HK1118279A

HK1118279A - Benzoimidazole compound capable of inhibiting prostaglandin d synthetase

Info

Publication number: HK1118279A
Application number: HK08109418.7A
Authority: HK
Inventors: 良博里出; 由起田中; 敬子山根; 三千纪土河
Original assignee: 大鹏药品工业株式会社
Priority date: 2005-07-13
Filing date: 2006-07-12
Publication date: 2009-02-06

Description

Benzimidazole compounds for inhibiting prostaglandin D synthase

Technical Field

The present invention relates to a medicine containing a benzimidazole compound or a salt thereof as an active ingredient, and more particularly to a medicine containing a novel benzimidazole compound or a salt thereof as an active ingredient, which is useful as a prophylactic and/or therapeutic agent for allergic diseases and inflammatory diseases, or an inhibitor of the progression of alzheimer's disease or brain injury due to the prostaglandin D synthase inhibitory action.

Background

A series of lipid mediators, collectively known as eicosanoids (eicosanoids), such as prostaglandins and leukotrienes, are synthesized by an arachidonic acid cascade starting from arachidonic acid cleaved from membrane phospholipids with various stimuli. In particular, prostanoids are arachidonic acid metabolites synthesized in the arachidonic acid cascade as intermediates for prostaglandin H2 produced by the enzyme cyclooxygenase. It is known that prostaglandin D2, prostaglandin E2, prostaglandin F2 α, prostaglandin I2, thromboxane a2 and the like can also be synthesized by such a synthetic route.

Prostaglandins act as locally active hormone-like chemical transmitters and are generally synthesized in response to local tissue damage, stimulation by hormones, bacterial peptides, antigens, and stimulation by inflammatory mediators such as cytokines. The prostaglandins produced exhibit various effects in many tissues by binding to specific receptors expressed on the cell surface, and are known to exert an influence on many inflammatory responses and immune system functions in addition to the in vivo function-regulating actions such as gastric acid secretion and blood flow.

The synthase that produces prostaglandin D2 is called prostaglandin D synthase, and there are known two types of hematopoietic synthase and Lipocalin-type synthase.

Human hematopoietic synthetases are distributed mainly in the placenta, lung, fetal liver, lymph nodes, brain, heart, thymus, bone marrow and spleen. In addition, at the cellular level, it is reported that it is in the brain of microglia, bone marrow megakaryocytes and skin of Langerhans cells; kupffer cells of liver; macrophages; dendritic cells, and various antigen-presenting cells, mast cells, and Th2 cells.

On the other hand, Lipocalin-type synthetases are distributed in large amounts mainly in the central nervous system, heart, testicular epithelium, and testis of the brain and spinal cord, and it is known that prostaglandin D2 produced by Lipocalin-type synthetases not only has a function as a substance for regulating body fluid in sleep, a function for regulating brain nervous system by arachnoid, a function for regulating pain sensation such as tenderness, and a function for regulating sperm formation, but also has a function as a transporter for a fat-soluble low-molecular compound.

Specific receptors for prostaglandin D2 are known to be both DP1 and DP2 (sometimes also referred to as CRTH 2). It has been reported that DP1 is expressed in tissues such as bone marrow, brain, retina, digestive organs, respiratory epithelial cells, vascular smooth muscle, platelets, basophils, etc., and DP2 is expressed in tissues such as bone marrow, brain, thymus, heart, etc., TH2 cells, eosinophils, basophils, monocytes, etc. Prostaglandin D2 produced locally mainly by hematopoietic synthase due to various stimuli exhibits platelet aggregation inhibitory action, vasodilation, vascular permeability-enhancing action, mucus production-increasing action, airway smooth muscle contraction, mobilization and activation of antigen-presenting cells, Th2 cells, eosinophils, and the like by binding to the above receptors, and is considered to be involved in the onset and exacerbation of allergic diseases and inflammatory diseases in particular.

In allergic diseases such as bronchial asthma, allergic rhinitis and the like, arachidonic acid cascade is activated mainly in mast cells activated by binding of antigen to immunoglobulin E complex to release various inflammatory mediators, and is considered to have an important role in causing allergic symptoms. Among them, prostaglandin D2 is an inflammatory mediator produced and released in the largest amount, and is detected at a high concentration in bronchoalveolar lavage fluid of asthmatic patients (non-patent documents 1 and 2). In addition, it has been reported that asthma patients observed airway constriction due to inhalation of prostaglandin D2, as compared with healthy persons (non-patent document 3). In addition, under the nasal mucosa of allergic rhinitis patients or in nasal polyps of chronic paranasal rhinitis patients, expression of hematopoietic synthase in mast cells or inflammatory cells is high, and DP1 and DP2 are expressed in infiltrated eosinophils, DP2 is expressed in T cells (non-patent document 4), and DP2 positivity of skin lymphocyte homing antigen positive Cells (CLA) according to the severity of atopic dermatitis patients is high (non-patent document 5), whereby it is considered that prostaglandin D2 derived from hematopoietic synthase plays an important role in onset and exacerbation of allergic diseases (non-patent documents 6 to 8).

In recent years, it has been reported that allergy is promoted in mice overexpressing prostaglandin D synthase (non-patent document 9), whereas allergy is not shown in mice in which prostaglandin D2 receptor is knocked out (non-patent document 10). In addition, it has been reported that in the mice deficient in hematopoietic synthase, the enlargement of muscle necrosis or traumatic brain injury is slight.

