yl) benzyl} amino} benzoic acid (Example 6),

1- [4— (2,4-Dioxo-1,3-thiazolidine-5-inole) benzyl] —2-methyl-1,2,3,4-tetrahydroquinoline 7-strength luponic acid (Example 7),

5- [4- (N-methinolesnorehoninore N-phenenoleaminomethinole) fenenore]-1,3-thiazolidine-1,2,4-dione (Example 8),

5— [4— (N-Phylsulfonyl mono-N-phenylaminomethyl) fur] 1, 3-Thiazolidine mono 2,4-dione (Example 9), 3— {N— [4- (2, 4-Dioxo-1,3-thiazolidine-1-yl) benzil] 1 N— (methylsulfonyl) amino} benzoic acid (Example 10),

3— {N-Ptylsulfonyl-N— [4 (2,4-Dioxo-1,3-thiazolyzine-5-yl) benzyl] amino} benzoic acid (Example 1 1),

5— {4— [2— (2-Pyridyl) benzimidazole 1-1ylmethinole] Fe dil} — 1,3-Thiazolidine 1,2,4-dione (Example 15),

5— [4— (2—Fuenil Midazolo 1 1 Inole Mechinole) Fuel]-1, 3— Thiazolidine 1, 2, 4 1 dione (Example 16),

1- [4— (2,4-Dioxo-1,3_thiazolidine-5-yl) benzyl] 1-2-oxo-1-3-propyl-1,2-dihydroquinoline-7-carboxylic acid (Example 1) 7),

3— {N—cyclohexanecarbonyl mono N— [4 mono (2, 4-dioxo 1, 3, monothiazolidine mono 5-yl) benzyl] amino} benzoic acid (Example 18),

3— {N— [4-1, (2,4-dioxo-1,3, thiazolidine-1,5-yl) benzil] 1 N— (pyridine-1,3-carboro) amino} benzoic acid (Example 1 9), 3 — {N— [4 (2,4-Dioxo-1,3-thiazolidine-5-yl) benzil] -N- (3-phenylpropiol) amino} benzoic acid (Example 20), 3— {N— (biphenolate 4-canoleponole;) 1 N— [4 (2,4-dioxone 1,3 1-thiazolidine 1-yl) benzenole] amino} benzoic acid (Example 21), 3— {N— (phenylsulfoel) -N- [4— (2, 4-dioxone 1, 3— thiazolidine mono-5-inole) benzyl] amino} benzoic acid (Example 22), 3- {N— (4-Methylenophenylsulfonyl) -N- [4- (2,4-Dioxo — 1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (Example 23), 3 {N- (biphenylenole 4-snolehoninole) -N- [41 (2,4-dioxoso 1,3-thiazolidine mono-5-yl) benzyl] amino} benzoic acid (Example 24), 3- {N — (2-Naphtylsulfonyl) 1 N— [4 1 (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] amino} benzoic acid (Example 25), 3— {N- (benzylsulfo-nor) 1 N— [4 1 (2,4-dioxo-1,3-thiazolidine 1-5-yl) benzyl] amino} benzoic acid (Example 26),

1-[4- (2, 4-Dioxo-1,3-thiazolidine-5-inole) benzyl] — 2-Oxo 3-Propyl 2, 3— 1H-indole-6-carboxylic acid (Example 27) ,

1 1 [4— (2, 4—Dioxo 1,3—thiazolidine 1—yl) benzyl] —2—Oxo 1 3-propyl 1, 2, 3, 4, 5—tetrahydro 1H—benzo [b] azepine 8—force / reponic acid (Example 28),

3,3-Dimethyl 1 1 1 [4 1 (2, 4-Dioxo 1,3-Thiazolidine 1 5 —yl) Benzyl] —2-Oxo 1, 2, 3, 4-tetrahydroquinoline 1 7 / Levonic acid (Example 29),

1 '-[4- (2,4-dioxo-1,3_thiazolidine-5-yl) benzyl] —2,1, oxo 1', 4, dihydro 1,2, H-spiro [cyclopropane 1,

3 ′ —quinoline] — 7 ′ —carboxylic acid (Example 30),

3- {N-phenethyl mono-N- [2, one (1H-tetrazole mono 5- ^) biphenyl di-ruyl 4-ylmethyl] amino} benzoic acid (Example 32),

3- {N- [4- (2, 4-Doxo_ 1,3-Thiazolidine-1-yl) benzyl] -N- [(5-Methyl-2-phenyl_1,3-oxazole 4- Acetyl] amino} benzoic acid (Example 33),

3— {N- (3-Cyclohexylenopropanoyl) 1 N— [2, _ (1H-tetrazol 1-yl) biphenyl 1-ylmethyl} amino} benzoic acid (Example 3

6),

3-{N- (2-oxo-2-enylethyl) -N- [2, 1 (1H-tetrazol-5_yl) biphenyl 4-aminomethyl] amino} benzoic acid (Example 4 2), 3— {N— [4 1 (2, 4-Dioxo-1, 1, 3-thiazolidine 1 5-yl) Benzinore] 1 N— [4 1 (2-Methylorethiazolone 4-Inole) Benzenesulfonyl] Amino} benzoic acid (Example 6 3), and

3— {N— (biphenolate 4-monoremethinole) -N- [4- (2,4-dioxo-1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (Example 68) The compound according to claim 1 or a pharmacologically acceptable salt or esterole thereof selected.

[1 1] A medicament comprising the compound according to any one of [1] to [10], or a pharmacologically acceptable salt or ester thereof.

[1 2] For prevention or treatment of renal disorder, cerebral metabolic disorder or cardiovascular disease, comprising the compound according to any one of [1] to [10] or a pharmacologically acceptable salt or ester thereof Medicinal products, synthetic products.

[1 3] Cardiovascular disease is myocardial infarction, cardiac hypertrophy, heart failure, arteriosclerosis, coronary artery disease, peripheral circulation disorder, cerebrovascular disorder, hypertension, systolic hypertension or restenosis after angioplasty The pharmaceutical composition according to [1 2].

[14] The pharmaceutical composition according to [12], wherein the renal disorder is nephritis, nephropathy, nephrosclerosis or renal failure.

[15] The pharmaceutical composition according to [12], wherein the cerebral metabolic disorder is Alzheimer's disease or Parkinson's disease.

[16] A pharmaceutical composition for preventing or treating diabetic complications, comprising the compound according to any one of [1] to [10] or a pharmacologically acceptable salt or ester thereof.

[1 7] The pharmaceutical composition according to [16], wherein the diabetic complication is nephropathy, retinopathy, cataract, neuropathy, microvascular disorder or skin disorder.

[18] The pharmaceutical composition according to [16], wherein the diabetic complication is nephropathy. [19] A medicament or composition for the prevention or treatment of dialysis amyloidosis, comprising the compound according to any one of [1] to [10] or a pharmacologically acceptable salt or ester thereof.

[20] A pharmaceutical composition for preventing or treating a disease caused by aging, comprising the compound according to any one of [1] to [10] or a pharmacologically acceptable salt or ester thereof.

[2 1] The pharmaceutical composition according to [20], wherein the disease caused by aging is senile cataract.

[22] An AGEs production inhibitor comprising the compound according to any one of [1] to [10], or a pharmacologically acceptable salt or ester thereof.

[23] of [1] to [10] for the manufacture of a medicament for the prevention or treatment of renal disorders, cerebral metabolic disorders, cardiovascular diseases, diabetic complications, dialysis amyloidosis or diseases caused by aging Use of any one of the compounds described above or a pharmacologically acceptable salt or ester thereof.

[24] Use of the compound according to any one of [1] to [10] or a pharmacologically acceptable salt thereof or estenole for the manufacture of a medicament for the prevention or treatment of diabetic nephropathy.

[25] A renal disorder, brain metastasis disorder, heart, wherein a pharmacologically effective amount of the compound according to any one of [1] to [10] or a pharmacologically acceptable salt or ester thereof is administered to a warm-blooded animal. Prevention or treatment of diseases caused by vascular diseases, diabetic complications, dialysis amyloidosis or old age.

[26] A method for preventing or treating diabetic nephropathy, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of [1] to [10] or a pharmacologically acceptable salt or ester thereof. .

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, “AGE s” is a compound formed by sugar reacting non-enzymatically with an amino group of a protein and passing through a Schiff base “Amadori compound, and pentosidine, carboxymethyllysine, viralin, etc. are identified. Yes.

In the present invention, the “C _6- arylene group” is a divalent aromatic hydrocarbon group having 6 to 10 carbon atoms, such as 1,2-phenylene, 1, 3 —Phenylene, 1,4—Phenylene, 1,2—Naphthylene, 1,3—Naphthylene, 1,4 One naphthylene, 1,5 One naphthylene, 1,6 One naphthylene, 1,7—Naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,4 naphthylene and the like.

In X, phenylene is preferred.

In the present invention, "Ji ₆ alkylene group" is a one to six straight or branched chain alkylene group having a carbon atom, e.g., methylene, ethylene, pro propylene, trimethylene, 1-Echiru 1,2-Ethylene, 1-Propyl 1,2-Ethylene, 1-Isopropynole 1,2-Ethylene, 1-Butinole 1,2-Ethylene, 1,2-Dimethyl 1,2- Examples include ethylene, tetramethylene, pentamethylene, hexamethylene and the like.

Y ² is preferably a C i -s alkylene group, more preferably methylene or ethylene.

In the present invention, the ". ₈ alkyl group" is a linear or branched alkyl group having 1 to 8 carbon atoms, e.g., methyl, Echiru, propyl, I Sopuropinore, butyl, Isopuchinore , S-ptyl, t-petitenole, pentyl, 1-methinolevbutinore, 2-methinolevinole, 3-methinoreptinole, 1,1-dimethinorepropinole, 1,2-dimethyl pill, 2,2-dimethyl pill, 1 -Methyl pill, Hexinore, 1-Methinorepentinole, 2-Metinolepentinole, 3-Methinorepentinole, 4-Metinolepentinole, 1,1-Dimethinorebutinore, 1,2-Dimethinore Petitnore, 1,3-dimethinolevbutenore, 2,2-dimethinolevbutenore, 2,3-dimetinoreptinole, 3,3-dimethinoleputinole, 1-echinoleputinore, 2etino Lebutinore, 1, 1, 2—Torime Tylpropyl, 1,2,2-trimethylpropyl, heptyl, 1-methylpentyl, 2-methinolepentinole, n-heptynole, isoheptyl, sec-heptyl, tert-heptinole, n-octinore, isooctinore, tert- Octyl, 2-methylhexyl, 2-ethylhexyl and the like.

In R ¹

(1) When Y ¹ is a sulfole group, it is preferably a 6 alkyl group, more preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, and more preferably methyl or butyl.

(2) When Y ¹ is a single bond or a carbonyl group, preferably a C _{4 8} alkyl group, more preferably Puchinore a Penchinore, hexyl, heptyl, Okuchiru, more preferably a pentyl. '

In R ³ , a —5 alkyl group is preferred, and methyl, ethinole, propinole, butinole and pentinole are more preferred.

R ⁶ and R ⁷ are preferably Ci ₃ alkyl groups, and more preferably methinore, ethinore and propinore.

R ¹⁰ is preferably a C i ₄ alkyl group, and more preferably methyl, ethynole, propinole or petitnore.

In R ^{1 3} and R ^{1 4,} a suitably Haji ₃ alkyl group, more preferably Mechinore is Echinore.

In the present invention, the ". ₆ alkyl group" is a linear or branched alkyl group having 1 to 6 carbon atoms, e.g., methyl, Echiru, propyl, I an isopropyl, heptyl, isobutyl , S-Ptyl, t-Ptyl, Pentyl, 1-Methylptyl, 2-Methylptyl, 3-Methylptyl, 1,1-Dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-Ethylpropyl Xinole, 1-Metinorepentinole, 2-Methinorepentinole, 3-Methylenopentenole, 4-Methylpentyl, 1,1-Dimethylbutyl, 1,2-Dimethylbutyl, 1,3-Dimethylputyl, 2,2-Dimethyl Ptyl, 2,3-dimethylbutyl, 3, 3 -Dimethinolevbutinore, 1-etinolevbutinore, 2-ethinolevbutenole, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl and the like.

Substituent] 3 is preferably a C- ₃ alkyl group, more preferably methyl or ethenore.

In the present invention, - the term "C ₆ ₁₄ Ariru group" is a number 6 to 14 amino Kaoru aromatic hydrocarbon group having a carbon atom, e.g., phenyl, naphthyl, anthryl, Fuenanto Lil, Asenafuchireniru and the like.

In R ¹ is preferably a C ₆ - a ₁₀ § Li group, more preferably phenyl, naphthyl.

In R ^3, preferably a C ₆ _ ₁₀ Ariru group, more preferably phenyl, naphthyl.

In R ⁴ and R ^5, preferably a C ₆ _ ₁₀ Ariru group, more preferably in full Eniru.

In R ^10, it is preferably Ce-i. An aryl group, more preferably phenyl.

In the substituent J3, preferably a C ₆ _ ₁₀ Ariru group, more preferably a phenylene Honoré.

In the present invention, the “C _{6 —} ₁₄ aryl-Ci-6 alkyl group” is a group in which the above “C _{6 —} ₁₄ aryl group” is bonded to the above “di- ₆ alkyl group”. , 1 phenethinore, 2-phenethinore, 3-fenenorepropinore, 4 -1 fenenore pentinore, 5 _ feneno repeno chinole, 5-feneno hexenole, 1-naphthino remetinole, 2-naphthylethyl, anthrylmethyl, And phenanthrylmethyl, acenaphthylmethyl, and the like.

In R ¹ , preferably Ariru is an ₃ alkyl groups, base and more favorable suitable Njire, 1_ Fuenechinore, 2- Fuenechinore, 3-phenylene Norepuropiru, 1 - naphthylmethyl, 2-naphthylmethyl, 2- (1 one-naphthyl) Echiru, 2 — (2 naphthylethyl). In the present invention, “a 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms identical or different selected from a nitrogen atom, an oxygen atom and a sulfur atom” Pyrrolyl, furyl, chenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, biruryl, pyridyl, pyridazinyl, pyramidyl, pyramidyl, pyrazyl Azetiduyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, virazolinyl, piperidyl, piperazuryl, morpholinyl, thiomorpholinyl, perhydrodroazebuyl, perhydrodrazosinyl, 1, 4 The unsaturated heterocyclic group may be partially or completely reduced, such as, 6-tetrahydropyrimidinyl, 1, 2, 3, 6-tetrahydropyridyl. Indolinole, Indolinole, Benzofurinole, Benzocenyl, Benzimidazolinole, Benzisoxazolinole, Benzisoxazolinole, Benzthiazolinole, Benzy sothiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, Benzoxaziazolyl, Benzothiadiazolyl, Pirochilo pyrrolyl, Pirochilo oxazo linole, Pirochia thiazolinole, Pirochiri pirizi / re, Flopylori / le, Flopyridinole, Chenopyrrolyl, Cenopyridyl, Imidazopi crillyl, Imidazo Imidazolyl, imidazoxazolinole, imidazosoxazolinole, imidazothiazolinole, imidazo sothiazolyl, imidazopyridyl, imidazopyridazinole, imidazopyrimidinyl, imidazopyrazur Oxazoxazolyl, Oxazoisoxazolyl, Oxazothiazolyl, Oxazoisothiazolyl, Oxazopyridyl, Thiazoxazolyl, Thiazoisoxazolyl, Thiazothiazolyl, Thiazoisothiazolyl, Thiazopyridyl, etc. It may be a group in which saturated heterocyclic rings are condensed or a group in which a benzene ring and the above unsaturated heterocyclic ring are condensed.

In R ¹ , a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms, which is the same or different, preferably selected from a nitrogen atom, an oxygen atom and a sulfur atom (The heterocyclic ring may be condensed with a benzene ring), and more preferably pyridyl, oxazolyl, thiazolyl, quinolyl.

In R ³ , a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms, which is the same or different, preferably selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocycle is a benzene ring) And may be condensed), more preferably pyridyl or quinolyl.

In R ^{1 Q} , a 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms, which is the same or different, preferably selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocycle is a benzene ring) And may be condensed with pyridyl or quinolyl.

In the substituent, a 5- or 6-membered heterocyclic group containing 1 or 2 hetero-atoms, which are the same or different, preferably selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic ring is a benzene ring) It may be condensed) and is preferably imidazolyl, thiazolyl, oxazolyl, oxaziazolyl, or pyridyl. The heterocyclic group may be substituted by 1 to 3 of the above “. ^ 6 alkyl group”.

In the present invention, the “4- to 10-membered nitrogen-containing heterocycle” includes the same or different 1 to 3 heteroatoms selected from the above-mentioned “nitrogen atom, oxygen atom and sulfur atom”. 1 to 2 heterocycles that are the same or different and are selected from a nitrogen atom, an oxygen atom, and a sulfur atom, including at least one nitrogen among the rings constituting the “4- to 10-membered heterocyclic group” Rings that may contain atoms, such as, for example, pyronole, pyrazol / re, imidazole, triazol / re, tetrazo / re, etc .; azetidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, Pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, perhydroazepine, perhydroazocine, 1, 4, 5, 6-tetrahydropi Spermidine, 1, 2, 3, 6-tetrahydropyridine, etc., the unsaturated heterocyclic ring may be partially or fully reduced ring. Indole, Indoline, Benzymidazore, Piroguchi Piro-monore, Piro-Mouth Kisazo-no-re, Piroguchi Chiazonore; Piro-Mouth Pyridine, Flopirinore, Cenopiro-Minole, Imidazopi Mouth-Nole, Imidazo Imidazole, Imidazoxazole, Imidazoisoxazole, Imidazothiazole, Imidazoisothiazole, Imidazopyridine, Imidazopyridazine, Imidazopyrimidine, etc. A ring in which the unsaturated heterocycles are condensed or a ring in which the benzene ring and the unsaturated heterocycle are condensed may be used.

R ¹³ and R ¹⁴ are preferably an imidazole, pyrrolidine, piperidine, morpholine, or indole ring, and more preferably a pyrrolidine, piperidine, or morpholine ring.

In the present invention, “a 4- to 10-membered heterocyclic mono-C ^ ₆ alkyl group containing 1 to 3 heteroatoms identical or different selected from a nitrogen atom, an oxygen atom and a sulfur atom” the above "nitrogen atom, an oxygen atom and 4 to 1 0-membered heterocyclic group containing the same or different 1 to 3 heteroatom selected from sulfur atom" to "〇 bets ₆ alkyl group" described above For example, pyrrolylmethyl, furyl methinole, cheninolemethinole, cheninoleethyl, cheninopropynole, pyrazolinolemethyl, imidazolylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, Oxadiazolylmethyl, thiadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, pyranylmethyl, pi Lizinoremethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, azepi ninoremethinore, azosini / remethinore, azetijunoremetinore, pyrrolidino retinochinole, pylolinylmethyl, imidazolidyl-methyl, imidazolidylyl Nilmethyl, virazolinylmethyl, piperidylmethyl, piperazilmethyl, monorephorylmethinole, thiomorpholinylmethyl, perhydroazebuylmethyl, no. -Hydroazosinylmethyl, 1,4,5,6-tetrahydropyrimidinylmethyl, 1,2,3,6-tetrahydropyridylmethyl, indolylmethyl, indolininoremethinore, benzofuranoremethinore, benzoceninoremethinore, benz Imidazolinole Mechinole, Benzisoxazolidole methinore, Benzisoxazolinole methinore, Benzothiazolylmethyl, Benzisothiazolylmethyl, Quinolylmethyl, Isoquinori Noremethinore, Quinazolininoremethinole, Quinoxalininoremethinore, Benzoxaziazori Noremethinore, Benzothiadiazolinolemeti / le, Pyroxyl pyrrolinoremethinore, Pyroxoxazolylmethyl, Pyroxiazoazolmethyl, Pyrox Pyridylmethyl, furopyrrolylmethyl, furopyridylmethyl, chenopyrrolylmethyl, chenopyridylmethyl, imidazopyrrolylmethyl, imidazoimidazolylmethyl, imidazoxazolylmethyl, imidazoisoxazolylmethyl, imidazothiazolylmethyl, Imidazoisothiazolylmethyl, imidazopyridylmethyl, imidazopyridazinylmethyl, imidazopyrimidinylmethyl, imidazopyrazurylmethyl, oxazoxazolylmethyl, oxazoisoxazolylmethyl, Oxa Thiazolylmethyl, oxazisothiazolylmethyl, oxazopyridylmethyl, thiazoxazolylmethyl, thiazoxazolylmethyl, thiazothiazolylmethyl, thiazosothiazolylmethyl, thiazopyridylmethyl Etc.

In R ¹ , a 5- or 6-membered heterocyclic mono-C 3 alkyl group containing 1 or 2 heteroatoms, which is the same or different, preferably selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocycle is More preferably, oxazolylmethyl, thiazolylmethyl, pyridylmethyl, quinolylmethinole, cheninoreethinore, and cenoinopropinore.

In the present invention, the “C _{3 7} cycloalkyl group” is a cyclic alkyl group having 3 or 7 carbon atoms, and examples thereof include cyclopropyl, cycloptyl, cyclobentinole, cyclohexyl, cycloheptyl and the like. Can be mentioned.

R ¹ is preferably a C _{5 6} cycloalkyl group, and more preferably cyclopentenore or cyclohexenore.

Substituent] 3 is preferably a C _{4 6} cycloalkyl group, and most preferably cyclopentyl pentyl and cyclohexhexyl.

In the present invention, "C ₃ _ ₇ cycloalkyl one - 6 alkyl group" and, in the "C

₃ - ₇ cycloalkyl group "is a group attached to the alkyl group of" For example, consequent opening cyclopropylmethyl, 2-cyclopropyl E chill, consequent opening butylmethyl - 2-Silk Mouth Puchino Lechinoret, Siku Mouth Penchinore Mechinore, 2-Siku Mouth Pentinole Mechinore,

3-Cyclopentinorepropinore, 4-Cyclopentinoleptinole, 5-Cyclopentinole Pentinole, 6-Silk Mouth Pentinole Hexinore, Siku Mouth Hexino Lemethinore, 2-Sikh Mouth Xinoretinore, 3-Cyclohexinore Mouth Pinole 4-cyclohexenolevbutenole, 5-l-hexoxy pentenole, 6-l-hexenole hexinole, 2-l-octylmethinole, 2-l-l-octylethyl.

In R ¹ is preferably a C ₅ - ₆ cycloalkyl one C i - is 3 alkyl group, yo Ri preferably Kishiruechiru to consequent opening cyclohexylmethyl, to 2-Sik port.

In the present invention, the "C ₆ - - _{1 4} Ariru one carbonylation Lou C ₆ alkyl group", a group "C ₆ _ _{1 4} Ariru group" described above is bonded to a carbonyl group, further the above-mentioned "C i - ₆ alkyl group J bonded to the base, for example, Benzoirumechiru, 2 base down zone Inoreechinore, 3-base emission zone I Honoré prop zone les, 4 Benzoinorebuchi 7 Les, 5-base Nzoinore pentyl, 6 one base Nzoinore Hexinole, naphthoinole methinore, 2-naphthoinoletinole and the like.

In R ¹ is preferably a C ₆ - _{1 ()} Ariru Ichiriki Lupo two Lou C - a ₃ alkyl group, more preferably base Nzoirumechinore is Nafutoirumechiru.

In the present invention, “. 卜₆ aliphatic acyl group” refers to a group in which a hydrogen atom or a saturated or unsaturated chain hydrocarbon group having 2 to 5 carbon atoms is bonded to a carboel group. , Formyl, acetyl, propionyl, petityl, isoptylyl, norrelyl, isovaleryl, bivalloyl, hexanoyl, acryloyl, methacryloyl, crotonol and the like.

R ¹ is preferably a C i-4 aliphatic acyl group, and more preferably butyrinore.

In the substituents α and] 3, an aliphatic acyl group is preferable, acetyl and propionyl are more preferable, and acetyl is most preferable. In the present invention, - the term "C ₃ ₇ cycloalkane" is a carbon atom number of 3 carbon atoms to seven cyclic alkanes, e.g., cyclopropane, heptane and the like cyclobutane, consequent opening pentane, consequent opening hexane, to consequent opening Is mentioned.

R ⁶ and R ⁷ together, preferably C ₃ - ₅ cycloalkane is formed, more preferably form a cyclopropane.

In the present invention, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and a silicon atom.

In the substituents [3] and [3], each is preferably a fluorine atom, a chlorine atom, or a bromine atom, more preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom.

In the present invention, “di- ₆ alkoxy group” is a hydroxyl group substituted with the above C-6 alkyl group, for example, methoxy, ethoxy, 1-propoxy, 2_propoxy, 1-ptoxy, 2-ptoxy, 2- Methyl-1-propoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2_methyl-1-butoxy, 3-methyl-2-butoxy, 1-hexoxyloxy, 2-hexoxyloxy 3-hexyloxy, 2-methyl-1- 1-pentyloxy, 3-methyl-1-1-pentyloxy, 2-ethyl-1-1-butoxy, 2,2-dimethyl-1-one butoxy, 2,3-dimethyl-11 Butoxy and the like can be mentioned. In the substituents α and, each is preferably a C i — ₄ alkoxy group, more preferably methoxy or ethoxy, and most preferably methoxy.

In the present invention, the “di- ₆ alkylthio group” is a mercapto group substituted with the above Ci- ₆ alkyl group. For example, methylthio, ethylthio, 1-propylthio, 2-propylthio, 1_ptylthio, 2-ptylthio , 2-methyl-1-propylthio, 2-methyl-2-propylthio, 1-pentylthio, 2-pentylthio, 3-pentylthio, 2-methyl-1-2-butylthio, 3-methyl-2-butylthio, 1-hexinoretio, 2 —Hexinorethio, 3-Hexinoreio, 2-Methanole 1-Pentinoreio, 3-Methinoreol 1-Pentylthio, 2-Ethenoleol 1-Putinoreio, 2, Examples thereof include 2-dimethyl-11-l-ptylthio and 2,3-dimethyl-11-l-pylthio groups.

The substituents α and / 3 are each preferably a —4 alkylthio group, more preferably methylthio or ethylthio, and most preferably methylthio. In the present description, “.-6 alkylsulfonyl group” is a sulfol group (one so ₂ —) substituted with the above Ci- ₆ alkyl group, and examples thereof include methanesulfonyl, ethanesulfonole, and one propane. Sunolehoni Λ \ 2-Propanesunorehonoré, 1-Butanesulfonyl, 2-Butansnoleonyl, 2-Methyl-1 Monopropanesulfonyl, 2-Methylenore 2-Propanesenorehoni / Le, 1 Pentansnorehoninore 2—Pentane Snorehoninore, 3—Pentans Norehoninole, 2—Metinore 1—Panthans Norehoninole, 3—Metinore 1—Butans Norehoninole, 1—Hexans Norehoninole, 2—Hexans Nore Honore, 3— Hexanorehoninole, 2-Methanole 1-Pentans Norrehonoré, 3-Methinore 1-Pentans Norrehonore, 2-e Examples include chinole 1-butansnorehonore, 2,2-dimetinole 1-butansnorehoninole, 2,3-dimethylonole 1-butansnorehoninore.

In the substituents α and] 3, a —4 alkylsulfonyl group is preferred, methanesulfol and ethanesulfonyl are more preferred, and methanesulfonyl is most preferred.

In the present invention, the “haloalkyl group” is the above alkyl group substituted with 1 to 7 of the above halogen atoms, and examples thereof include fluoromethyl, difluoromethinole, dioctromometinole, dipromomethinole, trifnoleolomethinole, trichloro. Lomethinole, 2-Funoleoloetinole, 2-Promoetinole, 2-Chlorotechinole, 2-Chloroethyl, 2, 2-Difluoroethyl, 2, 2, 2-Trifluoroethyl, 2, 2, 2-Trichloro Ethynole, pentafluoroethyl, 3-fluoropropyl, 3-chloropropynole, 4-funoleolobutinole, 5-fluoropentinole, 6-funoleohexyl and the like. In the substituents beta, preferably a C! _ ₄ alkyl group substituted with 1 to 5 substituents Ha mouth Gen atoms, more preferably Furuoromechiru, chloromethyl, Jifuruorome chill, triflumizole Honoré Oro methyl, Pentafuru Oloethyl, most preferably trifluoromethyl.

In the present invention, the "C ₆ _ _{1 4} Ariru one carbonyl group", the above - is a group "C ₆ _{1 4} Ariru group" is bonded to a carbonyl group, for example, Benzoiru, naphthyl Rukarubo - le, Fouesnant And tolylcarbonyl.

In the substituent [3], C ₆ — is preferred. It is an aryl monocarbonyl group, most preferably a benzoyl group.

In the present invention, one ₆ The Arukokishiimino group J, the C - a ₆ Imino group substituted with an alkoxy group, for example, Metokishiimino, Etokishiimino, 1 Puropokishiimino, 2 Puropokishiimino 1- Butokishiimino 2-butoxyimino, 2-methyl-1-propoxymino, 2-methinoleyl 2-propoxyimino, 1-1-pentyloximino, 2-pentyloxymino, 3-pentyloxymino, 2-methyl-2 _Butoxymino, 3-methyl-2-butoxyimino, 1-hexoxyreximino, 2-hexoxyximino, 3-hexoxymino, 2_methyl-1-pentyloxymino, 3-methyl-1 —Pentyloxy Simino, 2-Ethyl 1-Butoxy Imino, 2,2-Dimethyl 1_Butoxy Imino, 2,3-Dimethyl 1 1 1 Kishiimino, and the like.

The substituent is preferably an alkoxyimino group, more preferably methoxyimino or ethoxyimino, and most preferably methoxyimino. In the present invention, A is preferably a group represented by the following general formula (A 1), (A 2) or (A 3).

In the present invention, X is preferably a single bond or phenylene. Here, when X is phenylene, B is preferably a 1 H-tetrazole-5-yl group, and when X is a single bond, B is preferably 2,4-dioxo. 1,3-thiazolidine-5-yl group. In the present invention, Y ¹ is preferably sulfonyl or carbonyl. In the present invention, the Y ^2, preferably Ci Ri one ₃ alkylene group or a single bond der, more preferably methylene, ethylene or a single bond.

In the present invention, Y ³ is preferably carbonyl or a single bond. In this effort, Y ⁴ is preferably a nitrogen atom.