Therefore, prostaglandin D2 produced by both enzymes, i.e., hematopoietic synthase and Lipocalin synthase, functions as a factor responsible for the onset and progression of various diseases including allergic diseases and is involved in vivo regulation mechanisms, and therefore, a drug for ameliorating abnormal production thereof is considered to be extremely effective as a drug for various diseases.

For example, HQL-79 (4-benzhydryloxy-1- {3- (1H-tetrazol-5-yl) -propyl } piperidine) (non-patent documents 11 and 12) has been reported as an inhibitor of hematopoietic synthase. HQL-79 is a compound having both antagonist effects of histamine H1, and has been reported to inhibit respiratory inflammatory conditions such as eosinophil infiltration of the respiratory tract and delayed asthmatic response in asthma disease models, but its activity cannot be said to be sufficient. In addition, it has been disclosed to provide other prostaglandin D synthase inhibitors (patent documents 8 and 9), and the enzyme inhibitory activity exceeds HQL-79, but the activity cannot be said to be sufficient.

Conventionally, as antiallergic agents to be used for the prevention or treatment of allergic diseases, an antihistamine, a chemical mediator release inhibitor, a leukotriene receptor antagonist, a thromboxane a2 synthesis inhibitor and receptor antagonist, a Th2 cytokine inhibitor, an immunosuppressant, and the like have been used (non-patent document 13). However, these antiallergic agents have insufficient drug efficacy, and have problems such as central side effects such as sleepiness and sedation symptoms, digestive organ symptoms such as diarrhea, or side effects such as immunosuppression, and are not easy-to-use agents. In addition, although steroid drugs have strong anti-inflammatory action and are therefore useful as drugs for the treatment of not only allergic diseases but also many inflammatory diseases, they are not easy to use because of their susceptibility to infection, side effects such as bone affection and growth disorders, or rebound phenomenon after withdrawal.

On the other hand, inhibitors of prostaglandin D synthase are expected to be useful as drugs for preventing and/or treating allergic diseases or inflammatory diseases involving prostaglandin D2 produced by hematopoietic synthase or metabolites thereof.

Conventionally, benzimidazole compounds have been widely studied as compounds useful for medicines and the like.

For example, patent document 1 (international publication No. WO 2004017963) describes a wide range of benzimidazole compounds including 5-phenoxybenzimidazole compounds as a factor Xa inhibitor.

Patent document 2 (Japanese patent application laid-open No. 2004-067629) describes a 5-phenoxybenzimidazole compound and a 5-benzoylbenzimidazole compound as activators of mitochondrial function.

Patent document 3 (international publication No. WO 2003035065) describes a wide range of benzimidazole compounds including 5-phenoxybenzimidazole compounds and 5-benzoylbenzimidazole compounds as protein kinase inhibitors.

Patent document 4 (Japanese patent application laid-open No. 2001-515482) describes 5-phenoxybenzimidazole compounds and 5-benzoylbenzimidazole compounds as FBP enzyme inhibitors.

Patent document 5 (International publication WO 2002076454) describes 5-phenoxybenzimidazole compounds and 5-benzoylbenzimidazole compounds as pharmaceutical applications for antitumor agents.

Patent document 6 (jp 2000 a-026430) describes a 5-phenoxybenzimidazole compound, and a pyridyl group, a furyl group, and a thienyl group are described as substituents at the 2-position of benzimidazole.

Patent document 7 (international publication No. WO 9965886) discloses a 5-benzoylbenzimidazole compound as an insect/mite repellent, and a thiazolyl group as a heterocyclic ring as a substituent at the 2-position of benzimidazole.

Patent document 1: international publication WO2004017963

Patent document 2: japanese laid-open patent publication No. 2004-067629

Patent document 3: international publication WO2003035065

Patent document 4: japanese Kohyo publication No. 2001-515482

Patent document 5: international publication WO2002076454

Patent document 6: japanese laid-open patent publication No. 2000-026430

Patent document 7: international publication WO9965886

Patent document 8: japanese laid-open patent publication No. 2004-2248

Patent document 9: japanese patent laid-open publication No. 2004-51600

Non-patent document 1: J.Immumol., 129, 1627-

Non-patent document 2: N.Eng.J.Med., 315, 800-

Non-patent document 3: n.eng.j.med., 311, 209-213(1984)

Non-patent document 4: prostagladins & other Lipid Med.73, 87-101(2004)

Non-patent document 5: J.invest.Dermatol.119, 609-

Non-patent document 6: j. Immunol., 143, 2982-2989(1989)

Non-patent document 7: j.biol.chem., 265, 371-

Non-patent document 8: j.biol.chem., 270, 3239-

Non-patent document 9: immunol., 168, 443-449(2002)

Non-patent document 10: science, 287, 2013-2017(2000)

Non-patent document 11: Jpn.J. Pharmacol, 78, 1-10(1998)

Non-patent document 12: Jpn.J. Pharmacol, 78, 11-22(1998)

Non-patent document 13: "clinic and research", vol 79, 2 nd phase, 30-33 pages (2002, 2 months)

Disclosure of Invention

The main object of the present invention is to provide a novel compound having a high inhibitory effect on prostaglandin D synthase, particularly hematopoietic prostaglandin D synthase, at a low dose.