In the present invention, Y ⁵ is preferably carbonyl or a single bond. In the present invention, R ¹ is preferably

A C- ₈ alkyl group (the Ci- ₈ alkyl group may be substituted with 1 to 5 C- ₆ aliphatic acyl groups),

C ₆ — ₁₄ aryl group (the C ₆ — ₁₄ aryl group is a ₆ to ₆ alkyl group and a C ₆ —

1 to 5 groups may be substituted with a group selected from the group consisting of ₄ aryl groups),

C ₆ — i ₄ aryl — C — ₆ alkyl group (the C ₆ — i ₄ aryl — C — ₆ alkyl group is

C ₆ - ₁₄ Ariru group, a halogen atom, - 6 alkoxy groups and C ₆ - ₁₄ Ariru - may be one to five substituted by a group selected from the group consisting of carbonyl group), a nitrogen atom, an oxygen atom and 5- to 10-membered heterocyclic group containing the same or different 1 or 2 heteroatoms selected from sulfur atoms (the heterocyclic group is a ₆ alkyl group and a C ₆ _i ₄ aryl group) 1 to 5 groups may be substituted with a group selected from the group consisting of:

A 5- to 10-membered heterocyclic monoalkyl group containing the same or different 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic monoalkyl group is a ₆ alkyl group, C ₆ - ₁₄ Ariru groups and CI- ₆ alkoxy Shiimino may be one to five substituted by a group selected from the group consisting of group),

C ₃ one ₇ cycloalkyl group (said C ₃ _ ₇ cycloalkyl group may be substituted with Okiso group),

Jinkalkill—ji ^ alkyl group

C ₆ _1-4 allele Luponiru C _ ₆ alkyl group, or

— 6 aliphatic acyl groups, And

More preferably,

C ₄ _ ₈ alkyl group (preferably heptyl, pentyl, hexyl, heptyl, Okuchiru) (the C ₄ - ₈ alkyl group has 1 to 5 in ₄ aliphatic Ashiru group (preferably Asechiru, propionitrile two Le) May be replaced)

C ₆ - ₁₀ Ariru group (preferably phenyl, naphthyl) (wherein C ₆ - ₁₀ Ariru group, C - s alkyl group (preferably methyl, Echiru) and C ₆ _ ₁₀ Ariru group (preferably Fueyuru) may be one to five substituted by a group selected from the group consisting of), C ₆ - ₁₀ Ariru one Ci one ₃ alkyl group (preferably a benzyl, 1-phenethyl, 2-phenethyl, 3-phenylene Norepuropiru, 1-naphthyl Honoré methylate Honoré, 2-naphthyl Honoré methylate Honoré, 2- (1 one Nafuchinore) Echiru, 2- (2-Nafuchiruechiru)) (the C ₆ one ₁₀ Ari route 〇 preparative ₃ alkyl groups, C ₆ -. Ariru group (preferably phenyl), halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom), -. ₄ alkoxy group (preferably a main butoxy, ethoxy) and Ji Ariru Ichiriki Ruponiru group ( Benzoy ) May be substituted with 1 to 5 groups selected from the group consisting of force ^), containing the same or different heteroatoms selected from nitrogen, oxygen and sulfur atoms 5- or 6-membered heterocyclic group (the heterocyclic ring may be condensed with a benzene ring, preferably pyridyl, oxazolyl, thiazolyl, quinolyl) (the heterocyclic group is a C ^ s alkyl group (preferably methyl, Echiru) and C ₆ - ₁₀ Ariru group (which may preferably been one to five substituted by a group selected from the group consisting of phenyl)),

A 5- or 6-membered heterocyclic 1 C i- ₃ alkyl group containing the same or different 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic ring is condensed with a benzene ring) (Preferably oxazolylmethyl, thiazolylmethyl, pyridylmethyl, quinolylmethyl, chenethylethyl, chenylpropyl)

(The heterocyclic 1 C- ₃ alkyl group is a 1 ₃ alkyl group (preferably methyl, ethyl),

C ₆ - ₁₀ Ariru group (preferably phenyl), one Arukokishiimino group (preferably 1 to 5 groups may be substituted with a group selected from the group consisting of methoxyimino and ethoxyimino),

C ₅ _ ₆ cycloalkyl group (preferably cyclohexyl cyclopentyl, cyclohexylene) (said C ₅ - ₆ cycloalkyl group may be substituted with Okiso group),

C ₅ 1 ₆ cycloalkyl 1 1 ₃ alkyl group (preferably cyclohexenolemethyl, 2-cyclohexenoretinole)

. . Aryl-carbonyl C alkyl group (preferably benzoylmethyl, naphthoylmethyl) or

Aliphatic acyl group (preferably petityl)

It is.

In the present invention, R ² is preferably a group represented by a hydrogen atom, a carboxyl group, a vinyl group, or C (O) NR ¹³ R ¹⁴ .

In the present invention, the R ^3, preferably hydrogen atom or C ₆ - a ₁₄ Arinore group, more preferably a hydrogen atom or a C ₆ - ₁₀ Ariru group (preferably phenyl, naphthyl).

In the present invention, R ⁴ and R ⁵ are preferably the same or different and each is a hydrogen atom or C 6-i. An aryl group, and more preferably a hydrogen atom or phenol.

In the present invention, the R ⁶ and R ^7, preferably, or together form a connexion C ₃ _ ₅ consequent Roarukan, or the same or different each represent a hydrogen atom or a C 3 alkyl group, more preferably Are the same or different and each represents a hydrogen atom or a C ₃ alkyl group (preferably methyl, ethyl, propyl).

In the present invention, R ⁸ and R ⁹ are preferably the same or different and each is a hydrogen atom or a carboxyl group, more preferably one is a hydrogen atom and the other is a carboxyl group.

In the present invention, R ^1G is preferably

Hydrogen atom, C ₄ alkyl group,

c ₆ — ₁₀ reel, or

A 5- or 6-membered heterocyclic group containing the same or different 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group may be fused with a benzene ring) And more preferably,

An alkyl group (preferably methyl, ethyl, propyl, butyl),

C ₆ — ₁₀ aryl group (preferably phenyl), or

A 5- or 6-membered heterocyclic group containing the same or different 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is fused with a benzene ring) (Preferably pyridyl, quinolyl).

In the present invention, R ¹¹ and R ¹² are preferably the same or different and each is a hydrogen atom or a carboxyl group, and more preferably a carboxyl group. In the present invention, R ¹³ and R ¹⁴ are preferably combined together as a 5- or 6-membered nitrogen-containing heterocycle (the nitrogen-containing heterocycle may be condensed with a benzene ring) (preferably imidazole , pyrrolidine, piperidine, morpholine, or form indole), or the same or different connexion each a hydrogen atom or a C i _ ₃ alkyl group (favorable suitable is methyl, Echiru).

Specifically, the following compounds are suitable.

3— {N— (3-phenylpropioel) -N- [2, 1 (1H-tetrazole — 5-yl) biphenyl 1-ylmethyl] amino} Benzoic acid (Example 1), 3- { N—Pheninorea cetinoleol N— [2,1 (1 H—Tetrazonolone 5— ^ Nole) Biphenyl-4-ylmethyl] amino} benzoic acid (Example 2),

3- {N- (4 monophenylbutyrinole) -N- [2,-(1H-tetrazole _5 —yl) biphenyl 4 monomethyl] amino} benzoic acid (Example 3), 3- {N —Cyclohexanecarbonyl mono-N— [2,-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amino} benzoic acid (Example 4), 3— {N— (Pyridine 1-3-Lupoel) -N- [2, 1 (1H-Tetrazole 1-yl) Biphenyl 2-ylmethyl] Amino} Benzoic acid (Example 5), 3- { N-pentyl mono N— [4- (2, 4-dioxo 1,3_thiazolidine mono 5-yl) benzyl} amino} benzoic acid (Example 6),

1_ [4- (2,4-dioxo-1,3-thiazolidine-5-inole) benzyl] 1-2-methyl-1,2,3,4-tetrahydroquinoline 7-strength rubonic acid (Example 7),

5— [4 -1 (N-methinolesulfoninole 1 N-pheninoreaminomethinole) phen-nore] 1,1,3-thiazolidine 1,2,4-dione

5- [4- (N-Phylsulfoninole N-phenylaminomethyl) fuel] 1,1,3-thiazolidine-1,2,4-dione (Example 9),

3— {N— [4— (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] -N- (methylsulfol) amino) Benzoic acid (Example 10),

3— {N-butylsulfonyl mono-N— [4- (2, 4-dioxo_ 1,3-thiazolidine mono 5-yl) benzyl] amino} benzoic acid (Example 1 1),

5— {4- [(2-Oxo 1 H-quinoline 1-yl) methinole] phenyl} 1, 1, 3-thiazolidine 1, 2, 4-dione (Example 1 2),

5- {4 -— [(2-Methylbenzimidazole-1yl) methyl] phenyl} -1,3-Thiazolidine-1,4-dione (Example 1 3),

5_ {4_ [(2-Propylbenzimidazole- 1 ^^) methyl] phenyl} 1,1,3-thiazolidine-1,2,4-dione (Example 14),

5— {4— [2— (2-Pyridyl) benzimidazole-1-ylmethyl] fur} — 1, 3--thiazolidine-1,4-dione (Example 15),

5— [4— (2-Pheninoreidazonole 1 Noremethinore) Fueninore]-1, 3 1 Thiazolidine 1, 4-Dione (Example 16), 1 1 [4- (2,4-Dioxo 1,3-thiazolidine 1-yl) benzyl] — 2-Oxo 1-Propyl 1,2-dihydroquinoline 1 7-Strong rubonic acid (Example 1 7 ),

3— {N—Cyclohexane Power Luponiru N— [4- (2,4-Dioxo-1,1,3-thiazolidine-5-yl) benzyl] amino} benzoic acid (Example 1 8),

3- {N- [4- (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] 1 N— (pyridine-1-3-carbonyl) amino} benzoic acid (Example 1 9), 3 — {N- [4 (2,4-Dioxo-1,3-thiazolidine-5-yl) benzil] 1 N— (3-phenylpropionyl) amino} benzoic acid (Example 20), 3- {N— (biphenolenol 4-carbol) 1 N— [4 1 (2, 4-dioxo-1,3-thiazolidine 1-yl) benzinore] amino} benzoic acid (Example 21), 3— { N— (phenylsulfur) _N_ [4- (2, 4-dioxo-1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (Example 22), 3-{N— (4 —Metinolevenolesnorephoninole) -N- [4- (2, 4-Dioxo — 1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (Example 23), 3-{N- ( Bifenenole 4-Snolehoninole) -N- [4- (2, 4-Dioxo1,3,1-thiazolidine-1,5-yl) benzyl] amino} benzoic acid (Example 24), 3-{N— (2— Naphthinolesnolejole) -N- [41 (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] amino} benzoic acid (Example 25), 3- {N- (Benzylsulfo Ninole) -N- [4- (2, 4-Dioxo-1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (Example 26), 1 [4- (2,4-Dioxo-1 1,3_thiazolidine-1-yl) benzyl] _2-oxo-1-3-propyl-1,3-H-indole-6-strength rubonic acid (Example 27),

1- [4- (2,4-Dioxo-1,3-thiazolidine-5-inole) benzyl] —2-Oxo 3-propyl-1,2,3,4,5-tetrahydro 1H-benzo [b] azepine 1-8-norebonic acid (Example 28), 3, 3-Dimethinole 1— [4— (2, 4-Dioxo-1, 3, 3-thiazolidine 1- 5-yl) benzyl] — 2-Oxo 1, 2, 3, 4--tetrahydroquinoline 1 7 (Example 29),

1, ― [4— (2, 4-Dioxo-1,3-Thiazolidine-1-yl) Benzyl] One 2 '—Oxo 1, 1, 4, 1, Dihydro 1, 2, H-Spiro [Cyclopropane 1, 3 ′ —quinoline] —7 ′ —carboxylic acid (Example 30),

1— [4-1, (2,4-Dioxo-1,3-thiazolidine-1,5-yl) benzyl] 1-2-propyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (Example 3) 1),

3- {N-phenethyl-N- [2,1- (1H-tetrazol-l-yl) biphenyl-l-ylmethyl] amino} benzoic acid (Example 32),

3— {N- [4 1 (2, 4 — Dioxo 1, 3 — Thiazolidine 1 5 — yl) Ben Zinore] -N- [(5—Methinore 2—Fueninole 1, 3—Oxazonore 1—4—Izure) Acetyl] amino} benzoic acid (Example 33),

3― {N- ((2,5-Dimethinole 1,3-oxazol-4-ynole) Force] 1 N— (4 (2,4-Dioxo-1,3-thiazolidine-5-yl) Benzyl Amino} benzoic acid (Example 34),

2-Oxo 3-Propyl 1- [2, 1 (iH-tetrazol 1-ylmethyl) biphenyl 4-ylmethyl] —2, 3, 4, 5-tetrahydro 1H-Benzo [b] Azepine 8—Strong rubonic acid (Example 3 5),

3— {N— (3-cyclohexylpropanoyl) 1 N— [2 '— (1H-tetrazole 1-5-yl) biphenyl / le 4-ylmethyl} amino} benzoic acid (Example 3 6 ),

3— {N— [(5-Methanole 2-Fenanole 1, 3-Oxazonore 4-Finole) Acetyl] 1 N— [2, 1 (1H-Tetrazole 1 5 T Nore) Bifuenol 4 1 Dimethyl) amino} benzoic acid (Example 37), 5— [4 ′-(2-phenylimidazole 1-l-methyl) biphenyl-1-yl] 1 1-H-tetrazole (Example 38),

5— [4, ― (4-Fuenorei Midazonore 1-Inole Mechinore) Bifuenore 2—yl ”1 H-tetrazole (Example 39),

5— [4, 1 (5-phenylimidazole 1-ylmethyl) biphenyl 2-yl] — 1H-tetrazole (Example 40),

2-propyl-1- 1- [2,1- (1H-tetrazol-5-yl) biphenyl 4-monoremethinole] 1,1,2,3,4-tetrahydroquinoline-7-carboxylic acid (Example 4 1),

3- {N- (2-oxo-2-phenylethyl) -N- [2,-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amino} benzoic acid (Example 4 2),

3- {N- (3-quinolinecarbonyl) -N- [2 '_ (1H-tetrazole-5-inole) biphenyl-4-ylmethyl] amino} benzoic acid (Example 43), 3- {N- (2 —Naphthoyl) 1 N— [2,-(1 H-tetrazole 1-5-yl) biphenylenoyl 4-1-ylmethyl] amino} benzoic acid (Example 44),

3— {N- (4-biphenylcarbonyl) -N- [2, 1 (1H-tetrazole 1-5-yl) biphenyl-1 4-ylmethyl] amino} benzoic acid (Example 45), 3— {N— [ (2,5-Dimethyl-1,3-oxazole) 4-N] [2,1- (1 H-tetrazole-5-yl) biphenyl 4-ylmethyl] amino} benzoic acid ( Example 46)

3- {N- [4— (5-Methyl-1,2,4-Oxaziazol-Lu 3-yl) Benzyl] One N— [2,-(1H-Tetrazole-5-yl) Biphenyl 1 4 —Ylmethyl] amino} benzoic acid (Example 47),

3-{N- [4- (2-Methylthiazole-4-yl) benzenesulfonyl] 1 N- [2, 1 (1 «[-tetrazol-5_yl) biphenyl- 4-ylmethyl] amino} Benzo Acid (Example 48), 3— {N- [4 (2-pyridyl) benzoyl] 1 N— [2, 1 (1H-tetrazol-5-yl) biphenyl 2 f rumethinole] amino) Benzoic acid (Example 4 9),

N— [3— (morpholinocarbonyl) phenyl] — N— [2, _ (1H—tetrazonole 1—5-inole) biphenol 2—noremethinore] 1—41 (2-pyridinole) benzamide (Example 50) ,

3— {N— [4— (2-Pyridyl) benzoinole] -N- [2, 1 (1H—Tetrazone 5—yl) Biphenyl 4-ylmethyl] amino} benzamide (Example 5 1) ,

N— [3— (morpholinocanoleponyl) phenyl] — N— [2,1, (1H—tetrazonole 5-ynole) biphenylenore 4-inolemethinole] quinoline 1—canolepoxamide (Example 52) ,

3- {N- (3-quinolinecarbonyl) 1 N— [2, 1 (1H-tetrazol-5-yl) biphenyl 4-isuremethyl] amino} benzamide (Example 53) 3- {N-benzolinole N— [2,1 (1H-tetrazonol-5-yl) biphenyl-4-ylmethyl] amino} benzoic acid (Example 54),

3— {N- (biphenylenole 4-ylmethylenole) -N- [2, 1 (1H-tetrazol-5-yl) biphenyl 4-ylmethyl] amino} benzoic acid (Example 55), 3-{N -(4 monochloro benzyl) -N- [2 '— (1H-tetrazole mono 5-yl) biphenyl di 4-methyl methyl] amino} benzoic acid (Example 56),

3— {N- (3,4-dimethoxybenzyl) -N- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amino} benzoic acid (Example 57), 3— { N— [2 ′ — (1H-tetrazol-5-inole) biphenyl-2-ylmethyl] 1 N— [2- (2-Cenyl) ethyl] amino} benzoic acid (Example 5 8), 3— {N — [2- (3,4-dimethoxyphenyl) ethyl] 1 N— [2 ′ — (1 H-tetrazol-5-yl) bifuryl 4-ylmethyl] amino} benzoic acid (Example 5 9), 3-{N— (2-Cyclohexino retinole) 1 N— [2, 1 (1H-tetrazonole —5-yl) bif ヱ 2ru 4-ylmethyl] amino} benzoic acid (Example 60), N— [4 — (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] —N-Fuel 1-1 Naphthalenesulfonamide (Example 6 1),

N— [4— (2,4-Dioxo-1,3-thiazolidine-1-yl) benzyl] —N-phenyl-2-naphthalenesulfonamide (Example 6 2),

3- {N- [4-1, (2,4-Dioxo1,3-thiazolidine-5-^) benzil] 1 N- [4- (2-methylthiazole-4-1yl) benzenesulfonole] amino } Benzoic acid (Example 63),

3— {N- [4_ (2, 4-Dioxo-1, 3- thiazolidine-5-yl) Benzyl] 1 N— [4 1 (5-Methinore 1, 2, 4 4-Oxaziazolone 1— Benzoyl] amino} benzoic acid (Example 64),

3— {N- [41 (2,4-Dioxo-1,3, thiazolidine-5-yl) benzil] -N- [41 (2-pyridyl) benzoyl] amino} benzoic acid (Example 6 5 ),

3— {N- [4- (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] 1 N— (Quinolin-3-carbonyl) amino} benzoic acid (Example 66), N — [4— (2, 4-Doxo1, 1,3-thiazolidine-1-benzyl) benzyl] -N- (2-biphenylyl) benzenesulfonamide (Example 67),

3— {N— (Bifeninore 4-Inolemethinole) 1 N— [4- (2, 4-Dioxo-1,3,1-thiazolidine-1-5-inore) benzyl] amino) benzoic acid (Example 68), 3 — {N— (2-Cyclohexylethyl) 1 N— [4 1 (2, 4-Dioxo1, 3 _thiazolidine 1-5-yl) benzyl] amino) Benzoic acid (Example 6 9), 3— { N-butylsulfonyl mono-N- [4- (2,4-dioxo-1,3-thiazolidine mono 5-yl) benzyl] amino} benzamide (Example 70), 5— {4 One [N— (3-Monolephorinocanolebonino refenoyl) -N- (2-Naphthalenesulfoyl) aminomethyl] Fuel} 1,1,3-Thiazolidine 1,2,4-dione Example 7 1),

5— {4— [{2— (2-naphthyl) imidazole-1-yl} methyl] phenyl} — 1,3, thiazolidine-1,2,4-dione (Example 72),

5- {4— [{2- (4-Bif ヱ nyl) imidazole 1 1 inore} methyl]} Phenyl leu 1,3-thiazolidine 1, 2, 4-dione (Example 73),

2-Oxo-N-Phenenolei N- [2,1- (1 H-Tetrazonol-1-5-Inole) biphenyl-4-41-methyl] valeramide (Example 74),

3— {N— (7-oxooctanol) —N— [2,1 (1H-tetrazol-5-yl) biphenyl-1-4-inolemethyl] amino} benzoic acid (Example 75), 3— { N- [4 (E) -methyminomine 4 _ (2-Chenyl) butyryl]-N— [2,1 (1H-tetrazole-5-inole) biphenyl-2-ylmethyl] amino} benzoic acid (Examples) 76),

3— {N— [4— (Z) -Metoximino 4 (2—Cheinole) Butyryl]-N— [2, 1 (1 H—Tetrazogray 5— ^ (; V) Bifuinolei 4 1 ^ Noremetinole] Amino} benzoic acid (Example 77),

3— {N- [2— (3-Benzylfuryl) propionyl] -N- [2,-(1 H-tetrazol-5-yl) biphenyl 4-ylmethyl] amino} Benzoic acid (Examples) 78), and

3— {N— (3-Oxo 1-cyclopentanecarbonyl) 1 N— [2, 1 (1 H-tetrazol 1-5-yl) biphenyl 4-1ylmethyl] amino} benzoic acid (Example 79) .

Furthermore, the following compounds are more suitable.

3— {N— (3-Feninorepropioninole) 1 N— [2, 1 (1H-Tetrazonol 1-5-yl) Biphenyl 4-1-methyl] Amino} Benzoic acid (Example 1), 3- {N-pentynole N- [4_ (2,4-dioxo1,3-thiazolidine 5-yl) benzyl} amino} benzoic acid (Example 6),

1- [4— (2,4-Dioxo 1,3-thiazolidine mono-5-inole) benzyl] —2-Methyl mono 1,2,3,4-tetrahydroquinoline mono-7-strength rubonic acid (Example 7),

5- [4- (N-methylsulfonyl-N-phenylaminomethyl) phenyl] 1,1,3-thiazolidine-1,2,4-dione (Example 8),

5— [4— (N-butylsulfonyl-N-phenylaminomethyl) phenyl] -1,3-thiazolidine-1-2,4-dione (Example 9),

3- {N— [4- (2,4-Dioxo-1,3-thiazolidine-1-yl) benzyl] -N- (methylsulfonyl) amino} benzoic acid (Example 10),

3— {N—butynolesulfonyl-N— [4- (2,4-dioxone 1,3-thiazolysine mono-5-yl) benzyl] amino} benzoic acid (Example 1 1),

5- {4— [2— (2-Pyridyl) benzimidazole-1-monoinolemethyl] phenyl} — 1,3-thiazolidine-1,2,4-dione (Example 15),

5- [4- (2-phenylimidazole-1-ylmethyl) phenyl] — 1,3-thiazolidine-1,4-dione (Example 16),

1 1 [4 1 (2,4-Dioxo-1,3-Thiazolidine-5-yl) benzyl] —2-Oxo 3-Propyl 1,2-dihydroquinoline 7-carboxylic acid (Example 1) 7),

3- {N—Hexane Force Luponiru N— [4— (2,4-Dioxo-1,1,3-thiazolidine-1,5-yl) benzyl] amino} benzoic acid (Example 1 8), 3 — {N— [4- (2, 4-Dioxo1,3-thiazolidine-5-yl) benzil] 1 N— (Pyridine-1-3-carbonyl) amino) Benzoic acid (Example 1 9), 3— {N— [4- (2,4-Dioxo-1,3-thiazolidine-1-yl) benzyl] -N- (3-phenylpropionyl) amino} benzoic acid (Example 20), 3— {N— (biphenylenole 4-strength luponyl) -N- [4- (2, 4-dioxo 1, 3 1-thiazolidine 1-yl) benzyl] amino} benzoic acid (Example 2 1), 3— {N- (phenylsulfonole) 1 N— [4 1 (2,4-dioxo-1,3-thiazolidine 1-5-yl) benzyl] amino) Benzoic acid (Example 22),

3— {N- (4-Metinolefenoresnorehoninole) 1 N— [4- (2, 4-Dioxo — 1, 3-thiazolidine 1-yl) benzyl] amino} benzoic acid (Example 23) , 3— {N— (biphenylenole 4-acenolehoninole) -N- [4— (2, 4-dioxo 1,3, 1 thiazolidine 1, 5 yl) benzyl] amino} benzoic acid (Example 24), 3 — {N -(2-Naphthinoresnolephonyl) -N- [4- (2,4-Dioxo-1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (Example 25),

3— {N— (Benzylsulfoninole) -N— [4— (2,4-Dioxo-1,3-Thiazolidine-1-5-inole) benzyl] amino} benzoic acid (Example 26),

1- [4- (2,4-Dioxo-1,3-thiazolidine-5-yl) benzenore] ― 2-Oxo 3-propyl-1, 2, 3 -1 H-indole 1 6-carboxylic acid (Examples) 27),

1- [4— (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] 1-2-oxo-1-3-propyl-1,2,3,4,5-tetrahydro-1H-benzo [ b] Azepine 1-8—Norebonic acid (Example 28),

3,3-Dimethinole 1- [4- (2,4-Dioxo-1,3-Thiazolidine-5-Inole) Benzyl] 1-2-Oxo 1,2,3,4-tetrahydroquinoline 1 7-carboxylic acid (Examples) 29),

1 '― [4- (2,4-Dioxo1,5-thiazolidine-5-yl) benzyl] 1-2,1-oxo-1,4,1dihydro-2, H-spiro [cyclopropane 1,3' —Quinoline] 17, monocarboxylic acid (Example 30),

3— {N—phenethylenol N— [2,-(1H-tetrazol-5-yl) biphenol, 4-ruyl 4-ethylmethyl] amino} benzoic acid (Example 32), 3— {N- [4 1 (2, 4 — Dioxo 1, 3 — Thiazolidine 1 5 — yl) Benzyl] 1 N — [(5-Methyl-2-phenyl 2, 3 — Oxazole 1 4 Nore) Acetyl] amino} benzoic acid (Example 33),

3— {N— (3-Cyclohexenolepropanol) 1 N— [2, 1 (1H-tetrazol 1-yl) biphenyl 4-aminomethyl} amino} benzoic acid (Example 3 6 ),

3— {N- (2-oxo-2-ethyl) -N- [2,1- (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amino} benzoic acid (Example 4 2),

3— {N- [4— (2, 4-Dioxo 1,3-thiazolidine 1-yl) benzil] 1 N— [4- (2-methylthiazol-4-yl) benzenesulfuronole] Amino } Benzoic acid (Example 63), and

3- {N— (biphenyl 4-methyl) 1 N— [4 4- (2,4-dioxoso 1,3-thiazolidine 5-benzole) benzinole] amino} benzoic acid (Example 68). The phenylene derivative represented by the above general formula (I) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method. Such a salt is not particularly limited as long as it is used medically and is pharmacologically acceptable. For example, when the phenylene derivative represented by the above general formula (I) has a basic group, it can be converted into an acid addition salt according to a conventional method. Such salts include, for example, hydrohalic acid salts such as hydrofluoric acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid; nitrates, perchlorates, sulfates, phosphates, etc. Inorganic acid salts; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid; salts of arylsulfonic acids such as benzenesulfonic acid and P-toluenesulfonic acid; glutamic acid, Salts of acidic amino acids such as aspartic acid; acetic acid, fumaroleic acid, tartaric acid, succinic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, carboxylic acids such as darconic acid, kenic acid Mention may be made of acid salts. A salt of hydrohalic acid is preferred. Further, when the phenylene derivative represented by the above general formula (I) has a carboxyl group, it can be converted into a metal salt according to a conventional method. Examples of such salts include alkali metal salts such as lithium, sodium and potassium; alkaline earth metal salts such as calcium, barium and magnesium; aluminum salts. Alkali metal salts are preferred.

The fuurene derivative represented by the above general formula (I) of the present invention can be converted into a pharmacologically acceptable ester according to a conventional method. Such an ester is not particularly limited as long as it is used medically and is pharmacologically acceptable.

Examples of the ester residue of the ester of the phenol derivative represented by the above general formula (I) of the present invention (that is, a group corresponding to R ^b in the case of an ester represented by R ^a COOR ^b ) include: A linear or branched alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C _{7 —} ₁₉₇ aralkyl group, a linear or branched C alkyl group carbonyl O alkoxy group substituted with linear or branched C _i-6 alkyl group, a linear or branched C i _ ₆ alkyl - O alkoxycarbonyl O alkoxy straight chain group is substituted or branched C ₆ alkyl le group, C ₃ _ ₇ cycloalkyl one Karuponiruokishi group a linear or branched alkyl group substituted, C ₃ _ ₇ cycloalkyl - is O carboxymethyl Cal Poni Ruo carboxymethyl group Substituted linear or branched —6 Alkyl group, C ₆ - 14 Ariru one carboxyalkyl Niruokishi group substituted with linear or branched C -s alkyl group, C ₆ - ₁₄ § Li one Roux O propoxycarbonyl Interview Ruo carboxymethyl straight group is substituted Tatara Having a straight or branched C ^ 6 alkyl group and a linear or branched C- ₆ alkyl group as a substituent at the 5-position (2-oxo-1,3-dioxolene-4-inore) The group can be listed.

Here, examples of the alkyl group, and Ci-6 alkyl in the alkyl monophenyl carbonyloxy group and the alkyl monooxycarbonyloxy group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, t-butylene , Pentyl, 1-methylol butyl, 2-methino levino ole, 3-methino lev 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropinole, 1-ethinorepropyl, hexinole, 1-methinorepentinole, 2-methylpentinole, 3-methinorepentinole, 4-Methylenopentyl, 1,1-Dimethylenolevbutinole, 1,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2,2-Dimethylbutyl, 2,3-Dimethylbutyl, 3,3-Dimethylbutyl, Examples thereof include 1-ethyl butyl, 2-ethyl butyl, 1,1,2-trimethylpropyl, and 1,2,2-trimethylpropyl pills, preferably linear or branched having 1 to 4 carbon atoms. It is a branched alkyl group, more preferably methyl, ethyl, propyl, isopyl pill, butyl or isobutyl, and most preferably methyl or ethyl.

C ₇ - _{1 9} The Ararukiru groups, such as benzyl, phenethyl, 3-Fuenirupu port pills, 4 one phenylene Norev Chino les, 1-naphthyl Honoré methylate Honoré, can be mentioned 2-naphthyl Honoré methylate Honoré or Jifueyurumechiru, preferably Benjiru.

C ₃ _ ₇ cycloalkyl one carbonyl O dimethylvinylsiloxy groups and C ₃ _ ₇ cycloalkyl Ichio alkoxy C ₃ in carbonyl O dimethylvinylsiloxy groups - The ₇ cycloalkyl, e.g. consequent opening pen chill, cyclohexyl, heptyl cyclohexane Preferred is cyclohexyl.

C ₆ - ₄ § Li one Roux force Lupo two Ruokishi groups and C ₆ _ ₄ Ariru - Okishikarubo Niruokishi in group C ₆ - The _{1 4} Ariru, such as phenyl or naphthyl can ani gel, preferably phenyl It is.