Another object of the present invention is to provide a pharmaceutical agent which is effective for the prevention and treatment of diseases mediated by prostaglandin D2 or its metabolites derived from the enzyme, has fewer side effects, and is highly safe, based on the prostaglandin D synthase inhibitory activity.

The present inventors have conducted extensive and intensive studies on a compound having an inhibitory activity against prostaglandin D synthase, and have found that a novel benzimidazole compound represented by the following general formula (I) or a salt thereof has an extremely excellent inhibitory activity against prostaglandin D synthase, and have further conducted extensive and intensive studies, thereby completing the present invention.

That is, the present invention provides a novel benzimidazole compound represented by the following general formula (I) or a salt thereof, a prostaglandin D synthase inhibitor containing the compound as an active ingredient, a method for preventing or treating a disease in which prostaglandin D2 or a metabolite thereof is involved, and the like.

Item 1: a benzimidazole compound represented by the following general formula (I) or a salt thereof,

in the formula, X¹Represents an oxygen atom or a carbonyl group, R¹Represents a furan ring having 1 to 3 substituents or may have 1 to 3 substituentsA pyrrole ring of group; provided that the compound represented by the general formula (I) wherein the substituent is a phosphoric acid group or a phosphate group is excluded.

Item 2: the benzimidazole compound or a salt thereof according to the above item 1, wherein X¹Is a carbonyl group.

Item 3: the benzimidazole compound or a salt thereof according to the above item 1, wherein X¹Represents an oxygen atom or a carbonyl group;

R¹represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents;

the substituent on the pyrrole ring or furan ring is selected from the group consisting of a halogen atom, a cyano group, a nitro group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, a cycloalkyl group having 3 to 7 carbon atoms which may have a substituent, an alkenyl group having 2 to 6 carbon atoms which may have a substituent, and — (C ═ O) — R²A group consisting of;

R²represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, or-NR³R⁴A group;

R³and R⁴Each of which is the same or different and represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, an amino group, a mono-or di- (C1-C6 alkyl) amino group which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent, or a saturated or unsaturated heterocyclic group which may have a substituent, or

R³And R⁴A saturated or unsaturated cyclic amino group which may form a ring structure together with an adjacent nitrogen atom and may have one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom, and the cyclic amino group may have a substituent.

Item 4: the benzimidazole of item 1 aboveAn azole compound or a salt thereof, wherein X¹Represents a carbonyl group, and represents a carbonyl group,

the substituent on the pyrrole ring or furan ring is halogen atom, cyano, nitro, and may have a structure selected from the group consisting of halogen atom, hydroxy and-NR^3’R^4’An alkyl group having 1 to 6 carbon atoms in which 1 to 3 groups in the group of groups are substituents, an alkenyl group having 2 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of a cyano group, a carboxyl group and a (C1-C6 alkoxy) carbonyl group as substituents, or- (C ═ O) -R²A group;

R²represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or-NR³R⁴A group;

R^3’and R^4’Each of which is the same or different and represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or

R^3’And R^4’A saturated or unsaturated cyclic amino group which may form a ring structure together with an adjacent nitrogen atom and may have one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, a cyano group, a mono-or di (C1-C6 alkyl) amino group which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent, or a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent, or

R³And R⁴May form a ring structure together with an adjacent nitrogen atom, and may have a structure selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atomA saturated or unsaturated cyclic amino group of one heteroatom in the group consisting of subgroups, the cyclic amino group may have 1 to 3 groups selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, a formyl group, a carboxyl group, an alkyl group of 1 to 6 carbon atoms which may have a substituent, an aryl group of 6 to 14 carbon atoms which may have a substituent, a (C1-C6 alkoxy) carbonyl group which may have a substituent, and a mono-or di (C1-C6 alkyl) aminocarbonyl group which may have a substituent as a substituent.

Item 5: the benzimidazole compound or a salt thereof according to the above item 1, wherein X¹Represents a carbonyl group;

R¹represents a furan ring having 1 to 3 substituents or a pyrrole ring having 1 to 3 substituents and hydrogen bonded to a nitrogen atom;

the substituent bonded to the pyrrole ring or furan ring is selected from the group consisting of a halogen atom, a cyano group, a nitro group, an alkyl group having 1 to 6 carbon atoms which may have a group selected from the group consisting of a halogen atom, a hydroxyl group, a dimethylamino group and a pyrrolidinyl group as a substituent, a vinyl group which may have 1 group selected from the group consisting of a cyano group, a carboxyl group and a (C1-C6 alkoxy) carbonyl group as a substituent, and- (C ═ O) -R²A group consisting of;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms which may have a substituent, an alkoxy group having 1 to 3 carbon atoms which may have a substituent, a phenyl group which may have a substituent, or a heterocyclic group [ the heterocyclic group may have a substituent ] selected from the group consisting of a morpholino group, an isoxazolyl group, an indolyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group and a benzothiazolyl group]Or is or

R³And R⁴May be combined with adjacent nitrogen atomsA saturated or unsaturated cyclic amino group which may have one hetero atom selected from a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure.