Specific examples of suitable ester residues include, for example, methinole, ethyl, propyl, isopropinole, petit / le, isobutinole, t-petite / le, benzinole, acetoxymethinole, 1- (acetoxy) ethyl, propionyl Xymethyl, 1- (propioninoleoxy) ethyl, petityloxymethyl, 1- (petityloxy) ethyl, isobutyl / lexis xymethinore, 1 (isobutyrinorexi) ethyl, valerinoreoxymethinore, 1 (valerinoreoxy) ) Ethinore, Isoparellinoreoxymethinole, 1— (Isovaleryloxy) ethyl, Bivalloyloxymethyl, 1— (Bivaloyloxy) ethyl, Methoxycarbonyloxymethyl, 1— (Methoxycarlo Ponyloxy) ethyl, ethoxycarbonyloxymethyl, 11 (ethoxycarbonyloxy) ethinore, propoxycanonponinoleoxymethinole, 11 (propoxycarbonyloxy) ethinole, isopropoxycarbonyloxymethyl, 11 (isopropoxycarbonyl) Oxy) ethyl, butyloxycarbonyloxymethyl, 1 — (butoxycarbonyloxy) ethyl, isoptoxycarbonyloxymethyl, 1- (isoptoxycarbonyloxy) ethyl, t-butoxycarbonyloxymethyl, 1 ― (T-Butoxycarbonyloxy) ethyl, Cyclopentanecarbonyloxymethyl, 11- (Cyclopentanecarbonyloxy) ethyl, Cyclohexanecarbonyloxymethyl, 1- (Cyclohexanecarbonyloxy) Honoré, consequent opening pliers Honoré O carboxymethyl Kano repo Nino les oxy methylate Honoré, 1- (consequent opening Penchiruoki deer Lupo Nino les oxy) Echinore, cyclohexyl O carboxymethyl Kano repo two Ruokishimechinore,

1— (Cyclohexyloxycanoleponoxy) ethyl, Benzyloxymethinole, 1— (Benzoinoleoxy) ethinore, Phenoxy / Reponinoreoxymethinole, 1- (Phenoxycarbonylo Xyl) ethyl, (5-methyl-2-oxo-1,3-dioxolenyl 4-methyl), 2-trimethylsilylethyl or phthalidinole, more preferably (5-methyl-2-oxo 1 , 3-dioxolene-4-yl) methyl, bivaluloyloxymethyl or 1- (isopropoxycarboninoleoxy) ethynole.

In the case where the fuurene derivative represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof forms a solvate (for example, a hydrate), all of these solvates are also present. Included in the invention.

Further, a compound that is metabolized in vivo and converted to a phenylene derivative represented by the above general formula (I) or a pharmacologically acceptable salt or ester thereof (for example, a so-called prodrug such as an amide derivative) All are included in the present invention. The phenylene derivative represented by the above general formula (I) of the present invention, and pharmacologically acceptable salts and esters thereof, are therapeutic or preventive agents (particularly therapeutic agents) for diabetic complications (particularly nephropathy). Useful as. The phenylene derivative represented by the above general formula (I) of the present invention, and pharmacologically acceptable salts and esters thereof are administered in various forms. The dosage form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, and the degree of disease. For example, it is administered orally in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules. In the case of injections, it is administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. In the case of a suppository, it is administered intrarectally. Oral administration is preferred.

These various preparations are prepared by adding known adjuvants that are usually used in known pharmaceutical preparation fields such as excipients, binders, disintegrating agents, lubricants, solubilizers, flavoring agents, and coating agents in accordance with conventional methods. Can be formulated.

When forming into tablets, a wide variety of carriers known in this field can be used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and key acids. Excipients, water, ethanol, propanol, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methylcellulose, potassium phosphate, polybylpyrrolidone and other binders, dry powder, sodium alginate, agar powder , Laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and other disintegrants, white sugar, stearin, cocoa butter, hydrogenated oil, etc. Inhibitor, Absorption accelerators such as quaternary ammonium base, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, strong oline, bentonite and colloidal key acid, purified talc, stearate, boric acid powder Examples thereof include lubricants such as polyethylene glycol. Furthermore, the tablets can be made into tablets with ordinary coatings, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. In molding into a pill form, a wide variety of carriers conventionally known in this field can be used as carriers, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc. Examples thereof include binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrating agents such as lamina lanthanum.

In molding into a suppository, a wide variety of carriers conventionally known in this field can be used as the carrier, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like. . When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood. When formed into these solutions, emulsions and suspensions, dilute Any of the agents commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. . In this case, a sufficient amount of sodium chloride, glucose, or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent may be used. Etc. may be added. Further, if necessary, colorants, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals may be included.

The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected. Usually, it is contained in an amount of 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

The dosage varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 1 day for adults, and the lower limit is preferably 0.1 mg (preferably 0.1 mg, more preferably 1 mg). The upper limit is 2, 0 0 O mg (preferably 1, 0 0 O mg, more preferably 2 O O mg), which can be administered once or several times. Hereinafter, the process for producing the phenylene derivative represented by the above general formula (I) of the present invention and the pharmacologically acceptable salt thereof and its ester will be specifically described. Of course, it is not limited to. Also build compounds In this case, the construction order is not limited to the one described below, and the steps may be appropriately replaced. Further, when there is a reactive functional group in each step, protection and deprotection can be appropriately performed without any particular explanation. Furthermore, in order to promote the progress of the reaction, reagents other than the exemplified reagents can be used as appropriate.

Method A

Of the vinylene derivatives represented by the general formula (I) of the present invention, the compound (la) wherein B is a 1H-tetrazol-5-yl group, and pharmacologically acceptable salts and pharmacologically Acceptable esters can be produced, for example, by the following method A.

( ^a1 ) ( ^a2 ) ( ^a3 ) (la)

(In the above formula,

A and X are as defined above,

A ¹ is the general formula (A1) to (A4), and when (A1), (A3) or (A4), R ² , R ⁸ , R ⁹ , R ¹¹ and R ¹² are A hydrogen atom, the same or different, a group selected from the above substituent group, — C (O) NR ¹³ R ¹⁴ (R ¹³ and R ¹⁴ are as defined above) or

Indicates a protected carboxyl group at C _ ₆ alkyl group,

D represents a leaving group such as a halogen atom or a sulfonyloxy group,

P ¹ represents a protecting group for an amino group such as a trityl group. )

In the above formula, starting materials a 1 and a 2 can be produced by a production method known per se.

Stage A 1

This step is a step of producing a compound (a 3) by reacting the compound (a 1) and the compound (a 2) in an inert solvent in the presence of a base. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material. Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chlorophonolem; acetone, Ketones such as: ethers such as jetyl ether, tetrahydrofuran and dioxane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; ethyl formate, ethyl acetate, etc. Examples thereof include sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof, more preferably dichloromethane, butanone, dioxane, N, N-dimethylacetamide or a mixed solvent thereof.

The base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably, an alkali metal carbonate such as sodium carbonate or potassium carbonate; sodium hydrogen carbonate, hydrogen carbonate Alkali metal bicarbonates such as lithium hydride; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t- Al-trimethyl alkoxides such as butoxide and lithium methoxide; triethylamine, disopropylethylamine, N-methinoremonoreforin, 1,8-diazabicyclo [5.4.0] Nen, 1,5-Zazabicyclo [4. 3. 0] Nona 5-Nen, 1, 4-Zazabicyclo [2. 2. 2] Tan, pyridine, picoline, organic amines such as 4-dimethylaminopyridine Nobirijin can be exemplified. Preferred are sodium hydrogen carbonate, potassium carbonate, diisopropylethylamine, sodium hydride or potassium t-butoxide.

The reaction temperature is 0 to 100 ° C, preferably room temperature to 60 ° C. The reaction time is 10 minutes to 2 hours, preferably 1 hour.

Step A 2

This step is a step for producing the target compound (I a) from the compound (a 3). In the compound (a 3), the tetrazolyl protecting group (P ¹ ) and, if necessary, A ¹ R ² , R ⁸ , R ⁹ , R ¹¹ or R ¹² are removed by protecting the carboxyl protecting group (C ^ ₆ alkyl group) by a conventional method or acid hydrolysis. Removal is done in a well-known manner, eg Green 'Watts, "Protective Groupsin Organic Synthesis, 3rd Edition" (US

W i l e y—Int rs s c i e n c e).

The compound in which R ² , R ⁸ , R ⁹ , R ¹¹ or R ¹² in A in compound (I a) is —C (O) NR ¹³ R ¹⁴ is R ² , R ⁸ , R ⁹ , R ¹¹ or It can also be produced by reacting a compound in which R ¹² is a carboxyl group with a corresponding amine R ¹³ R ¹⁴ NH by a known method of forming an amide bond. For example, it is carried out by a method similar to the method of acylating compound (b 2) in Step B 2 in Method B described later. Compound (I a ′) in which A is a group represented by the above general formula (A1) in compound (la) can also be produced by Method B.

(In the above formula D, P \ X and Y ¹ are as defined above,

R ² ′ is a hydrogen atom, a group selected from the above substituent group] 3, 1 C (O) NR ¹³ R ^X ⁴ (R ¹³ and R ¹⁴ are as defined above) or — ₆ alkyl group A canolepoxyl group protected with.

Step B 1

This step is a step for producing compound (b 2) by reacting compound (b 1) with compound (a 2), and is carried out by the same method as in step A1 in Method A. Suitable bases used include organic amines. The compound (b l) can be produced by a method known per se.

Stage B 2

This step is a step of producing the compound (b 3) by alkylating, acylating or sulfoniating the compound (b 2).

Alkylation

When Y ¹ is a single bond, R ¹ — D ¹ (D ¹ represents a leaving group such as a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group. However, R ¹ represents an aryl group, Except in the case of a heterocyclic group, it is carried out by alkylating the amino group of compound (b 2) with the compound represented by

This step is performed in the presence of a base in an inert solvent. The solvent, base, and reaction conditions used are the same as in Step A1 in Method A.

Acylation

When Y ¹ is a carbonyl group, the reaction is carried out by acylating the amino group of compound (b 2) using a compound represented by R ¹ —COD ² (D ² represents a halogen atom).

This step is performed in the presence of a base in an inert solvent. The solvent, base, and reaction conditions used are the same as in Step A1 of Method A.

Alternatively, a carboxylic acid represented by R ¹ —CO ₂ H can be used as a carbonylating agent and reacted with the compound (b 2) in the presence of a condensing agent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material. Halogenated hydrocarbons such as dichloromethane and black mouth form; Etherenoles such as tetrahydrofuran and dioxane Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; The condensing agents used include N, N-dicyclohexyl carpositimide, 1- (3-dimethylaminopropyl) 1 3 1-ethyl carpositimide hydrochloride, and other rubodiimides; diphenyl Examples include phosphoryl compounds such as phosphoryl azide and jetyl phosphoryl cyanide; carbodidiimidazole, triphenylphosphine monoazodicarboxylate and the like. When using a phosphoryl compound, it is desirable to carry out in the presence of a tertiary amine such as trichinoleamine or N-methylmorpholine.

Further, in an inert solvent (preferably, dihalogenated hydrocarbons such as dichloromethane and black honoreme, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene) Carboxylic acid represented by R ¹ — C 0 ₂ H is reacted with lower alkyl esters of chloroformate such as ethyl chloroformate and isobutyl chloroformate in the presence of tertiary amine such as triethylamine and N-methylmorpholine. To form a mixed acid anhydride and then react it with the compound (b 2), or to react the carboxylic acid with N-hydroxysuccinimide, N-hydroxybenztriazole, p-utrofenenole, etc. In the presence of carbodiimides such as N, N-dicyclohexylenocarbodiimide and the corresponding active ester. After having formed, it can also be carried out by reacting with a compound (b 2).

Sunolehoni / Rei

When Y ¹ is a sulfonyl group, R ¹ — S 0 ₂ D ³ (D ³ represents a halogen atom) is used to sulphonate the amino group of compound (b 2) Is done. This step is performed in the presence of a base in an inert solvent. The solvent, base, and reaction conditions used are the same as in Step A1 of Method A.

Step B 3

This step is a step of producing the target compound (la ′) from the compound (b 3). The tetrazolyl protecting group (P ¹ ) in the compound (b 3) and, if necessary, the carboxyl group of R ² ′ The protective group (alkyl group) is removed by alkali or acid hydrolysis in a conventional manner. This step is performed by the same method as in step A2 in method A. Among the ureurene derivatives represented by the above general formula (I) of the present invention, the compound (lb) in which B is a 2,4-1-dioxo-1,3-thiazolidine-5-inore group, and its pharmacology For example, the above acceptable salt opiester can be produced by the following method C.

(In the above formula, A, A \ D and X are as defined above, Z is a leaving group such as a halogen atom or a sulfonyloxy group, and P ² is a Ci- ₆ alkyl group. ) Step C 1

This step is a step of producing compound (c 2) by reacting compound (a 1) with compound (c 1), and is carried out by the same method as in Step A 1 in Method A. Compound (c 1) can be produced by a method known per se. Process C 2

This step is a step for producing the compound (c 3) by reducing the carboyl group in the compound (c 2) with a reducing agent in an inert solvent.

The reducing agent used is not particularly limited as long as it is usually used for the reaction of reducing a carbonyl group to a hydroxyl group. For example, an alkali metal borohydride such as sodium borohydride, lithium borohydride, or the like. Preferred is sodium borohydride.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, alcohols such as methanol and ethanol; ethers such as dioxane, etherol, and tetrahydrofuran / Les; Water or the above-mentioned mixed solvent may be mentioned, preferably methanol or a mixed solvent of water and tetrahydrofuran.

The reaction temperature is 1 78 ° C. to 10 ° C., and preferably 10 ° C. to 0 ° C. The reaction time is 10 minutes to 10 hours, preferably 1 hour to 5 hours. Process C 3

This step is a step for producing a compound (c 4) by converting a hydroxyl group in the compound (c 3) into a leaving group in an inert solvent.

When the leaving group is a halogen atom, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material, but ethers such as jetyl ether, tetrahydrofuran, and dioxane. Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chlorohonolem, 1,2-dichloroethane; acetonitrile Nitriles such as propionitryl; esters such as ethyl formate and ethyl acetate; or a mixed solvent thereof is more preferable, and halogenated hydrocarbons or etherols are particularly preferable. Is dichloromethane or tetrahydrofuran. The halogenating agent to be used is not particularly limited as long as it is usually used in a reaction for converting a hydroxyl group to a halogen atom, but thionyl halides such as thioluchloride, thionylpromide, thionylodide; sulfuryl chloride, sulfurylpromide, Sulfuryl halides such as sulfuryl iodide; phosphorus trichlorides such as phosphorus trichloride, phosphorus tribromide and phosphorus triiodide; phosphorus pentachloride, phosphorus pentabromide and phosphorus pentaiodide Mention may be made of pentahalogenous phosphorus; or oxynobrogenated phosphorus such as phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyiodide.

The reaction temperature is from 0 ° C. to under heating (boiling point of the solvent used), preferably from room temperature to under heating (boiling point of the solvent used). The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

When the leaving group is a sulfonyloxy group, the sulfonylating agent to be used is not particularly limited as long as it is usually used for a reaction for sulfonating a hydroxyl group. For example, methanesulfonyl chloride Sulfonyl halides such as p-toluenesulfonyl chloride; sulfones such as methanesulfonic anhydride, benzenesulfonic anhydride, trifluoromethanesulfonic anhydride Mention may be made of phonic anhydrides. Preference is given to methanesulfonyl chloride, monotoluenesulfonyl chloride or trifluoromethanesulfonic anhydride. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, lignin, and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, and benzene benzene; formic acid Examples include esters such as ethynole, ethyl acetate, propyl acetate, ptyl acetate, and jetyl carbonate; etheroles such as cetyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxetane, and diethylene glycol dimethyl ether. Preferred are halogenated hydrocarbons, estenoles, etherols, and more preferred is dichloromethane. The base to be used is not particularly limited as long as it is used as a base in a normal reaction, but preferably triethylamine, tripropylamine, triptylamamine, diisopropylethylamine, dicyclohexylamine. , N-methylpiperidine, pyridine, 4-monopyrrolidinopyridine, picoline, 4 -— (N, N-dimethyl / reamino) pyridine, 2,6-di (t-butyl) mono-4-methylpyridine, quinoline , N, N-dimethylaniline, N, N-jetylaniline, 1,5-diazabicyclo [4. 3. 0] noner 5-en (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5. 4. 0] Organic bases such as 7-ene (DBU), preferably triethylamine and pyridine.

The reaction temperature is 0 ° C to 50 ° C, preferably 0 ° C to room temperature. The reaction time is 10 minutes to 24 hours, preferably 0.5 to 2 hours.

Process C4

This step is a step for producing a 2-imino 4-oxo1,3-thiazolidine compound (c 5) by reacting the compound (c 4) with thiourea in an inert solvent. The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol and ethanol alcohols are suitable.

The reaction temperature is 50 ° C. to under heating (boiling point of the solvent used), preferably the boiling point of the solvent. The reaction time is 6 to 48 hours, preferably 12 to 24 hours.

Step C 5

This step is a step for producing the target compound (lb) by treating the 2-imino-1,4-oxo-1,3-thiazolidine compound (c5) with an acid.

Examples of the acid used include mineral acids such as hydrochloric acid and sulfuric acid; organic acids such as formic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and preferably hydrochloric acid. Examples of the solvent to be used include water; ananolols such as methanol and ethanol; ethers such as ethyl ether and dioxane, and water and alcohols are preferable.

The reaction temperature is room temperature to 1 20 ° C _S preferably 40 to 100 ° C. The reaction time is 1 to 24 hours, preferably 2 to 12 hours.

If necessary, the protective group for the carboxyl group of R ² , R ⁸ , R ⁹ , R ¹¹ or R ¹² (C ^ ₆ alkyl group) in A ¹ of compound (c 5) can be replaced with a conventional alkali. Alternatively, it may be removed by acid hydrolysis. Removal is performed by the same method as in step A2 of method A.

In addition, a compound in which R ² , R ⁸ , R ⁹ , R ¹¹ or R ¹² in A of compound (I b) is —C (O) NR ¹³ R ¹⁴ is R ² , R ⁸ , R ⁹ , R ¹¹ Alternatively, it can also be produced by reacting a compound in which R ¹² is a carboxyl group with a corresponding amine R ¹³ R ¹⁴ NH by a known method of forming an amide bond. The amidation reaction is carried out by a method similar to the method for acylating compound (b 2) in Step B 2 in Method B.

Method D

In compound (lb), compound (I b ′) in which A is a group represented by the above general formula (A 1) can also be produced via compound (d 2) as shown in Method D. it can. The compound (d 2) obtained by this method is converted into the compound (I b ′) in which A is the above general formula (A1) in the compound (lb) by the same method as in Step C 2 to Step C 5 be able to.

Method D

(In the above process, RR ² ′ D, PX and Y ¹ have the same meaning as above.) Step D 1

This step is a step for producing compound (d 1) by reacting compound (b 1) with compound (c 1), and is carried out by the same method as in Step A 1 in Method A. Suitable amines to be used include organic amines.

Step D 2

This step is a step of producing compound (d 2) by alkylating, acylating or sulfoninoylating compound (dl), and is performed in the same manner as in step B 2 in method B. .

Method E

The compound (lb ′) in which A is a group represented by the above general formula (A1) can also be produced via an aniline compound (e 3) as shown in Method E.

Step E4

db ')

(In the above process, RR ² ′, P ² , X and Y ¹ are as defined above.) Step 1

This step is a step for producing a compound (e 1) by subjecting the compound (d 1) produced in Step D 1 of Step D to a vinylate with salty acetyl. This step is carried out by the method of acylation in Step B and Step B2, and pyridine is raised as a suitable base.

Stage E 2 This step is the step of converting the compound (el) to the 2-iminothiazolidine mono-one compound (e 2), which is the same as the C method in step C 2 and the steps C 3 and C 4 It can be manufactured by sequentially performing these methods.

Step E 3

This step is a step of producing the aurine compound (e 3) by treating the compound (e 2) with hydrochloric acid, and is carried out in the same manner as in Step C 5 of Method C.

Step E 4

This step is a step for producing the compound (lb,) by alkylating, acylating or sulfonylating the compound (e 3), and is carried out by the same method as in Step B 2 in Method B.

After completion of the reactions in the above steps, the target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, and if insolubles are present, remove them by filtration, add water and an immiscible organic solvent such as ethyl acetate, wash with water, etc. It is obtained by separating the organic layer containing, and drying with anhydrous magnesium sulfate, and then distilling off the solvent.

When the obtained compound has a carboxyl group, it can be converted to the desired 1 C (O) NR ^{1 3} R ^{14 by} a method known per se.

If necessary, the product obtained in each of the above steps may be reconstituted by a conventional method, for example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, an adsorption column chromatography method, distribution Appropriate elution by combining a method using a synthetic adsorbent such as column chromatography, a method using ion exchange chromatography, or a normal / reverse phase column chromatography method using silica gel or alkylated silica gel. It can be separated and purified by elution with an agent.

The phenylene derivative represented by the above general formula (I) thus produced is converted into a pharmacologically acceptable salt, pharmacologically acceptable ester, pharmacologically acceptable prodrug or the like according to a conventional method. be able to. Example

The ability to explain the present invention in detail with the following examples, test examples and formulation examples The scope of the present invention should not be limited to these.

Example 1

3— {N— (3-phenylpropioel) -N- [2, 1 (1H-tetrazole —5-yl) biphenyl 4-aminomethyl] amino} benzoic acid

(1 a)

3- (3-Furpropionylamino) Methyl benzoate

Tetrahydrofuran (400 ml) solution of 3-phenylpropionic acid (21.0 g) and 1- [3- (dimethylamino) propyl] triethylcarbodiimide hydrochloride (25.5 g) A solution of methyl 3-aminobenzoate (20.1 g) in tetrahydrofuran (40 ml) was added dropwise at 15 ° C. The mixture was stirred at room temperature for 20 hours, diluted with water and ethyl acetate, and the ethyl acetate layer was separated. The ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate, 10% aqueous citrate and brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 4: 1 and 7: 3) to give the crystalline title compound (3 1.3 g).

Melting point 95—96 ° C.

(1 b)

3- {N— (3-phenylpropionyl) 1 N— [2, 1 (2-trityl-2 H —tetrazol-5-yl) biphenyl 4-ylmethyl] amino} methyl benzoate

Example 1 3- (3-phenylpropionylamino) benzoic acid methyl ester (5.0 g) obtained in a was added to a solution of N, N-dimethylformamide (300 ml) in 55% oily hydrogenated sodium ( 0.77 g) was added, and the mixture was stirred at 50 ° C for 30 minutes. To this was added 5- (4, 1-promomethylbiphenyl-1-2-inole) -1-trityl-2-H-tetrazole (9.8 g) under ice cooling, and the mixture was stirred at room temperature for 19 hours. reaction The solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, the ethyl acetate layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane acetate: 4: 1 and 7: 3) to give the title object compound (9.8 g).

(1 c)

3— {N- (3-phenylpropionyl) -N- [2, 1 (1H-tetrazole 1-5-yl) biphenyl 4-ylmethyl] amino} methyl benzoate

Example 3— {N— (3-phenylpropionyl) -N- [2,1 (2-tritinoleol 2 H-tetrazonolone 5— ^ fnorle) biphenylenore 4-inolemethyl] amino} obtained from lb A solution of methyl benzoate (3.0 g) in 30% aqueous acetic acid (30 ml) was stirred at 70 ° C for 5 hours. The temperature was returned to room temperature, water (10 ml) was added, the precipitated trityl alcohol was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to Siri-force gel force ram chromatography (3% methanol / dichloromethane) to give the title compound (1.

4 g) was obtained.

(I d)

3— {N— (3-phenylpropionyl) 1 N— [2, 1 (1H-tetrazole —5-yl) biphenyl-1 4-methyl] amino} benzoic acid

Example: 3— {N— (3-phenylpropionyl) -N- [2,-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amino} methyl benzoate obtained from L c To a solution of (1.4 g) in methanol (80 ml), 2N sodium hydroxide aqueous solution (6.75 ml) was added and stirred at 50 ° C for 6 hours. After the reaction, methanol was distilled off under reduced pressure, water (50 ml) was added, and the aqueous layer was washed with ether. To the aqueous layer was added 3% hydrochloric acid (5 ml), and the title target compound was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title target compound (1 · 34 g) as a foamy solid.

^X H NMR (CDC 13, 400MHz): δ 2.37 (2Η, t, 1 = 7.5H z), 2.90 (2H, t, J = 7.5Hz), 4.82 (2H, s ), 6. 97-7. 03 (7H, m), 7. 1 2-7. 2 1 (3H, m), 7. 3 1 (1 H, 's), 7. 3 1 -7. 47 (3H, m ), 7. 56 (1 H, t, J = 8. 0 Hz), 7. 87 (1H, d, J = 8.0 Hz), 8. 0 1 (1 H, d, J = 8. OH z ) Example 2

3— {N-phenylacetyl-N— [2,1 (1H-tetrazol-5-yl) biphenyl-4-ylmethyl] amino} benzoic acid

An amorphous powdery title compound was synthesized in the same manner as in Example 1 except that phenylacetic acid was used instead of 3-phenylpropionic acid in Example 1a.

^X H NMR (CDC 1 a, 400 MHz): δ 3.52 (2H, s), 4.91 1 (2 Η, s), 7.0 00-7. 27 (1 1 Η, m), 7. 40-7 55 (3 H, m), 7. 6 1 (1 H, t, J = 7.5 Hz), 7. 9 2 (1H, d, J = 7.0 Hz), 8. 0 1 (1H, d , J = 7.5 Hz;). Example 3

3— {N— (4-Phenylptylyl) -N- [2,1 (1H-tetrazole-5 yl) bifuryl 4-ylmethyl] amino} benzoic acid

An amorphous powdery title compound was synthesized in the same manner as in Example 1, except that 4-phenylbutyric acid was used instead of 3-phenylpropionic acid in Example 1a. ^ NMR (CDC 1 ₃ , 400 MHz): δ 1.84 (2 H, m), 2.0 6 (2H, t, J = 7.5 Hz), 2. 50 (2H, t, J = 7.5 Hz ), 4.84 (2H, s), 7.0 1-7.22 (l lH, m), 7.39-7.49 (3 H, m), 7.55 (1 H, t, J = 8. 0Hz), 7. 85 (1H, d, J 8.0 Hz), 8.01 (1H, d, J = 8.0 Hz). Example 4 3— {N—Cyclohexane Carbonyl N— [2 '— (1H-Tetrazole-5-yl) Biphenyl-2-ylmethyl] amino} Benzoic acid

(4 a)

3- {[2, 1 (2-trityl 1 2 H-tetrazol-5-yl) biphenyl 1-ylmethyl] amino} methyl benzoate

5— (4, 1-promomethylbiphenyl 1- 2 yl) 1 2-trityl- 2 H-tetrazole (3.2 g) in dioxane (16 ml) solution of methyl 3-aminobenzoate (4. 4 g) and diisopropylethylamine (2. Oml) were added and stirred at 85 ° C. for 10 hours. Ethyl acetate (40 ml) was added to the reaction solution, and the solution was washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (Ethyl acetate Z, toluene hexane = 1: 1: 1)

8 and 1: 1: 3) to give the crystalline title compound (2.8 g). Melting point 146-148 ° C.

(4 b)

3— {N-cyclohexane-strand 1-N— [2, 1 (2-trityl 1 2H-tetrazol-5-yl) biphenyl 4-ylmethyl] amino} methyl benzoate obtained in Example 4a 3— {[2,1 (2-trityl-2 H-tetrazol-5- ^ l) biphenyl 4-methyl] amino} methylbenzoate (0.5 1 g) in tetrahydrofuran (15 ml) solution At room temperature, disopropylethylamine (2.8 ml) and cyclohexane strength polyol (0.54 ml) were added, and the mixture was stirred at 40 ° C for 7 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in toluene and water, the toluene layer was separated, washed with water, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (toluene Z ethyl acetate = 20: 1) to obtain the title target compound (0.5 5 g) as a yellowish solid.

(4 c)

3— {N—Cyclohexane Carbonyl N— [2, 1 (1H-Tetrazole-5 —Inole) Biphenyl 2-4 Inolemethyl] Amino) Benzoic acid Example 4 3— {N-cyclohexanecarbodilue N— [2,1- (2 monotrityl-2H-tetrazol-5-inole) biphenyl-2-ylmethyl] amino} obtained in b) methyl benzoate (0 A solution of 55 g) in 25% aqueous acetic acid (16 ml) was stirred at 40 ° C. for 12 hours and concentrated under reduced pressure, and the remaining acetic acid was removed by azeotropic distillation with ethanol and toluene. The residue was dissolved in 25% τ-dioxane (16 ml), lithium hydroxide (54 mg) was added, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water and ethyl acetate, the aqueous layer was separated, and the ethyl acetate layer was extracted again with water. The aqueous layers were combined, acidified with aqueous potassium hydrogen sulfate solution, and the title compound was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title target compound (0.34 g) as a solid.

^X H NMR (CDC 1 a, 40 OMHz): δ 0.87-0.96 (2H, m), 1. 08-1.18 (lH, m), 1.43—1.55 (3H, m ), 1. 62 — 1. 65 (4H, m), 2. 05— 2. 08 (lH, m), 4. 82 (2H, s), 7. 03 (2H, d, J = 8. OHz ), 7. 07 (2H, d, J = 8. OHz), 7. 29 (1 H, d, J = 8. OHz), 7. 41- 7. 48 (3H, m), 7. 51- 7.59 (2H, m), 7.87 (1H, d, d, J = 1.5 and 8. OHz), 8. 06 (1H, d, J = 8. OHz :). Example 5

3— {N- (Pyridine 1_ Force Luponyl) -N- [2, 1 (1H-Tetrazole-5-yl) Biphenyl-2-ylmethyl] amino) Benzoic acid

A powdery title compound was obtained in the same manner as in Example 4 except that nicotinic acid chloride hydrochloride was used in place of the cyclohexane hydrate in Example 4b.

^ NMR (CDC 1 ₃ , 40 OMH z) δ 5. 1 0 (2H, s), 7.0 1- 7. 04 (3 Η, m), 7.20— 7.33 (4 Η, m), 7 38— 7. 45 (2Η, m), 7. 58 (1 H, d, t, J = 1.5 and 7.5 Hz), 7. 75 (1H, _s ), 7. 80 (1 H, d, J = 8. 0Hz), 7. 86 (1 H, d, J = 8. OHz), 7. 95 (1H, d, t , J = 1.5 and 8.0 Hz), 8.36 (1 H, d, d, J = 1.5 and 5. OHz), 8. 60 (1 H, d, J = 1.5 Hz) . Example 6

3- {N-pentyl mono-N- [4 mono- (2, 4-dioxo-1,3-thiazolidine mono-5 T) benzyl} amino} benzoic acid

(6 a)

3-Pentylaminobenzoic acid t-Ptyl

After stirring a solution of 3-butylaminobenzoate t-butyl (13 g) and valeraldehyde (7.1 ml) in dichloromethane (300 ml) at room temperature for 1.5 hours, ice-cooling, under a nitrogen atmosphere, Sodium triacetoxyborohydride (21.4 g) was added and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was diluted with dichloromethane, water was added and stirred, and then the organic layer was separated. The extract was washed successively with aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane acetate: 15: 1) to give the crystalline title compound (15.0 g).

(6 b)

2-Oxo 2- {4- [N-Pentyl N- (3-T-butoxycarbophenyl) aminomethyl] phenyl} Methyl acetate

Example 6 To a solution of t-butyl 3 ^ ntylaminobenzoate (6.5 g) obtained in a in N, N-dimethylformamide (1 1 Om 1), potassium carbonate (1 0.2 g) and 2— [ 4- (Bromomethyl) phenyl] methyl 2-oxoacetate (6.4 g) was added and the mixture was stirred at 60 ° C. for 1.5 hours. Ethyl acetate / hexane (3: 1) mixed solvent and water were added to the reaction solution, and the product was extracted into an organic solvent layer. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Residue Subject to silica gel column chromatography (hexane ethyl acetate = 9: 1 and 4: 1) to give the title compound as a syrup (7.1 g)

Got.

(6 c)

2-Hydroxy mono 2— {4- [N-pentyl-N— (3-t-butoxycarbonylphenyl) aminomethyl] phenyl} methyl acetate

Example 6 2-Oxo 1- {4— [N-pentyl-N- (3-t-butoxycarboylphenyl) aminomethyl] phenyl} methanol obtained in b) Methyl acetate (6.1 g) Sodium borohydride (0.16 g) was added to the (10 Om 1) solution at 0 ° C. or lower, and the mixture was stirred at 0 ° C. for 10 minutes. Acetone (2 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane Zethyl acetate 4: 1 and 3: 1) to give the title compound (6 O g) was obtained.

(6 d)

2 _Methaneshonhoninoreoxy 1— {4— [N-pentylone N— (3-tert-butoxycarbophenenole) aminomethyl] fenenore} methyl acetate

Example 6 2-hydroxy-1,2- {4-[N-pentyl-1-N- (3-t-butoxycarbolphenyl) aminomethyl] phenyl} methyl acetate (3. O g) obtained in c To a solution of triethylamine (1.23 ml) in dichloromethane (60 ml), a solution of methanesulfonyl chloride (0.6 3 ml) in dichloromethane (10 ml) was added dropwise at 0 ° C or lower, and the mixture was further cooled to 0 ° C at 0 ° C. Stir for 5 hours. The reaction mixture was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crystalline title compound (3.5 g).

(6 e)

3— {N—Pentinole N— [4 1 (2 Minor 4—Oxo 1, 1, 3-Thiazolidine 1 5— ^ f) benzyl] Amino} Benzoic acid t-Ptyl Example 6 2-Methanesulfonyloxy 2- {4- [N-pentyl mono-N- (3-t-butoxycarboxyl) aminomethyl] phenyl} methyl acetate obtained in d A solution of 3.0 g) and thiourea (0.9 g) in ethanol (30 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane z methanol = 25: 1) to give the title object compound (2.2 g) as a foamy solid.

(6 f)

3— {N—pentyl mono N— [4— (2, 4-dioxone 1, 3-thiazolidine mono 5-yl) benzyl] amino} benzoic acid

Example 6 3_ {N-pentyl-1-N_ [4- (2 ^ minol 4-oxo-1,1,3-thiazolidine-5-yl) benzyl] amino} benzoic acid t-butyl obtained in e Concentrated hydrochloric acid (8.8 ml) was added to a solution of (2.2 g) dioxane (22 ml), and the mixture was stirred at 80 ° C for 40 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to cosmosyl reversed-phase column chromatography (acetonitrile / water = 1: 4, 1: 2 and 1: 1) to give a crystalline title compound (0.93 g). Got.

Melting point 147-150 ° C.

^X H NMR (CDC 13, 400 MHz): 5 0.91 (3 H, t, J = 7. OH z), 1. 28-1. 38 (4H, m), 1. 63-1. 68 (2H , m), 3.41 (2H, t, J = 7.5Hz), 4.58 (2H, s), 5.35 (1H, s), 6.85 (1H, d, d, J = 2.5 and 8.5 Hz), 7. 23 -7. 25 (3H, m), 7. 27-7. 41 (4H, m). Example 7

1— [4 1 (2,4-Dioxo-1,3, thiazolidine-1,5 _yl) benzyl] 1 2-Methyl-1,2,3,4-tetrahydroquinoline 1 7-Canolepononic acid (7 a) 3-Nitro 1 _ (3-Oxoptyl) methyl benzoate. In mixed acid obtained from nitric acid (d = l. 4, 1. 65 ml) and concentrated sulfuric acid (20 m 1) Methyl benzoate (2.9 g) [Tetrahedron 'Letters Vol. 32, 2 1 2 1 (1 9 9 1), synthesized by the method described in the above] was added dropwise at a temperature of 5 to -10 ° C. Stir at temperature for 2 hours. The reaction mixture was transferred to ice, and the product was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crystalline title compound (3.2 g). .

(7 b)

2-methyl-1,2,3,4-tetrahydroquinoline 1-7-methyl rubonate Example 7 of 3-nitro-1- (3-oxoptyl) methyl benzoate (10.0 g) obtained in a 10% Palladium'carbon (5.0 g) was added to a mixed solution of tetrahydrofuran (35 ml) and methanol (1 30 ml), and the mixture was stirred at 40 ° C for 10 hours in a hydrogen atmosphere. After removing the catalyst by filtration, 10% palladium'carbon (5.0 g) was added again, and the mixture was stirred at 40 ° C for 5 hours in a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the title object compound (6.8 g).

(7 c)

2-Methyl-1, 2, 3, 4-tetrahydroquinoline mono 7-carboxylic acid

EXAMPLE 7 2-Methyl 1,1,2,3,4-tetrahydroquinoline obtained in Example 7b 7-Carboxylic acid (15.4 g) in methanol (140 ml) solution in 2 N aqueous sodium hydroxide ( 1 20 ml) was added and stirred at 45 for 2 hours. Methanol was distilled off under reduced pressure, and 2N hydrochloric acid was added to the remaining aqueous solution to precipitate the title compound (13.8 g) as crystals.

(7 d)

2-methyl-1,2,3,4-tetrahydroquinoline-1,7-carboxylic acid t-petitanol

Example 7 The solution of 2-methyl-1,2,3,4-tetrahydroquinoline obtained in Example 7c in 7-strength rubonic acid (13.3 g) in dichloroethane (350 ml) was mixed with Nyl (30.5 ml) was added and stirred for 2.5 hours under reflux. The reaction solution was concentrated under reduced pressure, and the remaining thionyl chloride was removed by azeotropic distillation with dichloroethane, and then the residue was dissolved in tetrahydrofuran (350 ml). To the solution, add vigorous r-t-butoxide (19.5 g) under ice-cooling. Stir at C for 30 min. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel force ram chromatography (hexane Z ethyl acetate 9: 1) to give the title object compound (7.2 g). (7 e)

1- [4 (2,4-Doxo1,1,3-thiazolidine, 1-5 benzyl)] 1-2-Methyl-1,2,3,4-tetrahydroquinoline 1-Strong rubonic acid In Example 6b Example 6 b Using t-butyl 2-methyl_1,2,3,4-tetrahydroquinoline obtained in Example 7d instead of t-butyl 3-pentylaminobenzoate Example 6 b — Amorphous powdery title compound was obtained by the same method as f.

_{H NMR (DMSO- d 6, 400MHz} ): δ 1. 1 3 (3H, d, J = 6. 5Hz), 1. 80- 1. 99 (2H, m), 2. 72- 2. 9 1 ( 2H, m), 3. 60-3. 62 (1 H, m), 4.5 1 (1H, d, J = 17.5H z), 4.57 (1H, d, J = 1 7. 5Hz), 5. 77 (1H, s), 6. 90 (1H, s), 7.03-7.09 (2H, m), 7.26 (2H, d, J = 8.5Hz), 7 37 (2H, d, J = 8.5Hz), 1 2.26 (1H, s), 1 2.42 (1H, s).

Example 8

5- [4- (N-Methylsulfonyl-N-phenylaminomethyl) phenyl] 1,1,3-thiazolidine _ 2,4-dione

(8 a)

2- [4 -1 (N-methinolesnorehoninole 1 N- phenenoreaminomethyl) fenenore] 1 2-methyl oxoacetate N- (phenyl) methanesulfonamide (2.0 g) and potassium carbonate (4.8 g) in N, N-dimethylformamide (60 ml) solution under ice-cooling, 2— [4- (promomethyl) phenyl] A solution of methyl 2--2-oxoacetate (4.0 g) in dichloromethane (20 ml) was added dropwise. The mixture was stirred at room temperature for 18 hours, then added with ethyl acetate and further acidified with aqueous potassium bisulfate solution. The ethyl acetate layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2: 1 and 1: 1) to obtain the crystalline title object compound (1.6 g).

(8 b)

2-Hydroxy 1 2- [4— (N-Methinoleszorephoninore 1 N-Pheninoreaminomethinole) Pheninore] Metinore acetate

Example 8 2- [4- (N-Methylsulfonyl-N-phenylaminomethyl) phenyl] —methyl 2-oxoacetate (1.6 g) obtained in a in methanol (30 ml) and dichloromethane (30 ml) ) Sodium borohydride (52 mg) was added to the solution at 0 ° C or lower, and the mixture was stirred at 0 ° C for 10 minutes. Acetone (5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crystalline title compound (1.6 g).

(8 c)

2 _Methanesulfonyloxy 2 _ [4- (N-methylsulfonyl-N-phenylaminomethyl) phenyl] methyl acetate

Example 8 2-Hydroxyl 2- [4- (N-methylsulfonyl-N-phenylaminomethyl) phenyl] obtained in b) Suspension of methyl acetate (1.6 g) in diclonal methane (30 ml) Add triethylamine (0.83 ml) to the solution, and then add a solution of methanesulfonyl chloride (0.43 ml) in dichloromethane (1 Oml). C was added dropwise. The mixture was stirred at 0 ° C for 1 hour, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crystalline title compound (2.0 g). (8 d)

2-Iminos 5— [4 (N-methylsulfonyl-N-phenylaminomethyl) phenyl] 1,1,3-thiazolidine 1-4

Example 8 2-Methanesulfonyloxy 1- [4— (N-methylsulfonilu-N-phenylaminomethyl) phenol] obtained in c) Methyl acetate (2.0 g) and thiourea ( A mixed solution of 0.7 g) of ethanol (30 ml) and dichloromethane (3 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the title object compound (1.5 g) precipitated by neutralization with aqueous sodium bicarbonate was collected by filtration.

(8 e)

5— [4— (N-methylsulfonyl-N-phenylaminomethyl) phenyl]

1,3-Thiazolidine-1,4-dione

Example 8 2-Iminos obtained from d 5-[4 (N-methylsulfonyl-N-phenylaminomethyl) phenyl] — 1,3-thiazolidine monoone (0.75 g) of ethanol Concentrated hydrochloric acid (7.5 ml) was added to the (15 ml) suspension, and the mixture was stirred at 80 ° C. for 36 hours. During this time, black form (8 ml) was added to dissolve the raw material after 18 hours. The reaction mixture was cooled, and the precipitated product was subjected to silica gel chromatography (dichloromethane) to give the crystalline title compound (0.40 g).

Melting point 183– 1 85 ° C.

^X H NMR (DMSO_d ₆ , 40 OMH z): δ 3. 08 (3H, s), 4.

88 (2H, s), 5.74 (1 H, s), 7.23—7.41 (9H, m). Example 9

5— [4— (N-Ptylsulfonyl-1-N-phenylaminomethyl) phenyl] ― 1,3-Thiazolidine-1,2,4-dione A crystalline title compound was obtained in the same manner as in Example 8 except that N- (phenyl) butanesulfonamide was used instead of N- (phenyl) methanesulfonamide.

Melting point 1 5 1— 1 53 ° C.

_{XH NMR (DMSO- d 6, 40} OMH z): δ 0. 89 (3H, t, J = 7. 5Hz), 1. 39 (2H, sextet, J = 7. 5Hz), 1. 66- 1. 74 (2H, m), 3. 20 (2H, t, J = 7.5H z), 4. 92 (2 H, s), 5. 73 (1 H, s), 7. 2 1— 7. 35 (7H, m), 7.41 (2H, d, J = 7.5 Hz :). Example 10

3— {N- [4— (2, 4-Doxo-1, 1, 3-thiazolidine, 1-5) Benzyl] 1 N— (Methylsulfur) Amino} Benzoic acid

(10 a)

3- {N— [4- (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] N- (methylsulfonyl) amino} Ethyl benzoate

A crystalline title compound was obtained in the same manner as in Example 8 except that 3- (methylsulfonylamino) benzoate was used in place of N- (phenyl) methanesulfonamide.

(10 b)

3— {N- [4 1 (2, 4 — Dioxo 1, 3 — Thiazolidine 1 5 — yl) Benzyl] -N- (Methylsulfonyl) amino) Benzoic acid

Example 10 3— {N— [4 (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] -N- (methylsulfonyl) amino} obtained from a) Ethyl benzoate ( To a suspension of 1.05 g) of methanol (10.5 ml) and water (10.5 ml), 2N aqueous sodium hydroxide solution (7 ml) was added and stirred at room temperature for 1 hour. reaction 2N hydrochloric acid was added to the solution to adjust the pH to 3.8, and methanol was distilled off under reduced pressure to obtain the precipitated crystalline title compound (0.89 g).

Melting point 239—241 ° C.

_{αΗ NMR (DMSO- d 6, 400MHz} ): δ 3. 1 1 (3H, s), 4. 93 (2H, s), 5. 73 (1 H, s), 7. 29- 7. 35 (4H , m), 7. 48 (1H, t, J = 8. OHz), 7. 6 7 (1 H, d, t, J = 2.0 and 8. OHz), 7. 82 (1H, d, d, J = 2.0 and 8. OHz), 7. 9 1 (1 H, t, J = 2. OHz). Example 1 1

3— {N—Butinolesnorehoninole 1 N— [4— (2, 4-Dioxo1, 3-thiazolidin 1-5-yl) benzyl] amino} benzoic acid

Crystalline title compound was obtained in the same manner as in Example 10 except that 3- (methylsulfonylamino) benzoate was used in place of 3- (methylsulfonylamino) benzoate.

Melting point 1 96—200 ° C.

_{NMR (DMSO- d 6, 400MHz)} : δ 0. 88 (3H, t, J = 7. OHz), 1. 40 (2H, setet, J = 7. 5Hz), 1. 66- 1. 73 (2H m), 3.24 (2H, t, J = 7.5Hz), 4.95 (2H, s), 5.73 (1H, s), 7.29 (2H, d, J = 8 OHz), 7. 34 (2H, d, J = 8. OHz), 7. 47 (1H, t, J = 8. OHz), 7. 68 (1H, d, d, J = 2.0 and 8. OHz), 7. 80 (1 H, d, d, J = 2.0 and 8. OHz), 7. 9 1 (1H, t, J = 2. OHz) ₀ Example 1 2

5- {4- [(2-Oxo 2 H-quinoline 1-yl) methyl] phenyl} 1,1,3-thiazolidine 1,2,4-dione N- (Phenyl) Using 1H-quinolin-2-one and strong r-tert-ptoxide instead of methanesulfonamide and potassium carbonate, respectively, a crystalline title compound was obtained in the same manner as in Example 8. It was.

Melting point 268-270 ° C (decomposition).

_{XH NMR (DMSO- d 6, 40} ΟΜΗκ): δ 5. 53 (2 H, s), 5. 76 (1Η, s), 6. 73 (1H, d, J = 9. 5Hz), 7. 21 -7. 2 6 (3H, m), 7. 35-7. 39 (3H, m), 7.5 1 (1H, d, t, J = 1.5 and 7.5 Hz), 7. 55 ( 1 H, d, d, J = 1.5 and 7.5 Hz), 8.00 (1 H, d, J = 9.5 Hz), 1 2.26 (1 H, s). Example 1 3

5— {4— [(2-Methylbenzimidazole 1-yl) methyl] phenyl} -1,3-Thiazolidine 1,2,4-dione

Using 2-methylbenzimidazole, the crystalline title compound was obtained in the same manner as in Example 12.

Melting point 287-289 ° C.

^X H NMR (DMSO—d 40 OMH z): δ 2.52 (3H, s), 5.49 (2H, s), 5.77 (1H, s), 7. 1 1— 7. 1 7 (4H, m), 7.38 (2H, d, J = 8.0 Hz), 7. 43-7. 46 (1H, m), 7.54—7.56 (1H, m). Example 14

5-{4— [(2 -propyl benzimidazole-1 -yl) methyl] phenyl} 1,1,3-thiazolidine 1,2,4-dione

Using 2-propylbenzimidazole, the crystalline title compound was obtained in the same manner as in Example 12.

Melting point 242—243 ° C. NMR (DMSO-d ₆ , 400 MHz): δ 0.94 (3H, t, J 8.0 Hz), 1. 76 (2H, sextet, J = 8. OHz), 2. 80 (2 H, t, J = 8. OHz), 5. 48 (2H, s), 5. 75 (1 H, s), 7. 07 (2H, d, J = 8. OHz), 7. 1 1— 7. 14 (2H , m), 7.35 (2H, J = 8. OHz), 7.38—7.40 (1H, m), 7.55—7.57 (1H, m). Example 1 5

5— {4 1 [2— (2-Pyridinole) benzimidazole 1 1 Inoremethinore] Fe dil} — 1, 3-Thiazolidine 1, 2, 4-dione

2- (Pyridine-1--2-ole) A crystalline title compound was obtained in the same manner as in Example 12 using benzimidazole.

Melting point 248—25 1 ° C.

NMR (DMSO-d ₆ , 40 OMH z): δ 5.71 (1H, s), 6.23 (2H, s), 7.16 (2H, d, J = 8. OHz), 7. 27-7. 3 2 (4H, m), 7. 49-7. 5 7 (2H, m), 7. 76-7. 78 (1 H, m), 8.0 1 (1H, d, t , J = 1.5 and 8. OHz), 8. 39 (1 H, d, J = 8. OHz), 8. 69 (1H, d, J = 3. OHz) ₀ Example 1 6

5- [4- (2-phenylene imidazoles one 1 one Irumechiru) phenyl] one 1, 3 one thiazolidine one _2, 4-dione

Crystalline title compound was obtained in the same manner as in Example 12 using 2-phenylimidazole.

Melting point 224-226 ° C (decomposition).

^{_{X H NMR (DMSO- d 6,}} 400MHz):. Δ 5. 34 (2H, s), 5. 77 (1 H, s), 7. 03-7 08 (3H, m), 7. 3 1 ( 1 H, d, J = 1.5 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.39-7.46 (3H, m), 7.55 (1 H, d, d, J = 1.5) And 8. OHz). Example 1 7

1- [4- (2, 4-Dioxo1,3-thiazolidine mono (5)) benzyl] — 2-Oxo 3-Propyl 1,2-dihydroquinoline 7-Strong rubonic acid (1 7 a)

4_promomethyl-3-nitrite ethyl benzoate

Add N-bromosuccinimide (1 8.56 g) and benzoyl peroxide (0.6 g) to a solution of ethyl 4-methyl-1-nitrobenzoate (25.0 g) in carbon tetrachloride (200 m 1). The mixture was refluxed for 7 hours with stirring. The reaction mixture was washed successively with water, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane acetate: 9: 1) to obtain the title target compound (15.66 g) as a solid.

Melting point 42-45 ° C.

(1 7 b)

2- (4-Ethoxycanoleponyl 1-nitrobenzyl) 1-2-propylmalonate dibenzinore

Under a nitrogen atmosphere, 55% oily sodium hydride (2.32 g) was added to a tetrahydrofuran (300 ml) solution of dibenzyl 2-propylmalonate (17.86 g) and stirred at 40 ° C for 20 minutes. . To this was added dropwise a solution of 4-hydromethyl-1-3-nitrobenzoate (15.00 g) in tetrahydrofuran (100 ml) obtained in Example 17a under stirring at room temperature, and the mixture was further stirred for 1 hour. did. Ethyl acetate was added to the reaction mixture, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane acetate: 9: 1) to give the title target compound (27.50 g) as an oil.

(1 7 c) 2-Oxo 1-Propyl 1,2-Dihydroquinoline 1-Strength of ethyl rubonate Example 1 7 _ (4-Ethoxycarboluyl 2-2-diethyl benzyl) 1 2-Propyl obtained in b To a solution of dibenzyl malonate (4.37 g) in ethanol (100 ml) was added 7.5% palladium Z carbon (54% water content, 2.00 g), and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. After the reaction, the catalyst was removed by filtration, and ethanol was distilled off under reduced pressure. The residue was subjected to Siri-force gel force ram chromatography (hexane Zethyl acetate 4: 1) to elute first 2-oxo-1-propyl-1,2,3,4-tetrahydroquinoline. 7-Strong rubonate followed by crystalline title compound 2-oxo-1-propyl-1,2-dihydroquinoline 7-strength rubonate (352 mg) was obtained.

Melting point 1 80—1 90 ° C.

(1 7 d)

1— {4- [Methoxy (Oxo) acetyl] benzyl} —2-Oxo-3-propyl-1,1,2-dihydroquinoline 7-ethyl ethylate

Example 1 2-Oxo-3-propyl-1,2-dihydroquinolinone 7-carboxylate (1.70 g) obtained in 7c in N, N-dimethylacetamide (2 Oml) solution To the solution, potassium t-butoxide (364 mg) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. 2- [4- (Promomethyl) phenyl] -2-methyl oxoacetate (1.11 g) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (tr / acetonitrile = 4: 1), and again subjected to silica gel column chromatography (hexane acetate: 4: 1) to give a crystalline title. The compound (399 mg) was obtained.

Melting point 142-144 ° C.

(1 7 e) 1 1 [4 1 (1-Hydroxy 1-Methoxy-2-oxosochinole) Benzyl] 1 2-Oxo 1-Propyl 1,2-Dihydroquinoline 1 7-Carboxylate • Obtained in Example 1 7d 1 1 {4 1 [Methoxy (oxo) acetyleno] benzinore)-2 1 oxo 1 3-propyl 1 1,2-dihydroquinoline 1 7-strength rubonic acid (0.87 g) in methanol (1 To a mixed solution of Om 1) and tetrahydrofuran (1 Om 1) was added sodium borohydride (23 mg) at 0 ° C, and the mixture was stirred for 10 minutes. Acetone (1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane Z ethyl acetate 1: 1) to obtain the crystalline title target compound (0.86 g).

Melting point 1 21—1 23 ° C.

(1 7 f)

1— [4- (1-Methanesulfonyloxy-1-Methoxy-2-oxoethyl) benzyl] — 2-Oxo_ 3-Propyl-1,2-dihydroquinoline 7-Carbonate

Example 1 1- [4- (1-Hydroxy-2-methoxy-1-oxoethyl) benzyl] — 2-oxo-1-3-propyl-1,1,2-dihydroquinoline 1 7-strength boronic acid obtained in 7e A solution of methanesulfonyl chloride (0.33 ml) in dichloromethane (2 ml) was added dropwise to a solution of ethyl acetate (0.84 g) and triethylamine (0.39 ml) in dichloromethane (20 ml) under ice-cooling. The mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.91 g) as an oil. This was subjected to the next reaction without purification.

(1 7 g)

1— [4— (2 ^ f Minnow 4-Oxo 1, 3-Thiazolidine 5- 5-yl) Benzyl] 1 2-Oxo 3-Propyl 1, 2-Dihydroquinoline 7-Strong Acid chinenore Example 1 1 1 [4- (1-Methanesulfoninoreoxy 2-methoxy 2-oxoethyl) benzyl] 1 2-oxo 1 3-propyl 1 1,2-dihydroquinoline 1 Thiourea (0.29 g) was added to a solution of ethyl carboxylate (0.91 g) in ethanol (20 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized in a small amount of ethanol, and the crystals were collected by filtration using ethanol monoethyl ether to obtain the crystalline title compound (0.70 g). .

Melting point 242-244 ° C.

(1 7 h)

1— [4— (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] 1-2-oxo3-3-propyl-1,2-dihydroquinoline _ 7-canoleponic acid ethyl

Example 1 1— [4 1 (2-Imino 4 1-oxo 1, 3-Thiazolidine 1-yl) benzyl] —2- 2-Oxo 1 3-propyl 1 1,2- Concentrated hydrochloric acid (10 ml) was added to an ethanol (20 ml) solution of 7-carboxyl ethyl quinoline (0.68 g) and refluxed for 16 hours with stirring. Ethyl acetate was added to the reaction mixture, washed successively with water, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.79 g) as a crystalline powder. This was subjected to the next reaction without purification.

(1 7 1)

1 1 [4- (2, 4-Dioxo-1, 3-thiazolidine 1-yl) benzyl] 1 2-oxo 1 3-propyl 1 1,2-dihydroquinoline _ 7-strength rubonic acid Example 1 7 1— [4— (2,4-Dioxo-1,3-thiazolidin-5-yl) benzyl] —2—oxo-1-3-propyl-1,1,2-dihydroquinoline 7—force obtained in h To a solution of ethyl rubonate (0.79 g) in ethanol (10 ml) was added 1 N sodium hydroxide aqueous solution (6 ml) and stirred at room temperature for 2 hours. 1 to reaction mixture N hydrochloric acid (6 ml) was added, and the product was extracted into a mixed solvent of dichloromethane and tetrahydrofuran. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% methanol Z dichloromethane) to obtain the title compound (0.36 g) as a crystalline powder. Melting point 260—270 ° C (decomposition).

_{aH NMR (DMSO- d 6, 40} OMHz) δ 0. 97 (3H, t, J = 7. 5Hz), 1. 63- 1. 69 (2H, m), 2. 60 (2H, t, J = 7.5H z), 5.58 (2H, s), 5.77 (1H, m), 7.20 (2H, d, J = 8. OHz), 7.38 (2H, d, J = 8. OHz), 7. 50 (1 H, d, J = 8. OHz), 7. 8 1 (1 H, d, J = 8. OHz), 7. 87 (1 H, s), 7. 93 (1 H, s). Example 18

3- {N—Cyclohexane Carbonyl N— [4-1, (2,4-Dioxo-1,3-thiazolidine-1,5-yl) benzyl] amino} Benzoic acid

(1 8 a)

3- {4- [Ethoxy (oxo) acetyl] Benzylamino} Ethyl benzoate

3-ethylaminobenzoate (7.9 g) and 2- [4- (promomethyl) phenyl] 1-2-oxoacetate (8.1 g) in dioxane (50 ml) in dioxane (50 ml) Min (6.1 m 1) was added and the mixture was stirred at 60 for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane dichloromethane: ethyl acetate = 5: 1: 1) to obtain the crystalline title object compound (5.2 g).

Melting point 68—72 ° C.

(1 8 b) 3-{N-Cyclohexane Carbonyl N-4-[Ethoxy (-oxo) acetyl] Benzylamino} Ethyl benzoate

Example 1 3- {4- [Ethoxy (oxo) acetyl] benzylamino} obtained in 8a Ethyl benzoate (2.0 g) and pyridine (0.54 ml) in dichloromethane (20 ml) Under ice-cooling, dichloromethane (5 ml) of cyclohexane hexachloride (0.9 ml) was added dropwise to the solution, and the mixture was stirred for 1.5 hours under water cooling. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated, washed successively with water, 1N hydrochloric acid, aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (toluene Z ethyl acetate = 9: 1) to obtain the syrupy title target compound (2.6 g).

(1 8 c)

3— {N—Cyclohexanole pononolei N— [4 (2-Ethoxy-1-hydroxyl 2-oxoethyl) benzyl] Amino} Ethyl benzoate

Example 1 3— {N-cyclohexanecarbonyl 1 N— 4— [Ethoxy (oxo) acetyl] benzylamino} obtained in 8 b to the methanol (25 ml) solution of ethyl benzoate (2.56 g) Sodium borohydride (63 mg) was added at 0 ° C and stirred for 10 minutes. After the reaction, acetone (10 ml) was added, and the mixture was further stirred at 0 ° C for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The residue was subjected to silica gel column chromatography (hexane Z ethyl acetate = 4: 1 and 2: 1) to give the syrupy title compound (1.7 g).

(1 8 d)

3— {N-cyclohexanocanbonbonolei N— [4 (2-Ethoxy-1-1-1methanesulfonyloxy-1-2-oxoethyl) benzyl} amino} ethyl benzoate Example 1 obtained in 8c 3 — {N—Cyclohexanocanoloxy N- [4 _ (2 ethoxy-1-hydroxy-1-oxoethyl) benzenole] amino} benzoic acid A solution of ethynole (1.67 g) and triethinoleamine (0.74 ml) in dichloromethane (20 ml) under ice-cooling, methanesulfonyl chloride (0.33 ml) in dichloromethane (5 ml) l) The solution was added dropwise. The mixture was stirred under ice-cooling for 30 minutes, diluted with dichloromethane and washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the syrup title target compound (1.9 1 g). Obtained.

(1 8 e)

3— {N-cyclohexane-powered sulfonyl-1-N— [4- (2-imino-4,1-oxo-1,1,3-thiazolidine-5-yl) benzyl] amino} ethyl benzoate Example 1 obtained in 8d 3- {N-cyclohexanecanole pononolei N— [41 ((2-Ethoxy _1-1-methanesulfonyloxy-1-2-oxoethyl) benzyl] amino} ethyl benzoate (1.9 1 g) A mixed solution of ethanol and thiourea (0.5 3 g) in ethanol (20 ml) and dichloromethane (20 ml) was stirred at room temperature for 96 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the pH was adjusted to 8 with aqueous sodium bicarbonate. The product was extracted into ethyl acetate, and the extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crystalline target compound (1.22 g).

Melting point 2 1 3-2 14 ° C.

(1 8 f)

3— {N—cyclohexanecarbonyl mono N— [4 mono (2, 4-dioxo 1, 1, 3 monothiazolidine mono 5-yl) benzyl] amino} ethyl benzoate

Example 1 3— {N—Cyclohexanecarborulue N— [4— (2—Imino 4-oxo-1,1,3-thiazolidine-5-yl) benzyl] amino} obtained from 8 e Ethyl benzoate To a solution of (1.2 g) in ethanol (12 ml), 6 N hydrochloric acid (12 ml) was added and stirred at 60-70 ° C for 28 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water and ethyl acetate, and the ethyl acetate layer was separated. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Toluene acetate = 4: 1) to obtain the target compound (0.60 g) as an amorphous solid. (1 8 g)

3— {N—Cyclohexane power N- [4— (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] amino} benzoic acid

Example 1 3- {N-Cyclohexanecarboluru N- [4- (2,4-dioxone 1,3-thiazolidine-1-yl) benzyl] amino} obtained in 8 f Ethyl benzoate (0 To a solution of 5 8 g) in ethanol (6 ml), 1N aqueous sodium hydroxide solution (3.6 ml) was added and stirred at room temperature for 2.5 hours. 1N Hydrochloric acid (3.6 ml) was added to the reaction solution, ethanol was distilled off under reduced pressure, the product was extracted into ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure, and the residue was subjected to OD S column chromatography (0.1% -containing acetonitrile-water Z water = 2: 3) to give the title compound (0. 46 g) as an amorphous powder. .