Item 6: the benzimidazole compound or a salt thereof according to the above item 1, wherein X¹Represents a carbonyl group;

R¹represents a furan ring having 2 or 3 substituents or a pyrrole ring having 2 or 3 substituents and hydrogen atoms bonded to a nitrogen atom, wherein the substituents on 2 carbon atoms constituting the furan ring and the pyrrole ring are alkyl groups having 1 to 6 carbon atoms, and the remaining 1 carbon atom is bonded with a hydrogen atom, or a cyano group or- (C ═ O) -R²As a substituent;

R²represents a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, or-NR³R⁴A group;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms which may have a substituent, an alkoxy group having 1 to 3 carbon atoms which may have a substituent, a phenyl group, a morpholino group, an isoxazolyl group, an indolyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group, or a benzothiazolyl group which may have 1 to 3 groups as substituents selected from the group consisting of a halogen atom, a cyano group, and an alkoxy group having 1 to 6 carbon atoms, or

-NR³R⁴The group represents pyrrolidinyl, thiazolidinyl, pyrazolinyl, morpholino or piperazinyl.

Item 7: the benzimidazole compound or a salt thereof according to the above item 1, wherein X¹Represents a carbonyl group;

R¹represents a furan ring having 3 substituents and bonded to the benzimidazole ring at the 4-position, or an azole ring having 3 substituents and bonded to the benzimidazole ring at the 4-position, wherein a hydrogen atom is bonded to a nitrogen atom,

among the substituents on the furan ring and the pyrrole ring, the substituents at the 3-position and the 5-position represent an alkyl group having 1 to 3 carbon atoms, and the substituent at the 2-position represents a cyano group or- (C ═ O) -R²A group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other represents a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms which may have a substituent, an alkoxy group having 1 to 3 carbon atoms which may have a substituent, or a phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom, a cyano group and an alkoxy group having 1 to 3 carbon atoms as substituents, or

-NR³R⁴The group represents a pyrrolidinyl group, a pyrazolinyl group or a morpholino group.

Item 8: the benzimidazole compound or a salt thereof according to the above item 1, wherein X¹Represents a carbonyl group;

R¹represents a pyrrole ring having 3 substituents and having a hydrogen atom bonded to a nitrogen atom and bonded to a benzimidazole ring at the 4-position,

among the substituents on the pyrrole ring, the substituents at the 3-and 5-positions represent methyl groups, and the substituent at the 2-position represents- (C ═ O) -R²A group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other represents an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms which may have a substituent, or

-NR³R⁴The group represents a pyrrolidinyl group or a morpholino group.

Item 9: the benzimidazole compound or a salt thereof according to item 1 above, which is:

(4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethyl-2-furylcarbonyl) pyrrolidine,

4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid,

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole,

N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide,

(N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide,

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide,

N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide,

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) morpholine,

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) pyrazoline, or

(N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide.

Item 10: a pharmaceutical composition comprising an effective amount of at least one of the compounds according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 11: a prostaglandin D synthase inhibitor comprising an effective amount of at least one of the compounds described in any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 12: a prophylactic and/or therapeutic agent for a disease in which prostaglandin D2 or a metabolite thereof is involved, which comprises an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 13: the prophylactic and/or therapeutic agent according to item 12 above, wherein the disease in which prostaglandin D2 or a metabolite thereof is involved is any one of an allergic disease, an inflammatory disease, Alzheimer's disease, and brain injury.

Item 14: a prophylactic and/or therapeutic agent for allergic diseases, which comprises an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 15: a prophylactic and/or therapeutic agent for an inflammatory disease, which comprises an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 16: an agent for preventing and/or treating Alzheimer's disease or brain injury, which comprises an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Item 17: a method for preventing or treating a disease in which prostaglandin D2 or a metabolite thereof is involved, which comprises administering an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof to a patient.

Item 18: use of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof for producing a prostaglandin D synthase inhibitor.

Effects of the invention

The present invention provides a novel benzimidazole compound represented by the general formula (I) or a salt thereof, which is useful as a prostaglandin D synthase inhibitor, particularly, a hematopoietic synthase inhibitor.

The benzimidazole compound or a salt thereof of the present invention has an excellent inhibitory activity on prostaglandin D synthase, for example, a more excellent inhibitory activity on hematopoietic prostaglandin D synthase than HQL-79, which is a conventionally known hematopoietic synthase inhibitor (see experimental example 1 described later).

Therefore, the benzimidazole compound or a salt thereof of the present invention is useful as a prophylactic and/or therapeutic agent for diseases in which prostaglandin D2 or a metabolite thereof is involved, for example, allergic diseases or inflammatory diseases, or a deterioration inhibitor for alzheimer disease or brain injury, based on its excellent prostaglandin D synthase inhibitory activity, and other useful pharmaceutical effects can be expected.

Detailed Description

Benzimidazole compounds of the present invention

The benzimidazole compound of the present invention is a compound represented by the following general formula (I).

(in the formula, X¹Represents an oxygen atom or a carbonyl group, R¹Represents a furan ring having a substituent or an azole ring which may have a substituent. In particular, R¹Represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents. Provided that the compound represented by the general formula (I) wherein the substituent is a phosphoric group or a phosphate group is excluded

The benzimidazole compounds represented by the above general formula (I) of the present invention are novel compounds and are not specifically disclosed in the above prior art documents.