^X H NMR (CDC 1 3, 40 OMH z): δ 0. 8 5— 0.97 (2 Η, m), 1. 1 0- 1. 28 (2H, m), 1. 50— 1. 7 3 (6 H, m), 2.04 — 2. 1 3 (1 H, m), 4.89 (2H, s), 5.34 (1 H, s), 7.2 1 (2H , D, J = 8. OHz), 7.26 (1 H, d, J = 8.0 Hz), 7. 3 3 (2H, d, J = 8. OH z), 7. 47 (1 H, t, J = 8. OH z), 7. 6 2 (1 H, s), 8. 06 (1 H, d, J = 7.5 H z). Example 1 9

3-{N- [4- (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] -N- (pyridine _ 3-carbonyl) amino} benzoic acid

In the same manner as in Example 1 8 b-g, the title target compound as an amorphous solid was obtained in the same manner as in Example 1 8 b-g, except that nicotinic acid chloride hydrochloride was used in place of the cyclohexane hexane chloride in 8b. .

_{NMR (DMSO- d 6, 40 OMH} z): 5 5. 1 6 (2H, s), 5. 79 (1 H, s), 7. 2 5- 7. 40 (7H, m), 7. 6 5—7.80 (3 H, m), 8. 4 5 (1 H, d, J = 5. OH z), 8.5 0 (1 H, s). Example 20

3— {N— [4— (2, 4-Doxo1, 1,3-thiazolidine 1-yl) benzyl] 1 N— (3-phenylpropionyl) amino} benzoic acid

The title target compound as an amorphous solid was prepared in the same manner as in Example 18 b-g, using 3-phenylpropioyl chloride in place of cyclohexanecarboyl chloride in Example 18b. Obtained.

^{_{X H NMR (DMSO- d 6,}} 40 OMHz): δ 2. 38 (2Η, t, J = 7. 5Hz), 2. 95 (2H, t, J = 7. 5Hz), 4. 88 (2H, s), 5. 34 (1 H, s), 7.01 (1 H, d, J = 7.5 Hz), 7.06 (1 H, d, J = 7.5 Hz), 7.1 5-7. 24 (5H, m), 7. 3 1 (2H, d, J = 8. Hz), 7.40 (1 H, t, J = 7.5H z), 8. 01 (1 H, d, J = 7.5 Hz) ₀ Example 21

3— {N— (Bihuenol 4 monocarbonyl) 1 N— [4 1 (2, 4-Dioxo-1, 3,3-thiazolidine 1-yl) benzyl] Amino} Benzoic acid

(2 1 a)

3— {N-acetylyl-N— [4 (2-Iminosyl 4-oxo-1,1,3-thiazolidin-5-yl) benzyl] Amino} Ethyl benzoate

A crystalline title target compound was obtained in the same manner as in Example 18 b-e, except that acetyl chloride was used in place of the cyclohexane hexyl chloride in Example 18 b.

Melting point 21 3-2 14 ° (:.

(2 1 b)

3— {N— [4— (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] amino} ethyl benzoate Example 21 3— {N-acetylyl N— [4- (2-imino-4-oxo-1,3-thiazolidine-1-yl) benzyl] amino} obtained from a) Ethyl benzoate (1.56 Concentrated hydrochloric acid (3.9 ml) was added to the ethanol solution (32 ml) of g) and stirred at 80 ° C for 23 hours. The reaction solution was concentrated, the residue was dissolved in ethyl acetate and sodium bicarbonate water, the ethyl acetate layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. The extract is concentrated and the residue is subjected to silica gel column chromatography (hexane

Z-ethyl acetate = 2: 1) gave the crystalline title compound (1.0 _g ). Melting point 98-100 ° C.

(2 1 c)

3— {N— (biphenolate 4—canoleboninole) 1 N— [4 (2,4-dioxo-1,3-thiazolidine-1-yl) benzyl] amino} ethyl benzoate Example 2 3— {N— [4- (2,4-Dioxo-1,3-thiazolidine-one 5 T) benzyl] amino} ethyl benzoate (0.7 g) and 4-biphenylcarbo Add a solution of pyridine (0.6 ml) in dichloromethane (7 ml) under ice-cooling to a dichloromethane (14 ml) solution of urea chloride (1. O g), and stir the mixture for 30 minutes under ice-cooling. did. The reaction solution was concentrated, the residue was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated. The ethyl acetate layer was washed successively with 1N hydrochloric acid, brine and aqueous sodium bicarbonate, and concentrated under reduced pressure. The residue was dissolved in ethanol (20 ml), sodium bicarbonate (4. O g) was added, and the mixture was stirred at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, the ethyl acetate layer was separated, washed with brine, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl hexanoacetate = 1: 1) to obtain the title compound (0.75 g) as an amorphous solid.

(2 1 d)

3— {N— (Bifenienore 4—Force / Reponinore) -N- [41 (2, 4-Doxo1, 1,3-thiazolidine-5-yl) benzyl] Amino} Benzoic acid Example 2 3— {N— (biphenyl 4-carbonyl) -N— [4 (2,4-dioxone 1,3-thiazolidine-5-yl) benzyl] amino} obtained in 1 c To a suspension of ethyl acid (0.85 g) in ethanol (8.5 ml), 1 N fty-dauda aqueous solution (4.6 ml) was added and stirred at room temperature for 4 hours. After adding 1 N hydrochloric acid (4.6 ml) to the reaction solution, ethanol was distilled off under reduced pressure, the product was extracted into ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure, and the residue was subjected to OD S column chromatography (0.1% containing acetonitrile / ^^ = 2: 3) to give the title compound (0.35 g) as an amorphous powder. It was.

_{NMR (DMSO- d 6, 400MHz)} : δ 5. 16 (1Η, d, J = 14. 5Hz), 5. 1 9 (1 H, d, J = 14. 5Hz), 5. 34 (1 H, s), 7. 1 5 (1 H, d, J = 8. OHz), 7. 25— 7. 28 (2H, m), 7. 28-7. 42 (9H, m), 7. 50 ( 2H, d, J = 8. OHz), 7.71 (1H, s), 7.85 (1 H, d, d, J = 1.5, 7.5 Hz). Example 22

3— {N— (phenylsulfur) 1 N_ [4 1 (2, 4-dioxo-1, 3-thiazolidine 1-ynole) benzyl] amino} benzoic acid

A crystalline title compound was obtained in the same manner as in Example 10 except that 3- (phenylsulfonylamino) benzoate was used in place of 3- (methylsulfonylamino) benzoate.

Melting point 1 88—1 89 ° C.

^{_{X H NMR (DMSO- d 6,}} 400MHz) δ 4. 85 (2H, s), 5. 72 (1H, s), 7. 28-7. 3 3 (5H, m), 7. 39 (1 H , t, J = 8. OHz), 7.60-7.64 (5H, m), 7.70-7.80 (2H, m). Example 23 3— {N— (4-Metinolefinolesulfoninole) -N- [4 (2, 4-Dioxo —1, 3-thiazolidine, 1-yl) benzyl] amino} Benzoic acid

A crystalline title compound was obtained in the same manner as in Example 10, except that 3- (4-methylphenylsulfo-amino) benzoate was used in place of 3- (methylsulfo-amino) benzoate.

Melting point 207-209 ° C.

^{_{X H NMR (DMSO- d 6,}} 400MHz):. Δ 2. 41 (3H, s), 4. 82 (2H, s), 5. 7 2 (1 H, s), 7. 28-7 43 ( 8H, m), 7.5 1 (2H, d, J = 8.0 Hz), 7.62 (1 H, t, J = 1.5 Hz), 7.78 (1 H, d, d, J = 1. 5 and 8. OH z). Example 24

3— {N— (Bifeninole 4-Snolehoninole) -N- [4 (2, 4-Dioxo 1,3-thiazolidine 5-yl) benzyl] amino} benzoic acid

3- (Methylsulfonylamino) Crystalline title compound was obtained in the same manner as in Example 10 except that 3- (biphenyl-1-4-sulfonylamino) benzoylate was used in place of ethyl benzoate. It was.

Melting point 226-228 ° C.

^{_{X H NMR (DMSO-d 6}} , 400 MHz): δ 4. 8 9 (2 H, s), 5. 72 (1H, s), 7. 3 2 (4H, s), 7. 3 9- 7 55 (5H, m), 7. 65-7. 7 1 (3H, m), 7. 74-7. 83 (3H, m), 7. 92 (2H, d, J = 9.0 Hz :) . Example 25

3— {N- (2-Naphtylsulfoel) 1 N— [4 1 (2, 4-Dioxo-1,3-Thiazolidine 1-yl) benzyl] Amino} Benzoic acid 3- (Methylsulfonylamino) Crystalline title compound was obtained in the same manner as in Example 10 except that 3- (2-naphthylsulfonylamino) benzoate was used in place of ethyl benzoate. It was.

Melting point 142-144 ° C.

_{XH NMR (DMSO- d 6, 400MHz} ): δ 4. 9 1 (2H, s), 5. 67 (1H, s), 7. 29- 7. 3 9 (5 H, m), 7. 58 ( 1 H, d, d, J = 2.0 and 8.5 Hz), 7. 66-7. 80 (4H, m), 8. 08 (1 H, d, J = 8.0 Hz), 8.1 5 (2H, t, J = 9.0 Hz), 8.39 (1H, d, J = 1.5 Hz). Example 26

3— {N— (Benzylsulfonyl) 1 N— [4— (2, 4—Dioxo-1,3, thiazolidine 1 5— ^ T) benzyl] amino} benzoic acid

Crystalline title compound was obtained in the same manner as in Example 10 except that 3- (benzylsulfonylamino) benzoyl ethyl was used instead of 3- (methylsulfonylamino) benzoyl ethyl.

Melting point 230–233 ° C.

^{_{X H NMR (DMSO- d 6,}} 400MHz): 6 4. 65 (2H, s), 4. 89 (2H, s), 5. 6 2 (1 H, s), 7. 24 (2H, d, J = 8. OH z), 7.30 (2H, d, d, 8.0Hz), 7.35—7.44 (6H, m), 7.49—7.52 (lH, m), 7 75-7. 80 (2H, m). Example 27

1— [4— (2,4-Dioxo-1,3-thiazolidine _ 5—yl) benzyl] —2-—Oxo 3-propyl-1, 2,3-H—indole 6-carboxylic acid (27 a)

4 (1-Methoxycarbonylptyl) 1 3-Nittomethyl benzoate Under ice-methanol cooling, 70% nitric acid (d = 1. 42) (3 3 ml) was added dropwise to sulfuric acid (25m 1) while maintaining the temperature at 0 ° C. Then, 4- (1-methoxycarbonylptyl) methyl benzoate (4.5 7 g) was added dropwise while maintaining the temperature below _5 ° C. The reaction mixture was stirred at 10 to 15 ° C for 0.5 hour, poured into ice and the product was extracted with ethyl ether. The ethyl ether layer was washed successively with water, aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel force ram chromatography (15% ethyl acetate / hexane) to give the title compound (4.62 g) as an oil.

(27 b)

3-Amino-4-1 (1-Methoxycarbo- / Lebutyl) Methyl benzoate

EXAMPLE 27 In a methanolic (50 ml) solution of 4 (1-methoxycarbonylptyl) 1 3-nitromethyl benzoate (4.62 g) obtained in a, 7.5% paradioxide carbon (53.7% (Containing water) (1.50 g) was added and stirred at room temperature for 1 hour in a hydrogen atmosphere. After the reaction, the catalyst was filtered off and concentrated under reduced pressure to obtain the title target compound (4.15 g) as an oil.

(27 c)

2-Oxo 3-Propinole 2, 3-Dihydro 1H-Indole 6-Strength methyl sulfonate

EXAMPLE 27 3-Amino 4- (1-methoxycanoleponyl quinolole) obtained in b In a solution of methyl benzoate (4.15 g) in toluene (50 ml)! ) Monotoluenesulfonic acid monohydrate (50 mg) was added, and the mixture was refluxed for 1.5 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel force ram chromatography (15% ethyl acetate Z dichloromethane) to obtain the crystalline title compound (2.63 g). Melting point 1 5 3— 1 55 ° C.

(27 d)

1 1 [4- (2, 4-Dioxo 1,3-thiazolidine 1-yl) benzyl] — 2-Oxo 1-Propyl 2, 3- 1H-indole 6-carboxylic acid Example 27 Instead of calium t-butoxide in Example 17 7d using 2-oxo-1,3-propyl-1,2-dihydro-1, H-indole-6-carboxylate obtained in c Amorphous title target compound was obtained in the same manner as in Example 17 dl except that% oily sodium hydride was used.

_{JH NMR (DMSO- d 6, 40} OMHz):. Δ 0. 75 (3Η, t, J = 6. 5Hz), 0. 75-0 8 1 (1 H, m), 0. 94- 1. 00 (1 H, m), 1. 72- 1. 77 (lH, m), 1. 83- 1. 89 (2H, m), 3.02 (1H, d, J = 1 3. OHz), 3 1 3 (1 H, d, J = 1 3. OHz), 5. 62 and 5. 64 (1H combined, both s), 6. 84 (2H, d, d, J = 1.5 and 8. OHz), 7. 10 (1H, d, d, J = l. 5 and 8. OHz), 7. 1 2 (1H, s), 7. 45 (l H, d, J = 7.5 Hz ), 7.59 (1H, d, J = 7.5 Hz;). Example 28

1- [4- (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] —2-Oxo 3-propyl-1, 2, 3, 4, 5-tetrahydro _ 1H-benzo [b] Azepine 1-8—Norebonic acid

(28 a)

2- [2- (4-Methoxycarbonylphenyl) 1-2-oxoethyl] 1-2-Pinolema Jetinore

Under a nitrogen atmosphere, 55% oily sodium hydride (5.41 g) was added to a tetrahydrofuran (320 ml) solution of jetyl propylmalonate (25. lg) at room temperature, and the mixture was stirred at 50 ° C for 20 minutes. Under ice cooling, a solution of methyl 4- (2-bromoacetyleno) benzoate (32.0 g) in tetrahydrofuran (250 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue on silica gel By subjecting to column chromatography (20% ethyl hexane), the title compound (29.2 g) as an oil was obtained.

(28 b)

2— [2— (4-Carboxyphenol) 1 2-Oxosochinole] —2-Propylmalonic acid

Example 28 Ethanol of 2- [2- (4-methoxycarbophenyl) 1-2-oxoethyl] 1-propynolemalonate ethynole (29.4 g) obtained in a

A solution of caustic soda (15.5 g) in water (100 ml) was added to the (200 ml) solution, and the mixture was refluxed for 1 hour with stirring. The reaction mixture was acidified with 12N hydrochloric acid (33 ml), and the product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crystalline title compound (24.3 g).

Melting point 172—1 74 ° C.

(28 c)

4- (3—forced hexoxyhexyl) benzoic acid

In the suspension obtained in Example 28 b, 2- [2- (4-Carboxyoxyl) -1-2-oxoethyl] — 2_propylmalonic acid (24.3 g) in xylene (250 ml) Concentrated sulfuric acid (0.5 ml) was added, and the mixture was refluxed for 1 hour with stirring. The reaction mixture was concentrated under reduced pressure to give the title object compound (23.4 g).

(28 d)

4 (Methyl benzoate) 3-methyl hexanol

Concentrated sulfuric acid (10 ml) was added to a methanol (500 ml) solution of 41- (3-l-poxyhexanol) benzoic acid (23.4 g) obtained in Example 28c and refluxed for 18 hours with stirring. . The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl ether, washed successively with water, aqueous sodium bicarbonate, and brine, and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure, and the residue was subjected to silica gel force ram chromatography (15% and 20% ethyl acetate / hexane) to give the title target compound (14.3 g) as an oil. .

(28 e) 4 1 (3-methoxycarbonylhexyl) methyl benzoate

Example 28 4- (3-methoxycarbonylhexanol) benzoic acid methylolene (14.3 g) obtained in tetrahydrofuran (300 ml) in tetrahydrofuran (300 ml) was added to a solution of paradium monocarbon hydroxide (containing 50% water) (7.0 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the reaction, the catalyst was filtered off, the solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (10% ethyl acetate / hexane) to give the title compound (1 1.9 g) as an oil. Got.

(28 f)

4- (3-Methoxycarbonylhexyl) 1 3-methyl nitrobenzoate

Example 28 4- (3-methoxycarbonylhexyl) methyl benzoate (11.9 g) obtained in e was nitrated in the same manner as in Example 27a to give an oily title Compound (13.3 g) was obtained.

(28 g)

3-Amino-4- (3-methoxycarbonylhexyl) methyl benzoate

4- (3-Methoxycarboxyl) _3-nitrate methyl benzoate (13.3 g) obtained in Example 28f was hydrogenated in the same manner as in Example 27b. The title compound (12.0 g) as an oil was obtained.

(28 h)

2-Oxo 1-Propyl 2, 3, 4, 5-Tetrahydro 1 H-Benzo [b] azepine 1 8-Carboxylic acid methyl

Cyclization of methyl 3-amino-4 mono (3-methoxycarbonylhexyl) benzoate (12.0 g) obtained in Example 28 g in the same manner as in Example 27c gave Of the title compound (8. 36 g) was obtained.

Melting point 1 28—1 30 ° C.

(28 i) 1 1 [4 1 (2, 4-Dioxo 1, 3-Thiazolidine 1 5 -yl) Benzyl] 1 2-Oxo 1 3-Propyl 2, 3, 4, 5-Tetrahydro 1 H-Benzo [b ] Azepine 8-carboxylic acid

Example 28 Using 2-methyl-1,3-propyl-1,2,4,4,5-tetrahydro-1 H-benzo [b] azepine 1 8-carboxylate obtained in Example 1 h In the same manner as in d-i, the amorphous title compound was obtained.

_{XH NMR (DMSO- d 6, 400MH} z): δ 0. 7 7 (3Η, t, J = 6. 5H z), 1. 0 7- 1. 22 (3H, m), 1. 6 2- 1 7 2 (1 H, m), 1. 7 8-1. 8 8 (l H, m), 2. 00— 2. 1 0 (1 H, m), 2. 20-2.30 (1 H, m), 2. 46- 2.5 7 (1 H, m), 2.58—2.6 3 (l H, m), 4. 9 2 (1 H, d, J = l 5. 5H z), 5. 1 0 (1 H, d, J = 1 5.5 H z), 5. 74 (1 H, s), 7. 20 (2H, d, 8. 0 H z), 7. 3 1 (2H, d, 8.0 Hz), 7. 32 (1 H, d, J = 8.0 Hz), 7.70 (1 H, d, J = 8.0 Hz), 7.8 0 ( 1 H, s). Example 2 9

3, 3-Dimethyl 1 1 [4 1 (2, 4-Dioxo 1,3-thiazolidine 1 5 benzyl) Benzyl] _ 2-Oxo _ 1, 2, 3, 4, 4-Tetrahydroquinoline 1 7-Power norlevonic acid

(2 9 a)

4- (2-Ethoxycarbonoyl 2-methylpropyl) methyl benzoate

In a nitrogen atmosphere, add a solution of 1.6 M ptyllithium monohexane (26.9 ml) and diisopropylamine (4.5 7 g) in tetrahydrofuran (25 ml) to a solution of lithium diisopropylamide. Add a solution of ethyl isobutyrate (5.00 g) in tetrahydrofuran (5 ml) at a temperature below 60 ° C.

Stir for 20 minutes. This solution was added dropwise to a solution of methyl 4-promomethylbenzoate (9.85 g) in tetrahydrofuran (25 ml) at 0 to 15 ° C, and further at 15 ° C. The mixture was stirred for 30 minutes at room temperature. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% ethyl acetate hexane) to obtain the title compound (8. 06 g) as an oil.

(29 b)

3, 3-Dimethyl-2-oxo-1, 2, 3, 4-Tetrahydroquinoline 1 7-Methylole of canoleponic acid

Example 29 Using methyl 4- (2-ethoxycarbonyl-1-methylpropyl) benzoate obtained in a, in the same manner as in Example 27a-c, nitration, hydration and cyclization The crystalline title target compound was obtained.

Melting point 1 76—1 78 ° C.

(29 c)

3, 3-Dimethyl _ 1— [4— (2, 4-Dioxo _ 1, 3-Thiazolidine

5-yl) benzyl] —2-oxo-1,2,3,4-tetrahydroquinoline 7-force nolevonic acid

The same method as in Example 17 7d-i using 3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline 1-carboxylate obtained in Example 29b Gave the crystalline title compound.

Melting point 265—270 ° C (decomposition). '

_{XH NMR (DMSO- d 6, 400} MHz): 6 1. 1 5 (6H, s), 2.

95 (2H, s), 5.14 (2H, s), 5.77 (1H, s), 7.20 (2

H, d, 8. OHz), 7. 34-7. 4 1 (4H, m), 7.58 (1 H, d, d, J = 1.5 and 8. OHz :). Example 30 1,1 [4- (2, 4-Dioxo-1,3-Thiazolidine-5-yl) benzyl] —2,1, oxo1,4,1 dihydro-2, H-spiro [cyclopropane-1, 3, monoquinoline] 1, 7, monocarboxylic acid

(30 a)

4— {[1— (t-Butoxycarboninole) cyclopropyl] methinore} Benzoic acid t

In a nitrogen atmosphere, cyclopropanecarboxylic acid t was added to a lithium diisopropylamide solution prepared from 2.6 M ptynolethium monohexane solution (23 ml) and diisopropylamine (6.35 g) in tetrahydrofuran (45 ml). A solution of monobutyl (8.50 g) in tetrahydrofuran (10 ml) was added dropwise at 1-60 ° C or lower, and the mixture was further stirred at 1-60 ° C or lower for 20 minutes. This solution was added dropwise to a solution of tert-butyl bromomethylbenzoate (19.3 g) in tetrahydrofuran (45 ml) at 15 to 0 ° C. The mixture was stirred at 10 ° C for 30 minutes and then treated with saturated brine, and the product was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% ethyl acetate / hexane) to give the title compound (3.86 g) as a wax.

(30 b)

4- {[1 (carboxy) cyclopropyl] methyl} benzoic acid 'Example 4a obtained in Example 30a {[1 (t-Butoxycarbonyl) cyclopropyl] methyl} benzoic acid t-butyl' Trifluoroacetic acid (10 ml) was added to a solution of (5.82 g) in dichloromethane (50 ml) and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized in isopropyl ether and collected by filtration to obtain the target compound (3.65 g).

(30 c)

4- {{1 (methoxycarbonyl) cyclopropyl] methinore} methinole benzoate Example 30 4-({1- (carboxy) cyclopropyl) methyl} benzoic acid (3.65 g) obtained in b was treated with a diazomethane Z jetyl ether solution to give a cup-like title. Compound (3.80 g) was obtained.

(30 d)

2, 1-oxo 1 ', 4, -dihydro-1, 2, H-spiro [cyclopropane 1, 3 -'- quinoline] —7'-methyl carboxylate

Using 4-{[1- (methoxycarbonyl) cyclopropyl] methyl} methyl benzoate obtained in Example 30c, in the same manner as in Example 27a-c, nitrification, hydrogenation and Cyclization was performed sequentially to obtain the crystalline title compound.

Melting point 1 98—200 ° C.

(30 e)

1,1 [4- (2, 4-Dioxo-1,3-Thiazolidine-5-yl) benzyl]-2 'Monoxo 1,4, —Dihydro-1, H-spiro [Cyclopropane 1 , 3 '-quinoline] 1, 7, monocarboxylic acid

Example 30 Example 2, using 2, 1, 1, 4, dihydro-1, 2 H-spi [Cyclopropane 1,3, 1 quinoline] —7 In the same manner as in 1 7 d-i, a crystalline title compound was obtained.

Melting point 214—2 1 6 ° C.

_{^ NMR (DMSO- d 6, 400} MHz): δ 0. 82- 0. 85 (2 Η, m), 1. 1 6- 1. 20 (2H, m), 3. 00 (2H, s), 5. 1 7 (2 H, s), 5. 77 (1 H, s), 7.21 (2H, d, 8. OH z), 7. 30 (1 H, d, J = 8.0 Hz ), 7. 3 7 (2H, d, J = 8.0 Hz), 7.43 (1 H, d, J = l. 5 Hz), 7.58 (1H, d, d, J = 1.5) Okay 8. 0Hz;). Example 3 1 1 1 [4- (2, 4-Dioxo 1, 3-thiazolidine 1-yl) benzyl] 1 2-propyl 1, 2, 3, 4-tetrahydroquinoline 1 7-carboxylic acid (3 1 a)

2-Propyl 1, 2, 3, 4-tetrahydroquinoline 1 7-methyl carboxylic acid

4- (3-Oxobutyl) Instead of methyl benzoate, 4- (3-oxohexyl) methyl crystalline benzoate was used in the same manner as in Example 7 ab, except that the crystalline target compound was obtained. Obtained.

Melting point 65-67 ° C.

(3 1 b)

1— [4 1 (2, 4—Dioxo 1,3, thiazolidine 1 5— ^ Nole) Benzyl] — 2-Propyl 1, 2, 3, 4-Tetrahydroquinoline 1 7-Carboxylic acid methyl

Example 3 Using 2-propyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (0.64 g) obtained in 1a, the same as in Example 6b-ί By the method, an amorphous title target compound was obtained.

(3 1 c) '

1 1 [4- (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl] — 2-propyl-1,2,3,4-tetrahydroquinoline 7-carboxylic acid Example 3 1 b 1 1 [4 1 (2, 4-Dioxo-1, 3-thiazolidin 1 5 f) benzyl] 1 2-propyl 1, 1, 2, 3, 4-tetrahydroquinoline 1 7-strength rubonic acid A mixed solution of methyl (0.64 g) in acetic acid (7 ml) and concentrated hydrochloric acid (7 ml) was stirred at 100 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to ODS column chromatography (0.1% -containing 50% aqueous acetonitrile) to obtain the crystalline title compound (0.46 g).

Melting point 206—208 ° C. ^{_{l H NMR (DMSO- d 6,}} 40 OMH z): δ 0. 87 (3H, t, J = 7. 0Hz), 1. 1 9- 1. 58 (4H, m), 1. 86- 1. 95 (2H, m), 2.50-2.87 (2H, m), 3.43 (lH, m), 4.50 (1 H, d, J = 17.5Hz), 4, 6 1 (1 H, d, J = 17.5 Hz), 5. 78 (1H, s), 6. 90 (1H, s), 7. 03— 7. 08 (2H, m), 7. 27 (2H , D, J = 8.0 Hz), 7. 37 (2H, d, J = 8. OH z), 1 2.26 (1 H, s), 1 2.43 (1 H, s) ₀ Example 32

3— {N—phenethyl mono-N— [2 ′-(1H-tetrazole mono 5-f)] Bifu Nenolet 4-monoremethyl] amino} benzoic acid

(3 2 a)

3-ethyl etheryl benzoate

A solution of 2-bromoethylbenzene (2.00 g) and 3-aminoaminoethyl benzoate (3.57 g) in xylene (40 ml) was refluxed for 10 hours with stirring. The reaction solution was diluted with ethyl acetate, washed successively with water, aqueous sodium bicarbonate, and brine, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (20% ethyl acetate / hexane) to give the title target compound (0.80 g) as an oil.

(3 2 b)

3— {N-phenethyl-N— [2 '— (2-trityl 1H-tetrazole-5-yl) biphenyl 4-ylmethyl] amino} ethyl benzoate

Example 32 Ethyl 3-phenethylaminobenzoate (0.80 g), 5- (4′-bromomethylbiphenyl 2-yl) 1-2-trityl 1 2H-tetrazole (1. A solution of 99 g) and diisopropylethylamine (0.78 ml) in dioxane (10 ml) was stirred at 80 ° C. for 24 hours. The product was extracted with ethyl acetate, and the extract was washed sequentially with aqueous sodium bicarbonate, water, and brine, and then dried over anhydrous sodium sulfate. Dried. After concentrating the solution under reduced pressure, the residue was subjected to silica gel column chromatography.

(10% and 20% ethyl acetate_hexane) to give the amorphous title compound (1.65 g).

(3 2 c)

3— {N-phenethyl-N— [2,1 (1 H-tetrazol-5-yl) biphenyl-4-ylmethinole] amino} ethyl benzoate

3— {N-phenethyl mono-N— [2,-(2-tritinole 1 H-tetrazol-5-yl) biphenyl-2-ylmethyl] amino} benzoyl benzoate obtained in Example 32b 1. 65 g) of a 25% aqueous acetic acid (30 ml) suspension was stirred at 80 for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (3 ° / ₀ methanol Z dichloromethane) to obtain the crystalline title object compound (0.88 g).

Melting point 149 1 1 5 1 ° C.

(3 2 d)

3- {N-phenethyl mono N- [2,-(1H-tetrazol mono 5-yl) biphenyl mono-methyl] amino} benzoic acid

Example 32 of 3- {N-phenethyl mono-N- [2,1- (1H-tetrazol mono 5-yl) biphenyl mono 4-ylmethyl] amino} ethyl benzoate (0.88 g) obtained in Example 32c Lithium hydroxide monohydrate (367 mg) was added to a dioxane (8.5 ml) and water (8.5 ml) solution, and the mixture was stirred at 80 ° C for 1 hour. 1N Hydrochloric acid (8.8 ml) was added to the reaction solution, and the product was extracted into dichloromethane. The extracted solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% methanol Z dichloromethane) to obtain the crystalline title target compound (0.64 g).

Melting point 210-2 1 2 ° C (decomposition).

^{_{X H NMR (DMSO- d 6,}} 400MHz): δ 2. 87 (2Η, t, J = 7. 5H z), 3. 64 (2H, t, J = 7. 5Hz), 4. 55 (2H, s), 6. 9 2 (1 H, d, d, J = 2.0 and 8. OH z), 7. 0 3 (2H, d, J = 8. OHz), 7. 1 3 (2H, d, J = 8. OHz), 7. 1 8-7. 29 (8H, m), 7.5 3 (2H, t, J = 8. OH z), 7. 6 1-7. 6 6 (2 H , m). Example 3 3

3— {N— [4 1 (2, 4—Dizo 1 1, 3—Thiazolidine 1—5-yl) Ben Zinore] 1 N— [(5-Methinore 2—Fuenolei 1, 3-Oxazonore 1 4 1 Inole) Acetyl] Amino} Benzoic acid

(5-Methyl-2-phenyl-1,3-oxazole 14-yl) acetyl chloride and Example 1 8 produced in 8a 3- {4 -— [Ethoxy (oxo) acetyl] benzylamino} Ethyl benzoate In the same manner as in Example 18 b-g, an amorphous target compound was obtained.