For example, patent document 1 (international publication No. WO 200417963) describes a wide range of benzimidazole compounds including 5-phenoxybenzimidazole compounds as a factor Xa inhibitor. However, the benzimidazole compound of the present invention having a pyrrole ring and a furan ring as a substituent at the 2-position of benzimidazole is not specifically disclosed.

Further, patent document 2 (Japanese patent application laid-open No. 2004-067629) describes a 5-phenoxybenzimidazole compound and a 5-benzoylbenzimidazole compound as activators of mitochondrial function. However, the compounds disclosed in this patent have a phenyl group, a pyridyl group, etc. as a substituent at the 2-position of benzimidazole, unlike the compounds of the present invention having a pyrrole ring and a furan ring as substituents at the 2-position of benzimidazole.

Patent document 3 (international publication No. WO 2003035065) describes a wide range of benzimidazole compounds including 5-phenoxybenzimidazole compounds and 5-benzoylbenzimidazole compounds as protein kinase inhibitors. However, the benzimidazole compound of the present invention having a pyrrole ring and a furan ring as a substituent at the 2-position of benzimidazole is not specifically disclosed.

Patent document 4 (Japanese patent application laid-open No. 2001-515482) describes 5-phenoxybenzimidazole compounds and 5-benzoylbenzimidazole compounds as FBP enzyme inhibitors. However, this patent compound has a phosphate group or a phosphate group as a substituent on the furyl group at the 2-position of benzimidazole, which is different from the compound of the present invention.

Patent document 5 (International publication WO 2002076454) describes 5-phenoxybenzimidazole compounds and 5-benzoylbenzimidazole compounds as pharmaceutical applications for antitumor agents. However, the benzimidazole compound of the present invention having a pyrrole ring and a furan ring as a substituent at the 2-position of benzimidazole is not specifically disclosed.

Patent document 6 (Japanese patent application laid-open No. 2000-026430) describes a 5-phenoxybenzimidazole compound and claims a pyridyl group, a furyl group, and a thienyl group as substituents at the 2-position of imidazole. However, this patent compound has a substituent at the 6-position of benzimidazole and is different from the compound of the present invention having no substituent at the same 6-position.

Patent document 7 (international publication No. WO 9965886) describes a 5-benzoylbenzimidazole compound as an insect/mite repellent, and discloses a thiazolyl group as a heterocyclic ring of a 2-position substituent of imidazole, which is different from the compound of the present invention having a pyrrole ring and a furan ring as a 2-position substituent of benzimidazole.

The compounds represented by the general formula (I) are further described below.

Among the compounds of the present invention, X is preferred¹A compound (I) which is a carbonyl group.

Further, the compound of the present invention is typically a benzimidazole compound represented by the general formula (I) wherein:

X¹represents an oxygen atom or a carbonyl group,

Specifically, as the compound of one embodiment of the present invention, a benzimidazole compound represented by the general formula (I) wherein:

X¹represents a carbonyl group, and represents a carbonyl group,

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other is a hydrogen atom, a hydroxyl group, or a group havingAn alkyl group having 1 to 6 carbon atoms which may have a substituent, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, a cyano group, a mono-or di (C1-C6 alkyl) amino group which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent, or a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent, or

R³And R⁴A saturated or unsaturated cyclic amino group which may have one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in a ring structure in addition to the adjacent nitrogen atom, and the cyclic amino group may have 1 to 3 groups selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, a formyl group, a carboxyl group, an alkyl group which may have a substituent, an aryl group which may have a carbon number of 6 to 14, an alkoxycarbonyl group which may have a carbon number of 1 to 6 and a mono-or di (C1-C6 alkyl) aminocarbonyl group which may have a substituent as a substituent.

In the present specification, the phrase "may have a substituent" means that 1 or 2 or more "substituents" may be present at a position on a structure which may be chemically substituted. In the present specification, the phrase "having a substituent" in a structure means that 1 or 2 or more "substituents" are provided at positions that can be chemically substituted in the structure.

The kind of the substituent(s) present (or may be present) in the structure, the number of the substituent(s), and the substitution position are not particularly limited, and when 2 or more substituents are present, they may be the same or different. Examples of the "substituent" include: halogen atom, hydroxyl group, cyano group, nitro group, alkyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, alkenyl group having 2 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, - (C ═ O) -R²Radical, -NR³R⁴Radical, -NR^3’R^4’An oxo group, a saturated or unsaturated heterocyclic group, an aryl group having 6 to 14 carbon atoms, and the like, and when the above-mentioned substituents are present, the number thereof is typically 1 to 3.

Examples of the "halogen atom" include: fluorine atom, chlorine atom, bromine atom, iodine atom.

The "alkyl group having 1 to 6 carbon atoms" represents a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like.

Examples of the "cycloalkyl group having 3 to 7 carbon atoms" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

Examples of the "alkenyl group having 2 to 6 carbon atoms" include: vinyl, allyl, butenyl, butadienyl, hexatrienyl, and the like.

The "alkoxy group having 1 to 6 carbon atoms" represents a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexoxy, and the like.