^: H NMR (DMSO-d ₆₎ 40 OMHz): δ 2. 14 (3Η, s), 3. 42 (2H, s), 4. 9 2 (2H, s), 5. 7 7 (1 H, s), 7.30 (2 H, d, J = 8. OH z), 7. 3 5 (2H, d, J = 8. OH z), 7. 46 — 7.5 6 (5 H, m ), 7. 8 5- 7. 9 2 (4H, m). Example 34

3— {N— [(2,5-Dimethyl-1,3-oxazol-4-yl) Carbon] N- [41 (2,4-Dioxo-1,3-thiazolidine-5-yl) Benzyl] amino} Benzoic acid

(2,5-Dimethyl-1,3-oxazol-4-inole) Using canoleponyl chloride and 3- (4-ethoxy (oxo) acetyl) benzenoreamino} ethyl benzoate prepared in Example 18a Example 1 8 Amorphous title target compound was obtained in the same manner as in b-g. ^X H NMR (DMSO—d ₆ , 400 MHz): δ 2. 16 (3H, s), 2.3 6 (3H, s), 5.1 5 (2H, s), 5. 7 5 (1 H, s), 7.28 (2 H, d, J = 8.0 Hz), 7. 3 2- 7. 3 9 (4H, m), 7.65 (1 H, s), 7. 7 2-7. 74 (1 H, m). Example 3 5

2-Oxo 1- 3-Propyl 1 1 [2, _ (1 H-Tetrazole-5-Ilmethyl) Bihue / Lee 4 f Noremethinole] 1, 2, 3, 4, 5—Tetrahydrol 1 H—Benzo [b] Azepine 8—Strong Rubonic Acid

Example 28 2-oxo_3-propyl-1,3-, 4,5-tetrahydrol 1 H-benzo [b] azepine 1-8-methyl methyl sulfonate and 5- (4,- Promomethinolebienenole 2-yl) Amorphous title target compound was obtained in the same manner as in Example 1b-d using 2-tritinole 2H-tetrazonole.

NMR (CDC 1 ₃ , 40 OMH z): δ 0.80 (3Η, t, J = 7Η ζ), 1. 1 1-1. 2 7 (3 Η, m), 1. 73-1. 77 ( 1 Η, m), 1. 9 1— 1. 9 8 (1 Η, m), 2. 06-2. 1 1 (1 Η, m), 2. 28— 2. 3 3 (l H, m ), 2.54-2.60 (2Η, m), 4.84 (1 Η, d, J = 1 5. ΟΗζ), 5. 04 (1 Η, d, J = 1 5. ΟΗζ) , 7, 04 (2Η, d, J = 8. 0H z), 7. 1 4 (2Η, d, J = 8. ΟΗ ζ), 7. 2 9 (1 Η, d, J = 7.5H z ), 7. 4 1 (1 Η, d, J = 8. ζ ζ), 7. 47 (1 Η, t, J = 8.0 Hz), 7.5 5-7. 5 8 (1 Η, m), 7.76 (1 Η, s), 7.8 6-7.91 (2H, m). Example 3 6

3— {N- (3-Cyclohexylenopropanoyl) 1 N— [2 '_ (1 H-tetrazol-5-yl) biphenyl 1-4-ylmethyl} amino} benzoic acid The crystalline title target compound was prepared in the same manner as in Example 4b-c, except that 3-cyclohexahexiopropuoluclide was used in place of the cyclohexacarboxylate lid in Example 4b. Obtained.

Melting point 1 57—1 59 ° C.

_{αΗ NMR (DMSO- d 6, 40} OMH z):. δ 0. 69- 0. 77 (2 H, m), 0. 98-1 1 6 (4H, m), 1. 30- 1. 6 1 (7H, m), 2.03-2.09 (2H, s), 4. 88 (2H, s), 7.02 (2H, d, J = 7.5 Hz), 7.13 (2H, d, J = 8. 0Hz), 7.36 (1H, J = 7Hz), 7.49-7.75 (6H, m), 7.89 (1H, d, J = 8. OH z). Example 37

3— {N- ((5-Methinore _ 2-—Finole 1, 3-Oxazonore 1— 4-Inole) Acetinore] 1 N— ] Amino} Benzoic acid

Example 4 b—c Example 4 b—c Using acetylene / rechloride instead of cyclohexanecarboyl chloride in Example 4b (5-Methylolene 2-Feninoreol 1, 3-Oxazonore 1 4-Isle) In the same manner as above, an amorphous target compound was obtained.

_{XH NMR (DMSO- d 6, 40} OMH z): δ 2. 14 (3H, s), 3. 41 (2H, s), 4. 9 1 (2H, s), 7. 0 1 (2H, d , J = 8. OH z), 7. 20 (2H, d, J = 8.0 Hz), 7. 44-7. 5 7 (7H, m), 7. 64 (2H, d, J = 7. 5Hz), 7. 8 6—7.9 1 (4H, m). Example 38

5- [4 '1 (2-phenylimidazole 1 1-methyl) biphenyl 2-yl] 1 1H-tetrazole (38 a)

5— [4, 1 (2-phenylimidazole 1-methyl) biphenyl 2-yl] — 2-trityl 1 2 H-tetrazole

5- (4′-bromomethylbiphenyl) was prepared by the same method as in Example 1b except that 2-phenylimidazole was used in place of methyl 3- (3-phenylpropionylamino) benzoate in Example 1b. (2-phenol) 2-trityl 2 H-tetrazole was reacted with to give the amorphous title compound (4.18 g).

(38 b)

5— [4, 1 (2-Phenolenoimidazole 1 1-Frumethyl) Biphenylinole 2 —Inole] 1 1H—Tetrazonole

Example 38 5— [4,1 (2-fenidylidone 1-yl methinole) biphenyl-2-yl] obtained in a— 2-trityl 2H-tetrazole (4.18 g) Of 25 ° / ₀ aqueous acetic acid (8 Oml) was stirred at 80 for 1 hour. Water (40 ml) was added to the reaction mixture, the precipitated crystals were separated by filtration, and the filtered product was washed with 50% aqueous acetic acid. The filtrate and washings were combined and concentrated under reduced pressure. The residue was subjected to silica gel gel chromatography (10% and 20% methanol / dichloromethane) to give the target compound (2. 35 g) in the form of amorphous. It was.

^X H NMR (DMSO-d ₆ , 400MHz): δ 5. 3 1 (2Η, s), 6. 96 (2Η, d, J = 8. OHz), 7. 05 (2H, d, J = 8. 0Hz), 7. 06 (1 H, d, J = l. OHz), 7. 35 (1 H, d, J = 1. OHz), 7. 40-7. 47 (3H, m), 7. 49—7.58 (4H, m), 7. 6 3 7.68 (2H, m). Example 39

5— [4, 1 (4 1-phenylimidazole 1 1-ylmethyl) biphenyl 2— inore] — 1H-tetrazonole (3 9 a)

5— [4 '― (4 1-phenylidazol 1 1-inole metinore) biphenylenore 2—yl] 1 2-trityl-2 H-tetrazole and 5— [4,1 (5-phenylimidazole-1 monomethyl) biphenyl 1 2-yl] 1 2-trityl 1 2 H-tetrazonole

4 4-Pheninoreimidazole (1.00 g) was used in the same manner as in Example 38a. 5 1 (4, 1 Bromomethylbiphenyl 1 2-Inole) 1 2-Trityl 2 H-tetrazole (4.64 g), and the product is subjected to Siri-gel gel chromatography (3% methanol_dichloromethane) to give amorphous 5— [4, (4-phenylimidazole 1_ylmethyl) biphenyl 1 2 —Yil] —2— Trityl 2 H-tetrazole (4.03 g) and 5— [4, 1 (5-phenol imidazole 1 1-methyl) Biphenyl 2-yl] — 2 _Trityl 1 2 H-tetrazole (0.19 g) was obtained.

(3 9 b)

5— [4, 1 (4-Fenino Ray Midazolene 1—Inole Mechinore) Bihueninore 2—Il] 1 1H-Tetrazole

Example 39 b Using 5_ [4,1 (4 1-imidazole-1-ylmethyl) biphenyl-1-2-yl] -2-trityl 1 2 H-tetrazonole obtained in Example a To give an amorphous title compound. ^{_{X H NMR (DMSO- d 6,}} 40 OMH z):. Δ 5. 23 (2Η, s), 7. 10 (2Η, d, J = 8. ΟΗζ), 7. 16-7 25 (3Η, m ), 7. 3 1- 7.36 (2Η, m), 7.5 1 -7.59 (2Η, m), 7. 6 5— 7.75 (5Η, m), 7. 84 (1 H , d, J = 1. OHz). Example 40

5-[4,1 (5-phenylimidazole 1-ylmethyl) biphenyl-2-yl] — 1H-tetrazole Example 39 Reaction in the same manner as Example 38b using 5- [4 '-(5-phenylimidazole-1-ylmethyl) biphenyl-2]] 2-trityl-2H-tetrazole obtained in a. To give the amorphous title compound. ^{_{X H NMR (DMSO- d 6,}} 400MHz): δ 5. 28 (2Η, s), 6. 88 (2H, d, J = 8. OHz), 7. 09 (2H, d, J = 8. 0Hz ), 7.09 (1H, s), 7.29-7.42 (5H, m), 7.49 (1H, d, J = 8. OHz), 7.5 3-7. 5 7 (1H , M), 7. 63-7. 67 (2 H, m), 7. 90 (1 H, s :). Example 41

2-Propyl 1 _ [2, 1 (1H-tetrazol 1-5-yl) biphenyl 1 4-ylmethyl] _ 1, 2, 3, 4-tetrahydroquinoline 1 7-carboxylic acid Example 1 b 3— ( 3) -Phenylpropionylamino) Instead of methyl benzoate, Example 3 1 Using 2-propyl-1,1,2,3,4-tetrahydroquinoline-7-carboxylate prepared in 1a Example 1 Crystalline title compound was obtained by the same method as b-d.

Melting point 1 72— 1 74 ° C (decomposition).

aH NMR (DMSO—d ₆ , 400 MHz): δ O. 88 (3H, t, J = 7H z), 1. 1 9- 1. 5 7 (4H, m), 1. 79— 1.98 (2H , m), 2. 70-2. 89 (2H, s), 3.4 1 (1 H, brs), 4. 49 (1H, d, J = 17.5 Hz), 4.62 (1H, d, J = 17.5Hz), 6.96 (1H, s), 7.03-7.09 (4H, m), 7.19 (2H, d, J = 7Hz), 7. 54-7. 5 8 (2H, m), 7. 63— 7.70 (2H, m). Example 42

3— {N- (2-Oxo-1-2-phenylethyl) -N- [2,1- (1H-tetrazol-5-yl) biphenyl-2-isolemethyl] amino} benzoic acid (42 a)

3-— (2-oxo-2-phenylethylamino) Ethyl benzoate

2-Bromoacetophenone (5.00 g) was added to a solution of ethyl 3-aminobenzoate (8.14 g) (DN, N-dimethylformamide (5 Oml)) and stirred at room temperature for 1 hour. Ethyl acetate was added to the solution, and the solution was washed successively with water, aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure The residue was subjected to silica gel column chromatography (15% ethyl acetate hexane). As a result, a crystalline title compound (3.41 g) was obtained.

Melting point 1 1 8—1 20 ° C.

(42 b)

3— {N- (2-Oxo 1-phenylethyl) 1 N— [2, 1 (1H-tetrazol-5-yl) biphenyl 4 1 ^ f-methyl] amino} benzoic acid

Example 42 3- (2-oxo-2-phenylethylamino) benzoate and 5- (4, 1-promomethylbiphenyl-1-2-inole) 1-trityl-2 obtained in a Using H-tetrazole, the amorphous target compound was obtained in the same manner as in Example 32b-d.

^{_{X H NMR (DMSO- d 6)}} 400MHz): δ 4. 66 (2Η, s), 5. 18 (2H, m), 6. 7 5- 6. 79 (1Η, m), 7. 05- 7 09 (3 H, m), 7. 14-7. 1 8 (2H, m), 7. 28 (2H, d, J = 8.0 Hz), 7.5 3-7. 6 9 (7H m), 8. 04 (2H, d, J = 7. OH z) ₀ Example 43

3— {N- (3-quinolinecarbonyl) -N- [2 '— (1 H-tetrazonolone 5-f ^) biphenyl-2-ylmethyl] amino} benzoic acid

(43 a) 3— {[2,1 (2-trityl-2H-tetrazole-5-yl) biphenyl 2 4-inolemethinole] amino} ethyl benzoate

5 One (4, 1 Promomethino Levieninole 2-Inole) 1 2-Trityl 1 2 H-Tetrazole (20. 25 g) in dioxane (105 ml) solution with 3-aminobenzoyl ethyl (30. 0 g) and disopropylethylamine (13.3 ml) were added and stirred at 85 ° C. for 22 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then crimped under reduced pressure. The residue was subjected to silica gel column chromatography (toluene-no-ethyl acetate = 19: 1 and hexane / ethyl acetate = 4: 1) to give the crystalline title compound (10.5 1 g). .

Melting point 145—148 ° C.

(43 b)

3— {N— (3-quinolinecarbonyl) 1 N— [2, 1 (2-trityl 2 H-tetrazonol 1 5 _yl) biphenyl 2 4-inolemethyl] amino} ethyl benzoate

Example 43 3-{[2,1- (2-trityl_ 2 H-tetrazol-5-yl) biphenyl-1-4-methyl]] amino} benzoate (2.60 g) of tetrahydrofuran (40 m l) Add diisopropylethylamine (3.54 g) to the solution under ice-cooling, and then add a solution of quinoline mono-3-carbonyl chloride hydrochloride (4.0 g) in tetrahydrofuran (10 ml). It was dripped. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and water. The ethyl oxalate layer was separated, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to NH silica gel column chromatography (ethyl acetate / hexane = 1: 1) to obtain the crystalline title compound (4.04 g).

Melting point 1 79— 1 8 1 ° C.

(4 3 c) 3— {N— (3-quinolinecarboyl) 1 N— [2 '— (1H-tetrazole-5-yl) biphenylenoyl 4-monomethyl] amino} ethyl benzoate

Example 43 3- {N- (3-quinolinecarbonyl) -N- [2,1- (2-trityl-2H-tetrazol-1-yl) biphenyl-1-4-methyl] amino} benzoic acid obtained in b A solution of ethyl (0.99 g) in 25% 7 acetic acid (10 ml) was stirred at 60 ° C for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / form Kolform = 1: 10) to obtain a crystalline target compound (0.78 g).

Melting point 143-145 ° C.

(43 d)

3- {N— (3-quinoline carboninole) -N- [2, 1 (1H-tetrazole

5-yl) biphenyl-4-methyl] amino} benzoic acid

Example 43 3- {N- (3-quinolinecarbonyl) -N- [2 '-(1H-tetrazole-5-inole) biphenyl mono-4-ylmethyl] amino} obtained in c) Ethyl benzoate (0. IN Caustic soda solution (3.8 ml) was added to a suspension of 70 g) in ethanol (7 ml) and stirred at room temperature for 5 hours. Acetic acid was added to the reaction solution to adjust to pH 5, and precipitated sodium acetate was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting syrup was allowed to stand to give the title object compound (0.59 g) containing 1 to 3 molecules of ethanol as crystals.

Melting point 192—195 ° C (decomposition).

^{_{X H NMR (DMSO- d 6,}} 40 OMH z):. Δ 5. 21 (2Η, s) s 7. 06 (2H, d, J = 8. 0Hz), 7. 26-7 30 (3H, m ), 7. 3 3-7. 37 (1 H, m), 7. 47—7.54 (2H, m), 7.58—7.67 (4H, m), 7.76—7.80 (2H, m), 7.91—7.93 (2 H, m), 8.42 (1 H, d, J = 1.5 Hz), 8. 73 (1H, d, J = 2.0 Hz) . Example 44

3— {N- (2-Naphthoyl) -N- [2 '— (1H—Tetrazonol 1-5-Inole) Biphenyl 2 4-methyl] Amino} Benzoic acid

The title target compound was obtained in the same manner as in Example 43b-d, except that 2-mononaphthyl chloride was used in place of the quinoline-1-carboyl chloride hydrochloride in Example 43b.

^X H NMR (DMSO_d ₆ , 40 OMHz): 5. 19 (2H, s), 7.0

6 (2H, d, J = 8. OHz), 7. 24-7. 3 1 (4H, m), 7. 37 (1 H, d, d, J = l. 5 and 8.5 Hz), 7 47— 7.58 (4H, m), 7. 6 1-7. 68 (3H, m), 7. 7 1— 7. 75 (2H, m), 7. 83-7. 86 (2H, m), 7.98 (1 H, s).

Example 45

3- {N- (4-biphenylenoleboninole) -N- [2,1 (1H-tetrazonole-5-yl) biphenylenole 4-inolemethyl] amino) Benzoic acid

In Example 43 b, quinoline _ 3-carbolucyl chloride In place of biphenyl 4-carbolucyl chloride in the same manner as in Example 43 b-d, the amorphous title A compound was obtained.

^X H NMR (DMSO— d ₆ , 40 OMH z): 5. 15 (2 H, s), 7.0 5 (2H, d, J = 8. OHz), 7. 26 (2H, d, J = 8. OHz), 7. 29-7. 45 (7H, m), 7. 52-7. 58 (4H, m), 7. 6 1-7.

72 (6H, m).

Example 46

3— {N- ((2,5-Dimethyl-1,3-oxazole-4-yl) carbonoyl] 1 N— (2,1 (1 H-tetrazol-5-inole) biphenyl-1 4-methyl) Amino} benzoic acid Example 43 b—d Using (2,5-dimethyl-1,3-oxazol-4-yl) strong lupoyl chloride instead of quinoline mono-3-carboyl chloride hydrochloride in Example 43 b In the same manner as above, the target compound in the form of an alpha was obtained.

_{XH NMR (DMSO- d 6, 40} OMHz): δ 2. 1 5 (3H, s), 2. 35 (3H, s), 5. 1 2 (2H, s), 7. 02 (2H, d, J = 8. OH z), 7. 18 (2H, d, J = 8. OHz), 7. 23— 7. 26 (lH, m), 7. 36 (1H, t, J = 8. OHz) , 7.5 1—7.57 (2H, ni), 7.63-7.68 (3H, m), 7.73—7.75 (1 H, m). Example 47

3— {N- [4— (5—Methyl-1, 2, 4, 4-oxadiazo 1-3-nore) Benzoinole] 1 N— [2, — (1H—Tetrazonole _ 5--inore) Bifuenore 1 4-Inolemethinole] amino} benzoic acid

Example 4 In the same manner as in 43b-d, a crystalline title compound was obtained.

Melting point 1 63—165 ° C.

_{XH NMR (DMSO- d 3, 40} OMHz): δ 2. 6 3 (3H, s), 5. 1 6 (2H, s), 7. 06 (2H, d, J = 8Hz), 7. 26- 7. 33 (4 H, dm), 7. 49-7. 58 (4H, m), 7. 65-7. 69 (4H, m), 7. 85 (2H, d, J = 8. OHz; ) Example 48 3— {N- [4 1 (2-Methinorethiazole – 4-Inole) Benzenoslehoninole] 1 N- [2 '— (1 H-Tetrazonole 1- 4-methylmethole) Biphenyl 1- 4-methylmethinore] Amino} Benzoic acid

Example 43 b In the same manner as Example 43 b-d, using 4- (2-methylthiazole-41-l) benzenesulfoalkoxide in place of quinoline 3-hydrocarbyl chloride in hydrochloride By the method, a crystalline title compound was obtained.

Melting point 221—223 ° C (arcmin.

^X H NMR (DMSO-d ₃ , 40 OMHz) δ 2.74 (3Η, s), 4.87 (2H, s), 7.01 (2H, d, J = 8Hz), 7.22 (2H , d, J = 8Hz), 7. 3 1 (1H, d, J = 9. OHz), 7. 41 (1H, t, J = 8. OHz) 7. 49 (1 H, d, J = 8 OHz) 7. 53-7. 5 6 (1 H, m), 7. 6 2-7. 69 (5 H, m), 7. 8 1 (1 H, d, J. OHz) 8. 16 (2H, d, J = 8. OHz), 8.22 (1H, s). Example 49

3— {N— [4— (2-Pyridyl) benzoisle] -N- [2 '— (1H-Tetrazol-5-yl) Bifuryl 4-f-methyl] amino) Benzoic acid

(49 a)

3— {N— [4- (2-Pyridyl) benzoyl] -N- [2, 1 (2-tritinole — 2 H-tetrazol 1-yl) biphenyl 1-ylmethyl] amino] Ethyl benzoate

Example 43 3- [2,1- (2-trityl-2H-tetrazol-5-yl) biphenyl-1-ylmethylamino] obtained in a) Ethyl benzoate (2.80 g) and triethylamine (1.8 ml ) In dichloromethane (28 ml) and a solution of 4- (2-pyridyl) benzoyl chloride hydrochloride (1.22 g) in dichloromethane (15 ml) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Stir. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated. Ethyl acetate The layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate Z-hexane 1: 4) to give the crystalline title compound (1.33 g).

(49 b)

3- {N— [4 (2-pyridyl) benzoyl] -N- [2, 1 (2-trityl 1 2 H-tetrazol 1-5-yl) biphenyl 2 4-ylmethyl] amino} benzoic acid

3 _ {N— [4- (2-Pyridyl) benzoyl] obtained in Example (49a) — N— [2,1- (2-trityl-1-2H-tetrazole-1-5-inole) biphenyl-1-ylmethyl Amino} 1N sodium hydroxide aqueous solution (3.3 ml) was added to a mixed solution of ethyl benzoate (1.33 g) in ethanol (15 ml) and tetrahydrofuran (15 ml), and the mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid (3.3 ml) was added to the reaction mixture, and further ethyl acetate and brine were added. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3% methanol _/ dichloromethane) to give the amorphous title compound (1.28 g).

(49 c)

3- {N— [4 (2-pyridyl) benzoyl] -N- [2, _ (1H-tetrazol-5-yl) biphenyl-2-ylmethyl] amino} benzoic acid

3_ {N- [4- (2-Pyridyl) benzoyl] -N- [2,-(2-trityl 2 H-tetrazole 1-5-yl) biphenyl 2 obtained in Example (49 b)

4-ylmethyl] amino} benzoic acid (0.45 g) in 75% aqueous acetic acid (9 ml) was stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, water (5 ml) was added, the crystals to be precipitated were removed by filtration, and the filtrate was washed with 50% aqueous acetic acid. The filtrate and washings were combined, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (5% methanol Z dichloromethane) to give the amorphous title target compound (0.30 g). ^{_{X H NMR (DMSO- d 6,}} 400MHz): δ 5. 1 6 (2H, s), 7. 06 (2H, d, J = 8. 0Hz) 7. 26- 7. 37 (6H, m), 7. 4 4 (2H, d, J = 8.0 Hz), 7.5 3-7.60 (2H, m), 7.65 -7. 7 1 (4H, m), 7.85 (1 H , d, t, J = l. 5 and 8. OH z), 7.93-7.99 (2H, m), 8.6 2-8.64 (1 H, m). Example 50

N- [3- (morpholinocarbonyl) fuel] 1 N— [2, 1 (1H—tetrazone 5 1-inore) bifuenole 4—inoremethyl] —4— (2-pyridinole) benzamide

(50 a)

N- [3— (morpholinocarboninole) fu]]-N- [2, 1 (2-trityl — 2 H-tetrazol-5-yl) biphenyl 1-ylmethyl] 1 4-— (2-pyridyl) benzamide

Example 49 3- [N— [4— (2-Pyridyl) benzoyl] 1 N 1 [2, 1 (2-Trityl 1 2 H-tetrazole 1-5-yl) biphenylenoyl 4-1-ylmethyl] obtained in b Amino] Benzoic acid (0.83 g), morpholine (0.11 g) and diisopropylamine (0.36 ml) in N, N-dimethylformamide (16 ml) under ice-cooling, O— Benzotriazole 1 1 1 1 N, N, N,, N, —tetramethyluronium 'hexafluorophosphate (HBTU, 0.47 g) is added and the mixture is allowed to reach room temperature for 1 hour. Stir. Ethyl acetate was added to the reaction solution, and the solution was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (2.5% methanole dichloromethane) to give the title compound (0.90 g) as a gum.

(50 b) N— [3— (morpholinocarbonyl) fuel] — N— [2,1 (1H—tetrazol 1-5-yl) biphenyl 2 4-ylmethyl] 1 4— (2-pyridyl) benzamide

Example 50 N— [3— (morpholinocarbonyl) phenyl] obtained in a — N 1 [2, 1 (2-trityl 1 2H-tetrazole 1 5 f) biphenyl 2 4 ylmethyl] —4— ( 2-Pyridyl) benzamide (0.90 g) was detritylated in the same manner as in Example 43c to obtain the amorphous title target compound (0.58 g).

_{τΗ NMR (DMSO- d 6, 400MHz} ):. δ 2. 50- 2. 60 (2H, m), 3. 00-3 10 (2H, m), 3. 35- 3. 50 (4H, m) , Five.

1 7 (2H, s), 6.96 (1 H, s), 7.06 (2H, d, J = 8. OH z), 7.14— 7. 1 6 (1H, m), 7. 29 (2H, d, J = 8.0 Hz),

7. 3 5-7. 41 (3H, m), 7. 44 (2H, d, J = 8.0 Hz) 7.

53 -7. 59 (2H, m), 7. 6 5— 7. 6 9 (2H, m), 7. 87 (1 H, d, t, J = l. 5 and 8.0 Hz), 7. 94 (1H, d, J = 8.0

Hz), 7.98 (2H, d, J = 8.0 Hz), 8.63—8.65 (1 H, m). Example 5 1

3- {N- [4 (2-Pyridyl) benzoyl] -N- [2, 1 (1H—Tetrazole-5- ^ f) Biphenyl 4-ylmethyl] Amino} benzamide (5 1 a)

3- [2, ― (2-Trityl-1H-tetrazol-5-yl) biphenyl-4-ylmethylamino] benzamide

An amorphous title compound was obtained in the same manner as in Example 43a using 3-aminobenzamide instead of ethyl 3-aminobenzoate.

(5 1 b) 3- {N- [4- (2-pyridinole) benzoinole] — N— [2, 1, (2-trichinole — 2 H-tetrazole-1-5-yl) biphenyl 2-4-inolemethyl] amino} benzamide

Example 5 1- [2-, (2-trityl-2H-tetrazol-5-yl) biphenyl 4-aminomethylamino] obtained in 1a was prepared in the same manner as in Example 43b. Acylation with (2-pyridyl) benzoyl chloride hydrochloride gave the crystalline title compound.

Melting point 1 78— 1 80 ° C (decomposition).

(5 1 c)

3- {N— [4- (2-Pyridinole) benzoyl] -N- [2, _ (1H-tetrazol-5-yl) biphenyl-2-ylmethyl] amino} benzamide Example (5 1 b ) 3— {N- [4- (2-Pyridyl) benzoinole] — N— [2, 1 (2-trityl 1 2 H-tetrazole-5-yl) bifureu

4-Ilmethinole] amino} benzamide was used for detritylation in the same manner as in Example 43c to obtain the crystalline title compound.

Melting point 1 55—1 60 ° C (decomposition).

_{αΗ NMR (DMSO- d 6, 400MHz} ): 6 5. 1 5 (2H, s), 7. 03 (2H, d, J = 8. OHz), 7. 08 (1 H, d, J = 8. OHz) ヽ

7. 2 1 (1H, t, J = 8. OHz), 7. 25 (2H, d, J = 8. OH z) _N 7. 3 1-7. 34 (1H, m), 7. 42 ( 2H, d, J = 8. OHz), 7.

5 1 -7. 67 (5H, m), 7. 77 (1 H, s), 7.8 3 (1H, d, t, J = 1.5 and 8. OHz), 7. 90-7. 9 5 (3H, m), 8. 60—

8. 61 (1H, m). Example 52 N— [3— (morpholino force ruponyl) 1] N— [2, 1 (1H—tetrazol-5-inore) Bifunore 4 1-inolemethinole] quinoline 1-canolepoxamide,

(5 2 a)

3— {N— (3-quinolinecarbonyl) 1 N— [2, 1 (2-trityl 1 2 H-tetrazol-5-yl) biphenyl 4-ylmethyl] amino} benzoic acid obtained in Example 43 b 3- [N— (3-Quinolinecarbonyl) -N- [2,1- (2-trityl-2H-tetrazol-15-yl) biphenyl 4-ylmethyl] Examples using ethyl benzoate The title compound was obtained in the form of a mono-refusal form by hydrolyzing al force in the same manner as in 49b.

(52 b)

N— [3— (morpholinocarbonyl) phenyl] — N— [2,1 (2-trityl 1 2H-tetrazonole 1-5-inore) biphenol 2 4-inolemethinole] quinoline 1 3 —carboxamide

Example 52 3— {N— (3-quinolinecarbonyl) 1 N— [2, — (2-trityl 2 H-tetrazole 1 5 f) biphenyl 1 4 f dimethyl] amino} benzoic acid obtained in a Triethylamine (0.22 ml) was added to a suspension of (1.OO g) in methylene chloride (20 ml) at room temperature, and then isobutyl chloroformate (0.30 g) was added. After stirring the mixture for 30 minutes at room temperature, monoreforin (0.19 g) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate Z-hexane 1: 1 and ethyl acetate only) to obtain the amorphous title compound (0.84 g).

. (5 2 c)

N— [3— (morpholinocarbonyl) fuel] -N- [2, _ (1H—tetrazonore 5— ^ nole) bifuenolei 4—ilmethinole] quinoline 1—canolepoxami Example 52 N— [3- (morpholino force Lupinole) phenyl] 1 N 1 [2, 1 (2-trityl 1 2 H-tetrazol-5-yl) biphenyl 1-ylmethyl] quinoline obtained in Example 52b A solution of 3-carboxamide (0.84 g) in 25% aqueous acetic acid (10 ml) was stirred at 60 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to Cosmoseal chromatography (30-50% aqueous acetonitrile) to obtain the crystalline title compound (0.40 g).

Melting point 143-145 ° C.