As "- (C ═ O) -R²R in the radical²Examples thereof include: hydrogen atom, hydroxyl group, alkyl group having 1 to 6 carbon atoms, alkoxy group having 1 to 6 carbon atoms, -NR³R⁴A saturated or unsaturated heterocyclic group, an aryl group having 6 to 14 carbon atoms, and the like.

As an "-NR³R⁴Radical 'and' -NR^3’R^4’R in the radical³、R⁴、R^3’And R^4’Each of which may be the same or different, and examples thereof include: a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an amino group, a mono-or di (C1-C6 alkyl) amino group, a (C1-C6 alkoxy) carbonyl group, a mono-or di (C1-C6 alkyl) aminocarbonyl group, a saturated or unsaturated heterocyclic group, an aryl group having 6 to 14 carbon atoms, and the like.

In addition, the "-NR³R⁴Radical 'and' -NR^3’R^4’Each of the groups "may form a saturated or unsaturated cyclic amino group (particularly, a 5-or 6-membered saturated or unsaturated cyclic amino group which may have one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom is formed together with the adjacent nitrogen atom), and examples thereof include: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, homopiperidinyl, imidazolyl, pyrrolyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolinyl, pyrazolinyl, pyrazolyl, triazolyl and the like.

Examples of the "saturated or unsaturated heterocyclic ring" include: pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, homopiperidinyl, imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolinyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 2, 3, 4, 5-tetrahydro-3-oxopyridazin-6-yl, and the like.

Examples of the "aryl group having 6 to 14 carbon atoms" include: phenyl, naphthyl, anthracenyl, and the like.

"Mono-or di (C1-C6 alkyl) amino" represents an amino group having as a substituent 1 or 2 linear or branched alkyl groups of 1 to 6 carbon atoms, and examples thereof include: methylamino, ethylamino, n-propylamino, n-hexylamino, dimethylamino, methylethylamino, ethylisobutylamino and the like.

Examples of "(C1-C6 alkyl) carbonyl" include: acetyl, propionyl, butyryl, and the like.

Examples of "(C1-C6 alkoxy) carbonyl" include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, n-hexyloxycarbonyl and the like.

Examples of the "mono-or di (C1-C6 alkyl) aminocarbonyl group" include: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, neopentylaminocarbonyl, n-hexylaminocarbonyl, dimethylaminocarbonyl, methylethylaminocarbonyl, ethylisobutylaminocarbonyl, and the like.

In the general formula (I), as R¹The substituent that the furan ring or the pyrrole ring may have is exemplified by the above-mentioned substituents, but is preferably a halogen atom, a cyano group, a nitro group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or — (C ═ O) -R²The group [ the alkyl group, the cycloalkyl group and the alkenyl group may further have the above-mentioned substituent]More preferred is a halogen atom, a cyano group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or- (C ═ O) -R²The alkyl group may have a group selected from the group consisting of a halogen atom, a hydroxyl group and-NR^3’R^4’A substituent for the above-mentioned alkenyl group, which may have a substituent selected from the group consisting of a cyano group, a carboxyl group and a (C1-C6 alkoxy) carbonyl group]As R¹The substituent which the pyrrole ring may have or the substituent which the furan ring has are particularly preferably a cyano group, an alkyl group having 1 to 6 carbon atoms or- (C ═ O) -R²And (4) a base.

In the general formula (I), as R¹The substituent of the furan ring or the substituent "halogen atom" which the pyrrole ring may have may be exemplified by the above-mentioned halogen atoms, preferably fluorine atom, chlorine atom or bromine atom, and the number of the halogen atoms is typically 1.

In the general formula (I), as R¹The substituent which the furan ring has or the substituent which the pyrrole ring may have "a carbon atom which may have a substituentExamples of the "alkyl group having 1 to 6 carbon atoms" of the alkyl group having 1 to 6 carbon atoms "may include the above-mentioned alkyl groups, preferably alkyl groups having 1 to 3 carbon atoms, and more preferably methyl groups or ethyl groups. Examples of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" include the above-mentioned substituents, preferably a halogen atom, a hydroxyl group, a di (C1-C6 alkyl) amino group or a saturated or unsaturated heterocyclic group, more preferably a 5-or 6-membered heterocyclic ring having 1 nitrogen atom as a heteroatom in the ring structure such as a di (C1-C6 alkyl) amino group or a pyrrolidinyl group, and the number of the substituents is typically 1.

In the general formula (I), as R¹The "cycloalkyl group having 3 to 7 carbon atoms" of the "cycloalkyl group having 3 to 7 carbon atoms which may have a substituent" of the furan ring or the pyrrole ring represented above may be exemplified by the above-mentioned cycloalkyl groups, and a cyclopentyl group or a cyclohexyl group is preferable. Examples of the substituent of the "cycloalkyl group having 3 to 7 carbon atoms which may have a substituent" include the above-mentioned substituents, and the number of the substituents is typically 1.

In the general formula (I), the "alkenyl group having 2 to 6 carbon atoms" of the substituent which the furan ring or the substituent which the pyrrole ring may have "the alkenyl group having 2 to 6 carbon atoms which may have a substituent" may be exemplified by the above-mentioned alkenyl group, and preferably the vinyl group. Examples of the substituent of the "alkenyl group having 2 to 6 carbon atoms which may have a substituent" include the above-mentioned substituents, and preferably include 1 to 3 groups selected from the group consisting of a cyano group, a carboxyl group and a (C1-C6 alkoxy) carbonyl group, more preferably a cyano group, and the number of the substituents is typically 1.