^{_{X H NMR (DMSO- d 6,}} 400MHz):.. Δ 2. 23- 2. 33 (2 H, m), 2. 64-2 74 (2H, m), 3. 33-3 47 (4H, m), 5.22 (2H, s), 7.05-7.07 (3H, m), 7.12 (1H, d, t, J = 1.5 and 7.5Hz), 7 32 (2H, d, J = 8.0 Hz), 7.40 (1H, t, J = 8.0 Hz), 7. 47—7.50 (1H, m), 7.5

2- 7.69 (5H, m), 7. 77-7. 8 1 (lH, m), 7. 90-7. 95 (2H, m), 8. 40 (1H, d, J = 2. 0H.z), 8.74 (1 H, d, J = 2.0 Hz). Example 53

3— {N— (3-quinolinecarbonyl) 1 N— [2, 1 (1H-tetrazole 1 5-inole) Bifuinolei 4 1-inolemethinore] amino} benzamide

Example 43 3— {N— (3-quinolinecarbonyl) 1 N— [2, — (1 H-tetrazol-5 _yl) biphenyl 1 4-methyl] amino} benzoic acid (1 0.5 g of N, N-dimethylformamide (10 ml) and 0.5 M methanol / methanol solution (30 ml) and jetyl cyanophosphate (0.43 g) were added to the solution for 5 hours at room temperature. Stir. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated. The extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (methanol). / Dichloromethane = 1:20) to give the amorphous title compound (0.

27 g) was obtained.

^{_{X H NMR (DMSO- d 6,}} 400MHz): 6 5. 22 (2Η, s), 7. 05 (2H, d, J = 8. 5Hz), 7. 1 7- 7. 23 (2H, m) 7.31 (2H, d, J = 8.5Hz), 7.40 (1H, s), 7.52— 7.69 (6H, m), 7.78 (1H, d, t, J = 1.5 and 8.5 Hz), 7.85 (1H, s), 7.90-7.94 (3H, m), 8.41 (1 H, d, J = 2. OHz), 8 72 (1 H, d, J = 2. OHz). Example 54

3— {N—Benzilou N_ [2,1 (1H-tetrazole-5-inole) biphenyl-2-ylmethyl] amino} benzoic acid

(54 a)

3— {N—Benzilou N_ [2, _ (2-tritinole 2H—tetrazole 1-5-yl) biphenyl 2-4-ylmethyl] amino} Ethyl benzoate

55% oily hydrogenated sodium hydride (0.3 g) of N, N-dimethylformamide (6

0 ml) In suspension the 3- [2 '-(2-trityl-2-H-tetrazol-5-yl) biphenol-4-methylmethylamino] benzoate (3.

6 g) was added and stirred at room temperature for 1 hour. Benzylpromide (1.44 g) was added thereto, and the mixture was stirred at 60 ° C for 24 hours. Ethyl acetate was added to the reaction solution, and the solution was washed with brine and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl oxalate Z-hexane = 1: 4) to give the title compound (2.13 g) as an amo / refusal form.

(54 b)

3— {N-Benzyl mono N_ [2, 1 (1H-tetrazole mono 5-yl) biphenyl 4-ylmethyl] amino} benzoic acid Example 54 3- {N-Benzyl-N- [2 '-(2-trityl-2H-tetrazol-5-inole) biphenyl-4-ylmethyl] amino} benzoic acid ethyl obtained in a Example 43 Detrityl and alkaline hydrolysis were carried out in the same manner as in c and d to obtain the title target compound in the form of amorph.

_{XH NMR (DMSO- d 6, 400MHz} ): δ 4. 7 3 (2Η, s), 4. 74 (2H, s), 6. 8 6- 6. 9 0 (1 H, m), 7. 0 7 (2H, d, J = 8.5H z), 7. 1 9- 7.25 (8H, m), 7. 3 1-ma. 3 6 (2H, m), 7.54-7.5 8 (2H, m), 7. 6 3-7. 67 (2H, m). Example 5 5

3- {N— (biphenyl 4-ylmethyl) 1 N— [2, 1 (1 H-tetrazole 5-yl) biphenyl 4-ylmethyl] amino} benzoic acid

In the same manner as in Examples 54a and b, 4-Fenenolevendinolev amide was used in place of the benzylamide in Example 54a to obtain a crystalline title target compound.

Melting point 1 6 2— 1 64 ° (:.

^J H NMR (DMSO—d ₆ , 40 OMH z): δ 4. 78 (4H, s), 6. 9 1-6. 93 (l H, m), 7.0 9 (2H, d, J = 8.5 Hz), 7. 2 1-7. 4 3 (8H, m), 7.45-7. 4 7 (2H, m), 7.5 5- 7. 5 8 (2H, m) 7. 6 3-7. 6 9 (6H, m). Example 5 6

3- {N— (4 _ kuroguchi benzyl) -N- [2, 1 (1 H-tetrazonol-1-yl) biphenyl 4-ylmethyl] amino} Benzoic acid

Using 54-benzylbenzamide instead of benzylpromide in Example 54a, an amorphous title compound was obtained in the same manner as in Examples 54a and b. ^α Η NMR (DMSO-d 6, 400MHz): δ 4.72 (2H, s), 4.74 (2H, s), 6. 8 7-6. 8 9 (1H, m), 7. 07 ( 2H, d, J = 8.5Hz), 7.1 8-7.27 (7H, m), 7.38 (2H, d, J 8.5Hz), 7.5 3-7.57 (2H, m), 7.62—7.67 (2H, m). Example 57

3— {N— (3,4-dimethoxybenzyl) 1 N— [2,-(1H-tetrazole 5—yl) biphenyl 2 4-methyl] amino} benzoic acid

An amorphous title compound was obtained in the same manner as in Examples 54a and b, except that 3,4-dimethoxybenzylbromide was used in place of the benzib mouthamide in Example 54a.

^{_{X H NMR (DMSO- d 6,}} 400MHz): δ 3. 68 (3Η, s), 3. 71 (3Η, s), 4. 62 (2 H, s), 4. 7 1 (2H, s) 6.73 (1 H, d, d, J = 2.0 and 8.0 Hz), 6. 86-6. 8 9 (3H, m), 7.07 (2H, d, J = 8.5 Hz) ), 7. 1 8—7.22 (4H, m), 7.29 (1H, t, J = 2.0 Hz), 7.55-7.57 (2H, m), 7. 6 3— 7 68 (2H, m). Example 58

3-{N— [2, 1 (1H—Tetrazonol 1-5-Inole) Bifuenole 4-Ilmethyl] 1 N— [2- (2-Chel) Ethyl] Amino} Benzoic acid

(58 a)

3— [2— (2-Chenyl) ethylamino] Ethyl benzoate

3- (2-Chenylacetoamino) Ethyl benzoate (3. 50 g) in tetrahydrofuran (35 ml) in nitrogen atmosphere at room temperature 1.0 M borane / tetrahydrofuran complex solution (12 ml) Was added dropwise, and the mixture was stirred at 50 ° C for 1 hour. Furthermore, 1. OM borane Z tetrahydrofuran complex solution (1 2m 1) was added and stirred at 50 ° C for 1 hour. Water and ethyl acetate (100 ml) were added to the reaction solution, and the ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate Z-hexane = 3: 7) to give the title target compound (2.62 g) as an oil.

(58 b)

3— {N— [2- (2-Cheninole) ethyl] -N- [2 '— (2-Tritinole 2 H-tetrazole 1-5-yl) Biphenyl 2 4 T ^ methyl] amino} benzo Acid ethyl

Example 58 3- [2- (2-Chenyl) ethylamino] obtained in a) Ethyl benzoate (1.OO g), 5- (4,1-promomethylbifuryl 2-yl) 1-2-trityl Contains 2 H-tetrazole (2.43 g) and baking soda (457 mg)

The 2-pentanone (20 ml) mixture was stirred in a nitrogen atmosphere under reflux for 24 hours. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate Z-hexane = 1: 4) to give the amorphous title compound (1.90 g). Got.

(58 c)

3— {N— [2, 1 (1 H-tetrazol-5-yl) biphenyl 1-4-1 methyl] 1 N— [2- (2-Cenyl) ethyl] Amino} Ethyl benzoate

Example 58 3- [N_ [2- (2-Cenyl) ethyl] -N- [2,-(2-tritinole 2H-tetrazonole 5-H-inore) biphenol 2 4-inole methyl] obtained in Example 58b Amino] Ethyl benzoate (1.90 g) in 25% aqueous acetic acid (40 ml) was stirred at 80 ° C for 2 hours, then the reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography. (5% methanol Z dichloromethane) to give the title compound (1.23 g) as a gum.

(58 d) 3— {N- [2, 1 (1H-tetrazol-5-yl) biphenol 2 4-inolemethyl] 1 N— [2— (2-Cyl) ethyl] amino} benzoic acid

Example 58 3— {N— [2 ′ — (1H-tetrazonol 5-5-inole) biphenyl 4-yl methyl] 1 N— [2- (2-Cenyl) ethyl] amino} ethyl benzoate obtained in Example 58c A mixed solution of (1.23 g) and lithium hydroxide monohydrate (506 mg) in water (12 ml) and dioxane (12 ml) was stirred at 60 ° C for 1.5 hours. The reaction mixture was diluted with water, acidified with aqueous citrate solution, and the product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then subjected to silica gel column chromatography (methanolol Z dichloromethane = 1: 9) to obtain the crystalline title compound (1.23 g).

Melting point 1 54—1 56 ° C.

^J H NMR (DMSO-d ₆ , 400MHz): δ 3.10 (2H, t, J =

7.5Hz), 3.70 (2H, t, J = 7.5Hz), 4.58 (2H, s), 6. 90-6.98 (3H, m), 7.04 (2H, d, J = 8.5Hz), 7.14 (2H, d, J = 8.5Hz), 7.24— 7.29 (3H, m), 7.35 (1 H, J = 5. OHz), 7.55 (2H, d, J = 8.0 Hz), 7.62 -7.68 (2H, m). Example 59

3— {N— [2— (3, 4-Dimethoxyphenyl) ethyl] 1 N— [2, 1 (1 H-tetrazol-5-yl) biphenyl- 4-methyl) amino} Benzoic acid Examples In the same manner as in Example 58a-d, using 3- (3,4-dimethoxyphenylacetamino) benzoate instead of 3- (2-phenylacetamino) benzoate in 58a The title compound was obtained. Melting point 230–233 ° C.

^{_{X H NMR (DMSO- d 6,}} 400MHz): δ 2. 80 (2H, t, J =

8.OH z), 3.59-3.65 (2H, m), 3.72 (3H, s), 3.7 4 (3 H, s), 4.57 (2H, s), 6.77 (1H, d, J = 8.0 Hz), 6.86-6.93 (3H, m), 7.05 (2H , d, J = 8.0 Hz), 7.15 (2H, d, J = 8.0 Hz), 7.19 — 7.27 (2H, m), 7.32 (1 H, s) 7.53-7.57 (2H, m), 7. 6 3-7.68 (2H, m). Example 60

3— {N- (2-cyclohexylethyl) 1 N— [2, 1 (1H-tetrazole 1 5 f) biphenyl 4-ylmethyl] amino} benzoic acid

(60 a)

3- (2-Cyclohexyl) ethyl benzoate

A solution of 2-cyclohexylethyl bromide (2.5 g) and 3-aminoethyl benzoate (1.5 g) in xylene (30 ml) was refluxed for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel gel ram chromatography (ethyl acetate / hexane = 1: 1 19) to give the crystalline title compound (1.64 g). .

Melting point 5 1—5 3 ° C.

(60 b)

3- {N— (2-Cyclohexylethinole) -N- [2, _ (1H-tetrazole —5— ^) Biphenyl-1,4-ylmethyl] amino} Benzoic acid

Example 60 Using crystalline 3- (2-cyclohexylethyl) aminobenzoate obtained in Example 60a, a crystalline title compound was obtained in the same manner as Example 58b-d.

Melting point 182— 1 84 ° C.

^X H NMR (DMSO—d ₆ , 400 MHz): δ 0.90—0.98 (2H, m), 1. 1 5— 1. 3 1 (4H, m), 1. 44— 1. 49 (2H , M), 1.60- 1.75 (5H, m), 3.44 (2H, t, J = 8.0 Hz), 4.5 6 (2H, s), 6.84 (1H, d, d, J = 2.0 and 8.0 Hz), 7. 05 (2H, d, J = 8.0 Hz), 7.15 (2H, d, J = 8.0 Hz), 7.20-7.24 (3H, m), 7.53-7.58 ( 2H, m), 7. 63 -7. 69 (2H, m;). Example 6 1

N— [4 (2, 4—Doxo1, 1,3-thiazolidine, 5-yl) benzyl] —N—Fuunole 1—Naphthalene norephone amide

(6 1 a)

5— [4 (anilinomethyl) phenyl] 1,1,3-thiazolidine-1,2,4-dione

Example 18 Using ananiline in place of ethyl 3-aminobenzoate in 8a, the methods described in Examples 18a, 21a, and b were sequentially performed to obtain a crystalline title compound.

(6 1 b)

N- [4- (2, 4-Dioxo1,3-thiazolidine-1-yl) benzyl]

—N—Fuenore 1 1 Naphthalene Norehon Amid

Example 6 5- [4 (anilinomethyl) phenyl] 1 1,3-thiazolidine 1,2,4-dione obtained in 1a was replaced with 1-naphthalene instead of 4-biphenylcarboureide in Example 21c. Using a sulfo-luclide, the compound was acylated in the same manner as in Example 21c to obtain a crystalline title compound.

Melting point 77—8 1 ° C.

lH NMR (DMSO-d ₆ , 40 OMH z): δ 4.89 (2H, s), 5.71 (1H, s), 7.07-7.10 (2H, m), 7.16 -7. 20 (3 H, m), 7. 26 (2H, d, J = 8.5 Hz), 7. 29 (2H, d, J 8.5 Hz), 7. 53 (1 H, d, t , J = l. 5 and 7.0 Hz) \ 7.

62-7. 67 (2H, m), 8. 09 (1 H, d, J = 8.0 Hz), 8.1 5 (1H, d, d, J = 1. 0 and 7.5 Hz), 8. 23 (1H, d, d, J = l. 0 and 8.5 Hz), 8. 28 (1H, d, J = 8. 0Hz). Example 62

N- [4- (2, 4-Dioxo-1,3-thiazolidine-5-inole) benzyl]

—N—Hueni / Lae 2—Naphthalenol

Example 6 1 Crystalline title compound was obtained in the same manner as in Example 6 1b using 2-naphthalenesulfonyl chloride in place of 1_naphthalenesulfuryl chloride in 1b.

Melting point 1 71— 1 74 ° C.

^{_{X H NMR (DMSO- d 6,}} 40 OMH z): 6 4. 89 (2H, s), 5.

72 (1 H, s), 7. 1 0 (2H, d, J = 8.0 Hz), 7. 1 9-7. 2

7 (3H, m), 7. 3 1 (4H, s), 7.5 9 (1 H, d, d, J = 2.0 and 8.5 Hz), 7. 66-7.76 (2H, m), 8, 08 (1 H, d, J = 8. OHz), 8.1 2-8. 1 7 (2H, m), 8. 37 (1 H, d, J

= 1.5 Hz). Example 63

3-{N- [4 1 (2, 4-Dioxo 1, 3, 3-thiazolidine 1 5-yl) Benzyl] 1 N— [4 1 (2-Methylthiazonol 1-yl) Benzenols Honinore] Amino} Benzoic acid

Example 2 In the same manner as in Examples 21c and d, using 4-benzene (2-methylthiazole_41-yl) benzenesulfonyl chloride instead of 4-biphenylcarbyl chloride in 1c. The title target compound was obtained.

_{XH NMR (DMSO- d 3, 40} OMH z): δ 2. 75 (3H, s), 4. 88 (2H, s), 5. 7 3 (1 H, s), 7. 30- 7. 42 (6H, m), 7. 65-7. 68 (3H, m), 7. 79 (1H, d, J = 7.5Hz), 8. 16 (2H, d, J = 8.5Hz) 8. 21 (1H, s ) Example 64

3— {N- [4 1 (2, 4—Dioxo 1, 3—thiazolidine 1 5-yl) Benzyl] -N- [4 1 (5-Methyl 1, 1, 2, 4-Oxazazol 1 Luo 3 — ^ Le) benzoyl] amino} benzoic acid

Instead of the 4-biphenyl carboerk mouthlid in Example 21c, 4- (5 1-methyl-1,1,2,4-oxadiazol-1-3-yl) benzoyllucide mouth was used, Example 2 1 An amorphous title compound was obtained by the methods c and d. ^{_{X H NMR (DMSO- d 3,}} 40 OMH z): δ 2. 63 (3H, s), 5. 1 7 (2H, s), 5. 78 (IH, s), 7. 29- 7. 40 (6H, m), 7.5 1 (2H, d, J = 8. OH z), 7. 66— 7. 6 7 (2H, m), 7. 84 (2H, d, J = 8. OHz ) Example 65

3— {N— [4— (2, 4-Dixo-1, 1,3-thiazolidine 1, 5) Benzyl] 1 N— [4 (2-Pyridyl) benzoyl] Amino} Benzoic acid

In the same manner as in Example 1 8 b-g, using 4-mono (2-pyridyl) benzoyl chloride hydrochloride instead of cyclohexanecarbonyl chloride in Example 18 b A compound was obtained.

τΗ NMR (DMSO—d ₆ , 400 MHz) S 5. 1 7 (2H, s), 5. 77 (1H, s), 7. 30-7. 39 (7H, m), 7. 44 (2H, d, J = 8.5 Hz), 7.65-7. 68 (2H, m), 7.84 (1 H, d, t, J = 1.0 and 7.5 Hz), 7. 92-7. 98 (3H, m), 8.62—8.64 (1H, m). Example 66

3— {N- [4- (2, 4-Doxo1, 1,3-thiazolidine-5-yl) benzil] -N- (Quinolin 3-carbon) amino} benzoic acid

Example 1 In the same manner as in Example 1 8 b-g, using the quinoline 1 3 carbonyl chloride hydrochloride instead of the cyclohexane hexyl chloride in 8 b, the amorphous form was used. The target compound was obtained.

^{_{X H NMR (DMSO- d 6,}} 400MHz): δ 5. 22 (2Η, s), 5. 78 (1H, s), 7. 29 (1H, t, J = 8. OHz), 7. 3 7 — 7. 4 2 (5H, m), 7.60 (1H, d, d, J = l. 0 and 7.5Hz), 7.65 (1H, d, t, J = 1.0 and 8) OHz), 7. 76-7. 80 (2 H, m), 7. 90-7. 94 (2H, m), 8. 42 (1 H, d, J = 1.5 Hz), 8. 74 (1 H, d, J = 2. OHz). Example 67

N- [4- (2, 4-Dioxo-1,3-thiazolidine-5-yl) benzyl]

-N- (2—Bihuyurenore) Benzenesulfonamide

Example 8 Using N- (biphenyl 2_yl) benzenesulfonamide instead of N- (phenyl) methanesulfonamide in Example 8a, using the same procedure as in Example 8a-e, The target compound was obtained.

XH NMR (DMSO-d ₆ , 400 MHz): δ 4.28 (l H, brs),

4.47 (1H, b r s), 5.70 (1 H, s), 6.69 (2H, d, J

= 8. OHz), 6. 92-6. 96 (3H, m), 7. 1 0 (2H, d, J =

8.OHz), 7.20 (1 H, d, d, J = 2.0 and 8.OHz), 7.

22-7. 27 (2H, m), 7.30— 7.39 (3H, m), 7.62— 7.66 (2H, m), 7.70— 7.79 (3H, m). Example 68 3— {N— (Bifenienore 4-Inolemethinole) 1-N— [4- (2, 4-Dioxo-1,3-Thiazolidine-5-yl) benzyl] Amino} Benzoic acid

(68 a)

3— (Bihu Nilu 4 1 ^ T Rumetinole) Aminobenzoic acid ethyl

Example 60 Crystalline title compound was obtained from 4-phenylbenzyl bromide and ethyl 3-aminobenzoate by the same method as in Example 60a.

(68 b)

2- {4- [N- (Bifenienore 4 1-inoremethinole) 1 N- (3-Ethoxycarpo 2-norefuenore) Aminomethyl] Hueninore} —2-Oxoacetate

Example 1 In the same manner as in 8a, 3- (biphenyl-4-alkylmethyl) aminobenzo #acid ethyl and 2- (4- (promomethyl) phenyl) -1-2-oxo obtained in Example 68a The amorphous title compound was obtained from ethyl acetate. (68 c)

3— {N— (Bifeniole 4 4-Inole Mechinole) -N- [4 1 (2, 4-Dioxo-1,3-Thiazolidine 1-yl) Benzyl] Amino} Benzoic acid

Example 68 2- {4- [N- (biphenyl-4-ylmethyl)] obtained in b

N- (3-Ethoxycanolepoenorepheninole) aminomethinore] Feninore} — Using 2-ethyl acetate, the amorphous title compound was obtained in the same manner as in Example 1 c _ g. It was.

XH NMR (CDC 1 ₃ , 40 OMH z): δ 4. 71 (2 (, s), 4.7

2 (2Η, s), 5.37 (1Η, s), 6.96 (1Η, d, J = 8. OHz),

7. 25-7. 30 (7H, m), 7. 34— 7. 49 (5H, m) _s 7. 55

-7. 59 (4H, m). Example 69

3- {N— (2-Cyclohexylethyl) 1 N— [4— (2, 4-Dioxo1, 3-thiazolidine 1-5-yl) benzenole] amino} benzoic acid (6 9 a)

2— {4— [N— (2-Cyclohexylethyl) -N- (3-Ethoxycarbonylphenyl) aminomethyl] phenyl} —2-Oxoethyl acetate

In the same manner as in Example 18a, 3- (2-cyclohexylethyl) aminobenzoate and 2- (4- (promomethyl) phenyl) -1-ethyl oxoacetate obtained in Example 60a were used. Gave the title compound as a gum.

(6 9 b)

3— {N— (2-Cyclohexylethyl) 1 N— [4 1 (2, 4-Dioxo-1,5, 3-thiazolidine 1-yl) benzyl] Amino} Benzoic acid

Example 6 9 2 2- {4- [N— (2-Silane hexenoleethyl) 1 N 1 (3-Ethoxycanoleponolefe-nore) aminomethyl] phenol} 2-Oxo obtained in 9a Using ethyl acetate, the target compound of an amorphous form was obtained in the same manner as in Example 18 c-g.

NMR (CDC 1 a, 0 OMH z): δ 0.93— 1. 0 1 (2 Η, m), 1. 1 5— 1. 30 (4H, m), 1. 52— 1. 5 7 ( 2H, m), 1.66 — 1.74 (5H, m), 3.43 (2H, t, J = 8. OHz), 4.56 (2 H, s), 5.36 (1H, s ), 6.85 (1 H, d, d, J = l. 5 and 8. OHz), 7. 24-7.27 (4H, m), 7.36—7.40 (3H, m). Example 70

3— {N—Putinolesnorehoninole 1 N— [4 1 (2, 4-Dioxo1, 3-thiazolidine 1-yl) benzyl] amino} benzamide

Example 1 3- {N-Butylsulfonyl-N- [4 (2,4-dioxo-1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (50 Omg) obtained in 1 Of 0.5 M ammonia / dioxan solution (4.32 ml) and jetyl cyanophosphate (93% purity, 284 m) in tetrahydrofuran (10 ml) solution g) was added and stirred at room temperature for 4 hours. The reaction solution was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (5% methanol / dichloromethane) to give the title compound (1 56 mg) as a powder.

_{^ NMR (DMSO- d 6, 40} OMHz): 6 0. 89 (3H, t, J = 7. 5Hz), 1. 35- 1. 45 (2H, m), 1. 65- 1. 75 (2H , M), 3.23 (2H, d, d, J = 7.5 and 8.5 Hz), 4.96 (2 H, s), 5.74 (1H, s), 7.30 (2H , D, J = 8. OHz), 7.33 (2H, d, J = 8. OHz) _N 7. 38—7.45 (2H, m), 7.5 3 (1 H, d, d, J = 2. 0 and 8. OHz), 7. 73 (1 H, d, d, J = 2. 0 and 8. OHz), 7. 93 (1 H, d, J = 2. OHz), 8 01 (1H, s). Example 71

5— {4— [N— (3_morpholinocarbonylphenyl) 1 N— (2-Naphthenosenophoninole) aminomethinole] Fueninore}-1, 3-Thiazolidine 1, 2, 4-dione

3— {N— (2-Naphtylsulfonyl) -1-N— [4_ (2,4-dioxo-1,3-thiazolidine-1-5-yl) benzyl] amino} benzoic acid (61) obtained in Example 25 HBTU (523 mg) was added to an N, N-dimethylformamide (12 ml) solution of (Omg), morpholine (120 mg) and N, N-diisopropylethylamine (0.24 ml) at room temperature. For 1 hour. Ethyl acetate was added to the reaction solution, washed with saturated brine and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol / dichloromethane = 1: 20) to obtain the amorphous title target compound (524 mg). ^J H NMR (DMSO—d ₃ , 400 MHz): δ 2. 78- 2.86 (2H, m), 3. 20-3. 27 (2H, m), 3. 45-3. 57 (4H, m ), 4.93 (2H, s), 5.72 (1 H, s), 7.05—7.06 (1 H, m), 7.21 -7.26 (2H, m), 7. 30 (4H, s), 7.35 (1H, t, J = 7.5Hz), 7.62 (1H, d, d, J = 2.0 and 8.5Hz), 7. 67-7. 77 (2H, m), 8.09—8.18 (3H, m), 8.39 (lH, d, J = 2.0 Hz;). Example 72

5- {4- C {2- (2-Naphtyl) imidazole 1 / l} methyl] phenyl} 1,1,3-thiazolidine 1,2,4-dione

Example 8a-e and N- (phenyl) methanesulfonamide in Example 8a and 2-naphthylimidazole and 55% oily sodium hydride were used in place of carbonated lithium. A crystalline title compound was obtained in the same manner.

Melting point 236-238 ° C.

^{_{X H NMR (DMSO- d 6,}} 400MHz): δ 5. 45 (2H, s), 5. 75 (1H, s), 7. 09 (2H, d, J = 8. 0Hz), 7. 1 3 (1H, d, J = l. 0Hz), 7. 37 (2H, d, J = 8. OH z), 7. 39 (1 H, d, J = 1.0 Hz) 7. 52— 7. 57 (2H, m), 7.74 (1H, d, d, J = 1.5 and 8.5Hz), 7. 86-7.98 (3H, m), 8.07 (1H, d, J = 1. 0Hz). Example 73

5- {4- [{2- (4-Bipheryl) imidazole-1-yl} methyl]} Phenol, 1,3-thiazolidine-1,4-dione Example 8 a— In place of N— (phenyl) methanesulfonamide and carbonated lithium in Example 8a, 2— (4-biphenylyl) imidazole and 55% oily hydrogen vinyl trimethyl were used respectively. A crystalline title compound was obtained by the same method as e.

Melting point 260—262 ° C.

^X H NMR (DMSO- d ₆ , 40 OMH z): 8 5.45 (2H, s), 5.75 (1 H, s), 7.09 (2H, d, J = 8.0 Hz), 7. 1 3 (1H, d, J = 1. 0Hz), 7. 37 (2H, d, J = 8. OHz) 7. 3 9 (1 H, d, J = 1. OHz) N 7. 52 -7. 57 (2H, m), 7.74 (1 H, d, d, J = 1.5 and 8.5Hz), 7.86—7.98 (3H, m), 8.07 (1 H, d, J = l.OHz) ₀ Example 74

2-Oxo N-phenyl _N— [2, 1 (1 H-tetrazole-5-yl) biphenylenoyl 4-monomethyl] valenoreamide

(74 a)

N—Fu-Lu N_ [2,1 (2-Trityl 1 2 H-tetrazol-5-yl) Biphenyl 2 f-Rumethyl] Amine

A crystalline title compound was obtained in the same manner as in Example 4a except that aniline was used in place of methyl 3-aminobenzoate in Example 4a.

Melting point 145-147 ° C.

(74 b)

2—Oxo N—Phenol N— [2, One (1H—Tetrazol-5-yl) Biphenyl 4-Nylmethyl] barrelamide

Example 74 N-phenyl-N— [2 ′ — (2-trityl 1 2 H-tetrazole 1-5-inole) biphenyl 1-ylmethinole] amine obtained in a. Acylation with 2-oxovaleryl chloride and deprotection were performed in the same manner as in c to obtain the amorphous title compound.

^{_{X H NMR (DMSO- d 6,}} 40 OMH z): δ 0. 71 (3Η, t, J = 7. 5Hz), 1. 42 (2H, sextet, J = 7. OHz), 2. 48 (2 H, t, J = 7. OHz), 4.93 (2H, s), 7.04 (2H, d, J =

7. OHz), 7. 1 1 ( 2H, d, J = 8. OHz), 7. 1 9 (2H, d, J = 8. OHz) s 7. 3 1-7. 38 (3H, m) 7.43 (1H, d, J = 8.OHz), 7.51 -7.62 (2H, m), 8.02 (1 H, d, J =

8. OHz). Example 75

3— {N— (7—Oxootatanyl) 1 N— [2, 1 (1H-tetrazole 1-5-yl) Biphenyl 1 4 T-methyl] amino) Benzoic acid

Using 7-oxooctanoic acid instead of 3-phenylpropionic acid in Example 1a, a crystalline title compound was obtained in the same manner as in Example 1a-d. Melting point 1 3 7— 1 39 ° C.

^X H NMR (DMSO—d ₆ , 40 OMH z): δ 1. 05— 1.16 (2 H, m), 1. 30— 1. 38 (2H, m), 1. 41-1.5 1 (2H, m), 2.00-2.10 (2H, m), 2.04 (3H, s), 2.34 (2H, t, J = 7. OHz) _N 4. 88 (2H, s ), 7. 02 (2H, d, J = 8. OHz), 7. 1 3 (2H, d, J = 8. OHz), 7. 36 (1 H, d, J = 8. OHz), 7 49-7. 59 (3H, m), 7. 64- 7.70 (2H, m), 7.75 (1H, s), 7.88 (1 H, d, J = 7.5 Hz). Example 76 3— {N- [4 1 {E) — Methoxyimino 4 — (2—Chenyl) pentyl] 1 N— [2 '— (1H—Tetrazol 5—i / les) Bifuenore 1 4-methylmethinore] Amino} Benzo acid

(76 a)

3— [4-Oxo 4- (2-Cenyl) Petylylamino] Ethyl benzoate In the same manner as in Example 1, 4-Oxy 4- (2-Cenyl) butyric acid and 3-ethylamino benzoate are condensed. The crystalline title compound was obtained.

Melting point 147—149 ° (.

(76 b)

3— [4-Methoxyimino 4— (2-Chenyl) butyrylamino] Ethyl benzoate

Example 76 To a solution of 3- [4-oxo-4- (2-chenyl) butyrylamino] obtained in a) ethynol benzoate (1.50 g) in ethanolol (30 ml) was added methoxyamine hydrochloride (654 mg). The mixture was further stirred for 3 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the residue was extracted into ethyl acetate, washed with brine and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 3: 7) to give the amorphous title compound.