In the general formula (I), as R²The "alkyl group having 1 to 6 carbon atoms" of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" may be exemplified by the above-mentioned alkyl groups, preferably alkyl groups having 1 to 3 carbon atoms, and more preferably methyl groups or ethyl groups. Examples of the substituent of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" include the above-mentioned substituents, and the number of the substituents is typically 1.

In the general formula (I), as R²The "alkoxy group having 1 to 6 carbon atoms" of the "alkoxy group having 1 to 6 carbon atoms which may have a substituent" may be exemplified by the above-mentioned alkoxy groups, preferably alkoxy groups having 1 to 3 carbon atoms, more preferably methoxy groups or ethoxy groups, and particularly preferably ethoxy groups. Examples of the substituent of the "alkoxy group having 1 to 6 carbon atoms which may have a substituent" include the above-mentioned substituents, and the number of the substituents is typically 1.

In the general formula (I), as R^3’And R^4’The "alkyl group having 1 to 6 carbon atoms" of the "alkyl group having 1 to 6 carbon atoms" may be exemplified by the above-mentioned alkyl groups, preferably alkyl groups having 1 to 3 carbon atoms, and more preferably methyl groups.

In the general formula (I), as-R^3’R^4’The "saturated or unsaturated cyclic amino group which may have one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring structure represented by the group, in addition to the adjacent nitrogen atom", includes, for example: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, homopiperidinyl, imidazolyl, pyrrolyl, cyclohexylimino, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl, pyrazolyl, triazolyl and the like, with pyrrolidinyl being preferred.

In the general formula (I), as R³And R⁴The "alkyl group having 1 to 6 carbon atoms" of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" may be exemplified by the above-mentioned alkyl groups, preferably alkyl groups having 1 to 3 carbon atoms, and more preferably methyl, ethyl or n-propyl. Examples of the substituent for the "alkyl group having 1 to 6 carbon atoms which may have a substituent" include the above-mentioned substituents, and preferred are a cycloalkyl group having 3 to 7 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a di (C1-C6 alkyl) amino group, (C1-C6 alkyl) carbonylamino group, (C1-C6 alkoxy) carbonyl group, a carboxyl group, and a saturated or unsaturated heterocyclic group (particularly, a saturated heterocyclic group having 1 or 2 nitrogen atoms in the ring structure)And or an unsaturated 5-or 6-membered heterocyclic group which may have 1 oxo group), a phenyl group having 1 or 2 groups selected from the group consisting of a halogen atom, an alkoxy group having 1 to 6 carbon atoms and a methylenedioxy group as substituents, more preferably a methoxy group, a dimethylamino group, an acetamido group, a methoxycarbonyl group, an ethoxycarbonyl group, a carboxyl group, a pyrrolidinyl group, a piperidinyl group, a pyridyl group, a methylenedioxyphenyl group, a dichlorophenyl group, a dimethoxyphenyl group, or a2, 3, 4, 5-tetrahydro-3-oxo-pyridazin-6-yl group, and the number of these substituents is typically 1.

In the general formula (I), as R³And R⁴The "alkoxy group having 1 to 6 carbon atoms" of the "alkoxy group having 1 to 6 carbon atoms which may have a substituent" may be exemplified by the above-mentioned alkoxy groups, and an alkoxy group having 1 to 3 carbon atoms is preferable. Examples of the substituent of the "alkoxy group having 1 to 6 carbon atoms which may have a substituent" include the above-mentioned substituents, and the number thereof is typically 1.

In the general formula (I), as R³And R⁴The "mono-or di (C1-C6 alkyl) amino group" of the "mono-or di (C1-C6 alkyl) amino group which may have a substituent(s)" may be exemplified by the above-mentioned mono-or di (C1-C6 alkyl) amino group. Examples of the substituent for the "mono-or di (C1-C6 alkyl) amino group which may have a substituent" include the above-mentioned substituents, and the number thereof is typically 1.

In the general formula (I), as R³And R⁴The "aryl group having 6 to 14 carbon atoms" of the "aryl group having 6 to 14 carbon atoms which may have a substituent" may be exemplified by the above-mentioned aryl groups, and a phenyl group is preferable. Examples of the substituent of the "aryl group having 6 to 14 carbon atoms which may have a substituent" include the above-mentioned substituents, preferably a halogen atom, a cyano group or an alkoxy group having 1 to 6 carbon atoms, more preferably a cyano group, the number of which is typically 1 to 3, particularly 1.

In the general formula (I), as R³And R⁴The "saturated or unsaturated hetero ring" of the "saturated or unsaturated hetero ring which may have substituents" mentionedExamples of the "ring" include the above-mentioned saturated or unsaturated heterocyclic ring, preferably monocyclic or bicyclic saturated or unsaturated heterocyclic ring, more preferably morpholino group, isoxazolyl group, indolyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, dihydrobenzofuranyl group and benzothiazolyl group. Examples of the substituent of the "saturated or unsaturated heterocyclic ring which may have a substituent" include the above-mentioned substituents, and the number thereof is typically 1 to 3.