(76 c)

3- {N— [4— (and Z) —Methoxyimino 1 4- (2-Chel) Butyryl] -N- [2 ′ — (2-Trityl 2 H-tetrazole 1-yl) Biferro- 4-1-ylmethyl] amino} ethyl benzoate

Example 76 3- [4-methoxyimino 4_ (2-chenyl) propylamylamino] obtained in b was added to a solution of ethyl benzoate (1.50 g) in tetrahydrofuran (3 Oml) under a nitrogen atmosphere. % Oily sodium hydride (158 mg) was added, and the mixture was stirred at 40 ° C for 30 min. After returning to room temperature, add 5- (4,1 bromomethylbifuryl-2-yl) 1 2-trityl 1 2 H-tetrazole (2.60 g) of N, N-dimethylacetamide. (15 ml) solution was added and stirred at room temperature for 1 hour. Reaction liquid The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (ethyl acetate Z dichloromethane = 1: 19), eluting first with the (Zy) monoisomer (0.95 g) of the amorphous title compound as the first elution. Amorphous E) monoisomer (1.23 g) was obtained.

(76 d)

3- {N- [4 1 (E) —Methoxyimino 1- (2-Che / re) Pytolyl]-N— [2, 1 (1 H-tetrazol-5-yl) biphenyl 1 4-methyl) amino } Ethyl benzoate

Example 76 3— {N- [4-((1) -methoxyimino 1- (2—chenyl) pentyl] -N- (2 ′ _ (2-trityl 1 2 H-tetrazole 1 5 f)) obtained in c P-toluenesulfonic acid monohydrate (50 mg) was added to a mixed solution of ethyl benzoate (1.23 g) in methanol (30 ml) and tetrahydrofuran (10 ml) at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (3% methanol / dichloromethane) to give the amorphous title compound (0.66 g). '

(76 e)

3— {N- [4 1 (E) — Metoximino _4 1 (2-Chenyl) pentyl] 1 N— [2 '— (1H-Tetrazole-5-yl) Biphenyl 1 4 1-methyl] amino} Benzo Acid

Example 76 3— {N— [4— (E) —Methoxyimino 1- (2 1-chenyl) -pentyl] 1-N— (2, _ (1 H-tetrazol-5-yl) biphenyl obtained in d [4-Irylmethyl] amino} ethyl benzoate was hydrolyzed with 1N aqueous sodium hydroxide solution in the same manner as in Example 1d to obtain an amorphous title target compound.

^X H NMR (CDC 1 ₃ -d, 400 MHz): δ 2.34 (2Η, t, J = 8.0 Hz), 2.94 (2H, t, J = 8. OH z), 3.72 (3H , s), 4. 8 1 (2H, s), 6. 92 (1 H, d, d, J = 3.5 and 5.0 Hz), 6. 9 7 (4H, s), 7. 1 6-7. 26 (3H, m), 7. 38— 7.5 5 (5H, m), 7.8 1 (1H, d, J = 7.5 Hz) _N 8.02 (1 H, d, J = 7.5 Hz ) Example 77

3— {N— [4 1 {Z) — Methoxyimino 1 4 — (2-Chenyl) pentyl] 1 N— [2, 1 (1H-tetrazol-5-yl) biphenyl 2 -ylmethyl] amino} Benzoic acid

Example 76 3— {N— [4 (ZJ-methoxyimino 1) (2 — chenyl) butyryl] —N— (2, 1 (2-trityl 2H-tetrazol 1-yl) biphenol obtained in c 2-Luyl-4-ylmethyl] amino} Using ethyl benzoate, the title target compound was obtained in the same manner as in Example 76d, e. ^X H NMR (CDC 1 ₃ — d, 40 OMH z ): Δ 2.44 (2Η, t, J 7. OH z), 3.01 (2H, t, J = 7. OH z), 3.90 (3H, s), 4.84 (2H, s) ), 6.96-7.06 (3H, m), 7.05 (2H, d, J = 8Hz), 7.28-7.52 (7H, m), 7.58 (1H, s), 7. 79 (1H, d, J = 7.5 Hz), 7. 98 (1 H, d, J = 7.5 Hz) Example 78

3— {N— [2— (3-Benzylphenylenol) propionyl] -N- [2 '— (1 H-tetrazonolone 5-yl) Biphenolate 4-ylmethyl] amino) Benzoic acid Example 1 in 3a —Amorphous title target compound was obtained in the same manner as in Example 1ad, using 2_ (3-benzoyl) propionic acid instead of phenylpropionic acid.

^{_{X H NMR (DMSO- d 6,}} 40 OMH z):. Δ 1. 34 (3H, d, J = 6. 5Hz) N 3. 72-3 77 (1H, m), 4. 80- 4. 93 (2H, m), 6.97 (2H, d, J = 8.0 Hz), 7.08 (2H, d, J = 8. OH z) _s 7. 20- 7. 24 (2H, m), 7. 38 — 7. 88 (14H, m), 7. 85 (1 H, d, J = 8.0 Hz). Example 79

3- {N— (3-Oxo 1-cyclopentanecarbonyl) -N- [2, 1 (1 H-tetrazole 1-yl) biphenyl 4-ylmethyl] amino} benzoic acid Example 1 in a Amorphous title target compound was obtained in the same manner as in Example 1ad, using 3-oxo-1-cyclopentane-powered ruponic acid instead of 3-phenylpropionic acid.

_{aH NMR (DMSO- d 6, 400MHz} ):. δ 1. 90- 2. 41 (6 Η, m), 2. 93-2 9 9 (1 Η, m), 4. 8 8 (2Η, s) _{s 7. 02 (2 H, d} , J = 8. 0Hz), 7. 1 2 (2H t d, J = 8. 0Hz), 7. 38 (1H, d, J = 8. OHz), 7, 52-7. 5 9 (3H, m), 7.65—7.69 (2H, m), 7.78 (1 H, s), 7.92 (1 H, d, J = 8. OHz) . Test example 1

AGEs production inhibitory effect

The dimethyl sulfoxide solution 50 1 of the test compound was added to 450 / i 1 (final concentration, serum of renal failure patient serum with informed consent) (final concentration 5 mM), and the mixture was incubated at 37 ° C. for 1 week. Pentosidine, one of the AGEs produced, was measured as follows. In order to liberate the pentosidine produced on the protein, 50 μ1 of 10% trichloroacetic acid was added to the sample 50 u 1 after the reaction, and the protein was precipitated by centrifugation and collected. The collected protein was washed with 30 μμl of 5% trichlorodiacetic acid, dried, then added with 100 μl of 6N hydrochloric acid, and hydrolyzed at 1 10 ° C. for 16 hours. HP LC (OD with fluorescence detector) SCI 8, 4.6 X 25 Omm, 335 nm, 385 nm) 0.1% trifluoroacetic acid-added distilled water Z 0.08% trifluoroacetic acid-added 80% acetonitryl as a mobile phase (30 The production weight (nmol lZl) of pennsinsine was measured for 1 minute by 1. Om lZ minutes). (Miyata T, eta 1, J. Am. O c.. Ne phrol., 7, 1 1 98 -1 206, 1 996,; Miyata T, etal, Proc. Na tl. Ac a d S ci. USA, 9 3, 235 3— 23 58, 1 996).

The AGEs production inhibitory effect was calculated as% of the production rate when compared to the amount of pentosidine produced by the control. The results are shown in Table 1. All of the test compounds showed an inhibitory effect on pentosidine production.

[table 1 ]

Example No. Pentosidine production rate (%) Example 1 2 0

Example 6 2 0

Example 7 1 3 Example 8 1 9 Example 9 2 0

Example 1 0 1 4

Example 1 1 1 1 Example 1 5 2 0 Example 1 6 1 5 Example 1 7 1 6 Example 1 8 1 5 Example 1 9 2 0 Example 2 0 8 Example 2 1 2 Example 2 2 1 5 Example 2 3 1 0 Example 2 4 9 Example 2 5 1 Example 2 7 1 2 Example 2 8 1 6 Example 2 9 1 4 Example 3 0 1 3 Example 3 2 1 9 Example 3 3 1 8 Example 3 6 2 0 Example 4 2 7 Example 6 3 2 0 Actually 6 8 2 0 Pentosidine is one of the AGE s structures, and since the compound of the present invention inhibits the production of pentosidine, it has been found that it has an AGE s production inhibitory effect and also has an AGE s production inhibitory activity. The compounds of the present invention are useful for the treatment of diseases associated with AGEs such as diabetes complications (particularly diabetic nephropathy). Formulation Example 1 Capsule

Compound of Example 1 10 mg

Lactose 1 10 mg

Corn 'starch 58 mg

Magnesium stearate 2 mg

180 ms total

Mix well the powder of each component shown above and pass through a 60 mesh sieve (mesh standard is based on Ty 1 er standard). Weigh 180 mg of the resulting powder and fill into gelatin capsules (No. 3) to prepare capsules. Formulation Example 2 Tablet

Example 11 Compound 10 mg

Lactose 85 mg

Corn 'starch 34 mg

Microcrystalline cellulose 20 mg

Magnesium stearate 1 mg

150 mg total

Mix the powders of the above ingredients well and compress them into tablets weighing 15 Omg each. If necessary, these tablets may be coated with sugar or film. Formulation Example 3 Granules

Example 1 Compound of 4 1 0 mg

Lactose 8 3 9 mg

Corn starch 1 5 0 mg

Hydrangea xip mouth pinoresenole mouth 1 mg

Total 1 0 0 0 mg

The powders of the above components are mixed well, moistened with pure water, granulated with a basket type granulator, and dried to obtain granules. Industrial applicability

The phenylene derivative represented by the above general formula (I), which is an active ingredient of the present invention, and also pharmacologically acceptable salts and esters thereof have an AGE production inhibitory effect and a renal protective action, Nephropathy (nephritis, nephropathy, nephrosclerosis, renal failure, etc.), diabetic complications (nephropathy, neuropathy, retinopathy, cataract, microvascular disorder, skin disorder, etc.), cardiovascular disease (cardiac myocardial infarction, Cardiac hypertrophy, heart failure, arteriosclerosis, coronary artery disease, peripheral circulation disorder, cerebrovascular disorder, hypertension, systolic hypertension, restenosis after angioplasty, etc. ) Dialysis complications in dialysis, peritoneal sclerosis, rheumatoid arthritis, photoelastic fibrosis, aging, senile cataract, etc. in patients with peritoneal dialysis It is. While some of the specific embodiments of the present invention have been described in detail, those skilled in the art will recognize that the specific embodiments shown are subject to various modifications without departing substantially from the teachings and advantages of the present invention. Modifications and changes can be made. Accordingly, all such modifications and changes are intended to be included within the spirit and scope of the invention as claimed in the following claims. This application is based on Japanese Patent Application No. 2005-251826 filed in Japan (filing date: August 31, 2005), the contents of which are incorporated in full herein.

Claims

Billed

1. General formula (I)

(I)

[Where

A is the following general formula (Al), (A2), (A3) or (A4)

(Al) (A2) (A3) (A4)

A group represented by:

B represents a 1H-tetrazole-5- ^ T group or a 2,4-dioxo 1,3-thiazolidine mono-5-yl group;

X represents a single bond or a C ₆ - shows a ₁₀ Ariren group;

Y ¹ represents carbonyl, sulfonyl or a single bond;

Y ² represents a C- ₆ alkylene group or a single bond;

Y ³ represents methylene, carbonyl or a single bond;

Y ⁴ represents a methine or nitrogen atom;

Y ⁵ represents methylene, carbonyl or a single bond;

R ¹ is

— 8 alkyl group (the alkyl group is a group selected from the following substituent group 0!

1 to 3 may be substituted)

A C _{6 —} ₁₄ aryl group (the C ₆ — ₁₄ aryl group may be substituted with 1 to 5 groups selected from the following substituent group 3); C ₆ - ₄ Ariru - C - ₆ alkyl group (the C ₆ - ₄ § Li one Roux C _ ₆ alkyl group may be one to five substituted with a group selected from the following substituent group), nitrogen A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an atom, oxygen atom and sulfur atom (the heterocyclic group is a group selected from the following substituent group 3) 1 to 5 may be substituted with

Nitrogen atom, 4 to 10-membered heterocyclic ring containing the same or different 1乃optimum three heteroatom selected from oxygen atom and a sulfur atom - alkyl group (said heterocyclic one Omicron _chi _ ₆ alkyl groups, the following 1 to 5 groups may be substituted with a group selected from the substituent group),

C ₃ _ ₇ cycloalkyl group (said C ₃ _ ₇ cycloalkyl group may be one to five substituents by a group selected from the following substituent group),

C ₃ one ₇ cycloalkyl one C DOO ₆ alkyl group (the C ₃ - ₇ consequent opening alkyl -. Bok ₆ § alkyl group is optionally be one to five substituted with a group selected from the following substituent group] 3 Is good)

C ₆ - ₄ § Li one Roux force Ruponiru - C - ₆ alkyl group (the C ₆ _ i ₄ Ariru - force Lupo sulfonyl one C _i-6 alkyl groups, 1 to 5 groups selected from the following substituent group May be replaced) or

. ₆ aliphatic acyl group (this ₆ aliphatic group may be substituted with 1 to 5 groups selected from the following substituent group)

Indicates;

R ² represents a hydrogen atom, a group selected from the following substituent group, a carboxyl group, or a group represented by —C (O) NR ¹³ R ¹⁴ ;

R ³ is

Hydrogen atom,

C ^ s alkyl group (the one ₈ alkyl group may be 1 to 3 substituted with a group selected from the following substituent group monument), C ₆ - ₁₄ Ariru group (said C ₆ - ₁₄ Ariru group may be one to five substituted with a group selected from the following substituent group J3), or

R ⁴ and R ⁵ are the same or different, a hydrogen atom or a C ₆ each - ₁₄ Ari Le group (the C ₆ _ ₁₄ Ariru groups, one to five location with a group selected from the following substituent group] 3 May be converted);

R ⁶ and R ^7, the force to form the connexion C ₃ _ ₇ cycloalkane such together, or the same or different connexion each a hydrogen atom or a C i _ ₈ alkyl group (the C - ₈ alkyl group, the following substituents 1 to 3 groups may be substituted with a group selected from the group);

R ⁸ and R ^9, the same or different and each represents a hydrogen atom, a group selected from the following substituent group] 3, a carboxyl group or a C (O) group represented by NR ¹³ R ^14; R ¹⁰ is ,

Hydrogen atom,

— 8 alkyl groups (the alkyl groups may be substituted by 1 to 3 groups selected from the following substituent group),

C ₆ - ₁₄ Ariru group (the C ₆ _ ₁₄ 7 aryl group may be one to five substituted with a group selected from the following substituent group] 3), or

A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms identical or different selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is selected from the following substituent group) 1 to 5 of these groups may be substituted)

R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a group selected from the following substituent group] 3, a carboxyl group, or a group represented by 1 C (O) NR ¹³ R ¹⁴ ; R ¹³ and R ¹⁴ together form a 4- to 10-membered nitrogen-containing heterocycle (the nitrogen-containing heterocycle may be substituted with 1 to 5 groups selected from the following substituent group). Or are the same or different and each represents a hydrogen atom or a C i- ₈ alkyl group.

The alkyl group may be substituted with 1 to 3 groups selected from the following substituent group.

However,

(1)! If ^^ is an alkyl group and Y ¹ is a single bond, B is a 2,4-dioxo1,3, thiazolidine-5-yl group,

(2) When Y ² is methylene, R ⁶ and R ⁷ are not both hydrogen atoms. (3) When R ¹ is an unsubstituted C ^ ₈ alkyl group, Y ¹ is not carbonyl and (4 ) When R ¹ is an unsubstituted C ₁₆ aliphatic acyl group, Y ¹ is not a single bond.

(Substituent group ο

Halogen atom, ₆ alkylthio group, — 6 aliphatic acyl group, alkylsulfur group, d_ ₆ alkoxy group, cyano group, and utro group.

(Substituent group) 3)

Halogen atom, CI- _C6 alkyl group, halo C ₆ alkyl group, C ₆ alkoxy group, C - 6 alkylthio group, Ji ₆ alkylsulfonyl group, an aliphatic Ashiru group, O Kiso group, Shiano group, nitro group, C ₃ _ ₇ cycloalkyl group, C ₆ - ₁₄ Ariru group, C _i-6 Arukokishiimino group, C ₆ -. ₁₄ Ariru one carboxy group, and a nitrogen atom, different identical or selected from oxygen radicals and sulfur atoms A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms. ]

Or a pharmacologically acceptable salt or ester thereof.

2. — General formula (I):

(I) [Where

A is the following general formula (A1) (A2), (A3) or (A4)

(Al) (A2) (A3) (A4)

A group represented by:

B represents a 1H-tetrazol-5-yl group or a 2,4-dioxo-3-thiozolidine-5-inore group;

X represents a single bond or a C ₆ _ ₁₀ Ariren group;

Y ¹ represents force sulfonyl, sulfonyl or a single bond;

Y ² represents an alkylene group or a single bond;

Y ³ represents methylene, carbonyl or a single bond;

Y ⁴ represents a methine or nitrogen atom;

Y ⁵ represents methylene, carbonyl or a single bond;

R ¹ is

_ ₈ alkyl group (said - ₈ alkyl group may be 1 to 3 substituted with a group selected from the following substituent group alpha),

A C _{6 —} ₁₄ 7 reel group (the C ₆ — ₁₄ aryl group may be substituted with 1 to 5 groups selected from the following substituent group),

C ₆ - ₄ § Li one Roux C _ ₆ alkyl group (the C ₆ - ₄ § Li one Roux C - ₆ alkyl group may be one to five substituted with a group selected from the following substituent group ) A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms identical or different selected from a nitrogen atom, oxygen atom and sulfur atom (the heterocyclic group is selected from the following substituent group) 3 1 to 5 of these groups may be substituted)

Nitrogen atom, the same or different 4-10 membered heterocyclic ring containing from 1 to terrorist atom 3 of the selected from oxygen atom and a sulfur atom - C _ ₆ alkyl group (said heterocyclic - C! — _1-6 alkyl groups may be substituted with a group selected from the following substituent group J3):

C ₃ one ₇ cycloalkyl group,

C ₃ - ₇ cycloalkyl one C - ₆ alkyl group or

C ₆ - i ₄ § Li one Roux force Ruponiru - C _ ₆ alkyl group (the C ₆ _ ₄ § Li one Rukarubo two Lou C ^ ₆ alkyl group, 1 to 5 groups selected from the following substituent group β May be replaced);

R ² represents a hydrogen atom, a group selected from the following substituent group] 3, a force lpoxyl group or a group represented by 1 C (O) NR ¹³ R ¹⁴ ;

R ³ is

Hydrogen atom,

An alkyl group (the alkyl group may be substituted by 1 to 3 groups selected from the following substituent group a);

A C _{6 —} ₁₄ aryl group (the C ₆ — ₁₄ aryl group may be substituted with 1 to 5 groups selected from the following substituent group), or

A 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms identical or different selected from a nitrogen atom, an oxygen atom and a sulfur atom (the heterocyclic group is a group selected from the following substituent group) 1 to 5 may be substituted);

R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or a C ₄ Ari Le group (said Ji ₆ _ ₁₄ Ariru groups are one to five substitution groups selected from the following substituent group 3 Can be)

R ⁶ and R ^7, together such connexion C ₃ - ₇ forces to form a cycloalkane, or same or different connexion each a hydrogen atom or a C i _ ₈ alkyl group (said C i _ ₈ alkyl group, Substituent 1 to 3 groups may be substituted with a group selected from the group of groups);

R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom, a group selected from the following substituent group / 3, a carboxyl group, or a group represented by one C (O) NR ¹³ R ¹⁴ ; R ¹⁰ is

Hydrogen atom,

An alkyl group (the alkyl group may be substituted by 1 to 3 groups selected from the following substituent group),

C ₆ one ₁₄ Ariru group (the 〇 ₆ _ ₁₄ Ariru group may be one to five substituted with a group selected from the following substituent group jS), or

1 to the same or different selected from nitrogen atom, oxygen atom and sulfur atom

A 4- to 10-membered heterocyclic group containing 3 heteroatoms (the heterocyclic group may be substituted with 1 to 5 groups selected from the following substituent group);

R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom, a group selected from the following substituent group, a carboxyl group, or a group represented by 1 C (O) NR ¹³ R ¹⁴ ;

R ¹³ and R ¹⁴ together are a 4- to 10-membered nitrogen-containing heterocycle (the nitrogen-containing heterocycle may be substituted with 1 to 5 groups selected from the following substituent group) ) to form formed the force, or the same or different and each is a hydrogen atom or a C alkyl group (the C E _ ₈ alkyl group, be 1 to 3 substituted with a group selected from the following substituent group monument Good).

However,

(1) When R ¹ is a C — s alkyl group and Y ¹ is a single bond, B is a 2,4-dioxo1,3-thiazolidine group,

(2) When Y ² is methylene, both R ⁶ and R ⁷ are not hydrogen atoms,

(3) When R ¹ is an unsubstituted C ₈ alkyl group, Y ¹ is not carbonyl,

(Substituent group a)

A halogen atom, a ₆ alkylthio group, a C- ₆ alkylsulfinole group, a 6 alkoxy group, a cyano group and a nitro group.

(Substituent group β) Halogen atom, Ci- ₆ alkyl group, halo Ci- ₆ alkyl group, Ci- ₆ alkoxy group, C-6 alkylthio group, ₆ alkylsulfonyl group, 6 aliphatic acyl group, cyano group, nitro group, C ₃ ₇ cycloalkyl, _6-1 ₁₄ § Li Ichiru group, and a nitrogen atom, 4 to 10-membered heterocyclic group containing 1 to 3 identical or different hetero atoms selected from oxygen atom and sulfur atom. ]

Or a pharmacologically acceptable salt or esterole thereof.

3. B is a 1H- Tetorazoru 5 I group, and X is C ₆ - ₁₀ Ariren group, according to claim 1 or a compound of the second aspect or a pharmacologically acceptable salt or Esutenore.

4. The compound according to claim 3, or a pharmacologically acceptable salt or ester thereof, wherein X is phenylene.

5. The compound according to claim 1 or 2, or a pharmacologically acceptable salt or esterole thereof, wherein B is a 2,4-dioxothiazolidine-5-yl group and X is a single bond.

6. The compound according to claim 1 or 2, or a pharmacologically acceptable salt or ester thereof, wherein A is a group represented by the general formula (A1), and R ² is a hydrogen atom or a force lpoxyl group. .

7. A is a group represented by the general formula (A2), and R ³ is a hydrogen atom or 〇 ₆ _ ₁₄ Ariru group (said C ₆ - ₁₄ Ariru groups are defined in claim 1 Or a pharmacologically acceptable salt or ester thereof. 3. The compound according to claim 1 or 2, which may be substituted with 1 to 5 groups selected from the group of substituents.

8. A is a group represented by the above general formula (A3), Y ³ is carbonyl or a single bond, and R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom or a carboxyl group. The compound according to claim 1 or 2, or a pharmacologically acceptable salt or ester thereof.

9. A is a group represented by the above general formula (A4), Y ⁵ is carbonyl or a single bond, and R ¹¹ and R ¹² are the same or different and each represents a hydrogen atom. Or a pharmacologically acceptable salt or ester thereof according to claim 1, which is a carboxyl group. .

10. 3— {N— (3-phenylpropionyl) 1 N— [2, 1 (1H-tetrazol-5-yl) biphenyl 4-ylmethyl] amino} benzoic acid (Example 1), 3-{ N-Pentinole N- [41 (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl} amino} benzoic acid (Example 6),

1— [4- (2,4-Dioxo-1,3-thiazolidine-1-yl) benzyl] — 2-Methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (Example 7) ,

5— [4 -1 (N-methylsulphonyl-N-phenenoleaminomethinole) feninole] 1,1,3-thiazolidine 1,2,4-dione (Example 8),

5- [4- (N-Peptinolesnorehoninore N-Pheninoleaminomethinole) Pheninole] ― 1,3-Thiazolidine-1,2,4-dione (Example 9),

3— {N— [4 (2,4-Dioxo-1,3-thiazolidine-5-inole) benzil] 1 N— (methylsulfonyl) amino} benzoic acid (Example 10),

3— {N-Ptylsulfonyl-N— [4- (2, 4-Dioxo-1,3-thiazolyzine-5-yl) benzyl] amino) Benzoic acid (Example 11)

5- {4— [2— (2-Pyridyl) benzimidazole 1-ylmethyl] fe: ^ l} — 1,3-thiazolidine_2,4-dione (Example 15),

5- [4- (2-phenylimidazole 1-ylmethyl) phenyl]-1, 3 -thiazolidine 1 2, 4-dione (Example 16),

3— {N—cyclohexane strength sulfonyl 1 N— [4 1 (2,4-dioxo 1,3 1 thiazolidine 1 5 —inole) benzyl] amino} benzoic acid (Example 18), 3— {N— [4 (2,4-Dioxo1,3-thiazolidine- 1f) benzyl] -N- (pyridine-1-3-carbonyl) amino} benzoic acid (Example 1 9), 3— {N— [4- (2,4-Dioxo1,3-thiazolidine-1,5- ^ f) benzyl] -N— (3-phenylpropionyl / le) amino) Benzoic acid (Example 20), 3-— N— (Bihuenil 4 1-canoleponyl) 1 N— [4 1 (2,4-Dioxo 1, 3-thiazolidine 1-yl) benzyl] amino} benzoic acid (Example 21), 3— {N— ( Phenylsulfonyl) -N- [4- (2,4-dioxo-1,3-thiazolidine-1-yl) benzyl] amino} benzoic acid (Example 22), 3- {N- (4-methylthio) Enylsulfonyl) 1N— [4- (2, 4-dioxo-1,1,3-thiazolidine-1-5-benzyl) amino) benzoic acid (Example 23), 3-{N- ( Bifunenole 4-Snolehonore) -N- [4- (2, 4-Dioxo-1,3-thiazolidine-1-5-inole) benzenole] amino} benzoic acid (Example 24), 3- {N- (2-naphthylsulfonyl) ) 1 N— [4 1 (2,4-Dioxo1,3-thiazolidine 1-yl) benzyl] amino} benzoic acid (Example 25), 3— {N— (benzylsulfonyl) 1 N— [4 1 (2,4-Dioxo-1,3-thiazolidine-5-yl) benzyl] amino} benzoic acid (Example 26), 1- [4 (1,4-Dioxo-1,3-thiazolidine-1-5- B) benzyl] —2-oxo-1-3-propyl-1, 2,3-1 H-indole-6-carboxylic acid (Example 27),

1 1 [4 1 (2, 4-Dioxo-1, 3-thiazolidine 1-yl) Benzyl] 1 2-Oxo 3-Propyl 2, 3, 4, 5-Tetrahydro 1H-benzo [b] azepine 1-8-norebonic acid (Example 28),

3,3-Dimethyl 1— [4τ (2,4-Dioxo 1,3-Thiazolidine 1-5-yl) Benzyl] —2-Oxo 1,2,3,4-Tetrahydroquinoline 1-Canoleponic acid Example 29), 1, 1 [4- (2, 4-Dioxo-1,3-Thiazolidine-5-yl) benzyl] —2, 1, oxo 1 ', 4, Dihydro 2, H-spiro [Cyclopropane 1 , 3, monoquinoline] —7 '—force norevonic acid (Example 30),

3— {N—phenethyl-N— [2,1 (1H—tetrazonolone-5- ^ fnore) biphenol, 2-ru-4-ylmethyl] amino} benzoic acid (Example 32),

3— {N— [4— (2, 4—Dioxo 1, 3, 3 thiazolidine 1 5-inole) Ben Ginole] 1 N— [(5-Methinore 1—Fueninore 1, 3-Oxazonore 1—4-Inole) Acetyl] amino} benzoic acid (Example 33),

3— {N- (3-Cyclohexylpropanoyl) 1 N— [2, ― (1H—Tetrazonol 1-5-yl) Biphenyl 2-4-ylmethinole} Amino} Benzoic acid (Example 3 6 ),

3— {N- (2-oxo-2-enylethyl) 1 N— [2,1 (1H-tetrazol-5-yl) biphenyl 4-1-methyl] amino} benzoic acid (Example 4 2),

3— {N— [4— (2, 4-Dioxo-1,3, thiazolidine-5-yl) benzil] 1 N— [4- (2-methylthiazole-4-yl) benzenesulfonyl] amino} Benzoic acid (Example 63), and

3— {N— (Bifenienore 4 1-inolemethinole) 1 N— [4 1 (2,4-Dioxo1,3-thiazolidine 1-yl) benzyl] amino} benzoic acid (Example 68) The compound according to claim 1, or a pharmacologically acceptable salt or esterole thereof.

1 1. A medicament comprising the compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt or ester thereof.

1 2. A pharmaceutical composition for preventing or treating renal disorder, cerebral metabolic disorder or cardiovascular disease, comprising the compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt or ester thereof. object.

1 3. Cardiovascular disease is myocardial infarction, cardiac hypertrophy, heart failure, arteriosclerosis, coronary artery disease, peripheral circulation disorder, cerebrovascular disorder, hypertension, systolic hypertension or restenosis after angioplasty The pharmaceutical composition according to claim 12.

14. The pharmaceutical composition according to claim 12, wherein the renal disorder is nephritis, nephropathy, nephrosclerosis or renal failure.

15. The pharmaceutical composition according to claim 12, wherein the cerebral metabolic disorder is Alzheimer's disease or Parkinson's disease.

16. A pharmaceutical composition for preventing or treating diabetic complications, comprising the compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt or ester thereof.

1 7. The pharmaceutical composition according to claim 16, wherein the diabetic complication is nephropathy, retinopathy, cataract, neuropathy, microvascular disorder or skin disorder.

1 8. The pharmaceutical composition according to claim 16, wherein the diabetic complication is nephropathy.

19. A pharmaceutical composition for preventing or treating dialysis amyloidosis, comprising the compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt or ester thereof.

20. A pharmaceutical composition for preventing or treating a disease caused by old age, comprising the compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt or ester thereof.

21. The pharmaceutical composition according to claim 20, wherein the disease caused by aging is senile cataract.

2 2. An agent for inhibiting AGE production comprising the compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt or ester thereof.

2 3. Claims 1 to 1 for the manufacture of a medicament for the prevention or treatment of diseases caused by renal disorders, cerebral metabolic disorders, cardiovascular diseases, diabetic complications, dialysis amyloidosis or geriatric diseases Use of the compound according to any one of 0 or a pharmacologically acceptable salt or ester thereof.

24. Use of the compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt or ester thereof for the manufacture of a medicament for the prevention or treatment of diabetic nephropathy.

25. Renal disorder, cerebral metabolic disorder, cardiovascular administration, wherein a pharmacologically effective amount of the compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt or ester thereof is administered to a warm-blooded animal For the prevention or treatment of system diseases, diabetic complications, dialysis amyloidosis or diseases caused by aging.

26. A method for preventing or treating diabetic nephropathy, comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt or ester thereof. .