In the general formula (I), as-NR³R⁴The "saturated or unsaturated cyclic amino group which may have one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure formed together with the adjacent nitrogen atom" as shown above includes, for example: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, homopiperidinyl, pyrrolidinyl, imidazolyl, pyrrolyl, cyclohexylimino, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl, pyrazolyl, triazolyl and the like, preferably a 5-or 6-membered saturated or unsaturated cyclic amino group which may have one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure together with the adjacent nitrogen atom, more preferably pyrrolidinyl, thiazolidinyl, pyrazolinyl, morpholino, piperazinyl, piperidinyl, further preferably pyrrolidinyl, pyrazolinyl or morpholino, particularly preferably pyrrolidinyl or morpholino.

In the general formula (I), as-NR³R⁴The "saturated or unsaturated cyclic amino group which may have one or two hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom" in the ring structure may be a substituent represented by the above-mentioned general formula, and the substituent is preferably (a) a halogen atom, (b) a hydroxyl group, (C) a cyano group, (d) a nitro group, (e) a formyl group, (f) a carboxyl group, (g) an alkyl group having 1 to 6 carbon atoms, (h) an aryl group having 6 to 14 carbon atoms, (i) (C1-C6 alkoxy) carbonyl group, or (j) a mono-or mono-6 alkoxy groupThe di (C1-C6 alkyl) aminocarbonyl group, the alkyl group (g), the aryl group (h), the (C1-C6 alkoxy) carbonyl group (i) and the mono-or di (C1-C6 alkyl) aminocarbonyl group (j) may further have the above-mentioned substituent. The number of the substituents which the saturated or unsaturated heterocyclic ring may have (particularly, the substituents (a) to (j) described above) is 1 to 2, particularly 1.

Examples of the "halogen atom" in the above-mentioned (a) include the halogen atoms mentioned above.

Examples of the "alkyl group having 1 to 6 carbon atoms" of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" in the above-mentioned (g) include the above-mentioned alkyl groups. Examples of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" include the above-mentioned substituents, and the number thereof is typically 1 to 3.

The "aryl group" of the "aryl group having 6 to 14 carbon atoms which may have a substituent" in the above-mentioned (h) may be exemplified by the above-mentioned aryl group, and a phenyl group is preferable. Examples of the substituent of the "aryl group having 6 to 14 carbon atoms which may have a substituent" include the above-mentioned substituents, and the number thereof is typically 1 to 3.

The "alkoxycarbonyl group having 1 to 6 carbon atoms" of the "optionally substituted (C1-C6 alkoxy) carbonyl group" of the above-mentioned (i) may be exemplified by the above-mentioned alkoxycarbonyl group, preferably an ethoxycarbonyl group. Examples of the substituent of the "optionally substituted (C1-C6 alkoxy) carbonyl group" include the above-mentioned substituents, and the number thereof is typically 1 to 3.

As the "mono-or di (C1-C6 alkyl) aminocarbonyl group which may have a substituent(s)" in the above-mentioned (j), the above-mentioned mono-or di (C1-C6 alkyl) aminocarbonyl group can be exemplified. Examples of the substituent for the "mono-or di (C1-C6 alkyl) aminocarbonyl group which may have a substituent(s)" may include the above-mentioned substituents, preferably di (C1-C6 alkyl) amino, alkoxy group having 1 to 6 carbon atoms, or cycloalkyl group having 3 to 7 carbon atoms, more preferably dimethylamino group, methoxy group or cyclohexyl group, and the number thereof is typically 1.

Among the compounds represented by the general formula (I) of the present invention, the following compounds are more preferable.

(A) In the general formula (I),

X¹represents a carbonyl group;

-NR³R⁴The group represents a pyrrolidinyl group, a thiazolidinyl group, a pyrazolinyl group, a morpholino group or a piperazinyl group.

(B) In the general formula (I),

X¹represents a carbonyl group;

the furan ring and the pyrrole ringIn the substituents (C) and (C), the substituents at the 3-and 5-positions represent an alkyl group having 1 to 3 carbon atoms, and the substituent at the 2-position represents a cyano group or- (C ═ O) -R²A group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

-NR³R⁴The group represents a pyrrolidinyl group, a pyrazolinyl group or a morpholino group, or a salt thereof.

(C) In the general formula (I),

X¹represents a carbonyl group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

-NR³R⁴The group represents a pyrrolidinyl group or a morpholino group, or a salt thereof.

Examples of the substituent of the "alkyl group having 1 to 3 carbon atoms which may have a substituent" in the above-mentioned (a) to (C) include an alkoxy group having 1 to 6 carbon atoms, a di (C1-C6 alkyl) amino group, an acetamido group, (C1-C6 alkoxy) carbonyl group, a carboxyl group, a saturated or unsaturated heterocyclic group [ preferably a saturated or unsaturated 5-or 6-membered heterocyclic ring having 1 or 2 nitrogen atoms in the ring structure (the heterocyclic ring may have 1 oxo group), more preferably a pyrrolidinyl group, a piperidinyl group, a pyridinyl group, a2, 3, 4, 5-tetrahydro-3-oxo-pyridazin-6-yl group ], a cycloalkyl group having 3 to 7 carbon atoms, or a phenyl group having 1 or 2 of any of a halogen atom and an alkoxy group having 1 to 6 carbon atoms as a substituent, and the number thereof is 1.

In the above (a) to (B), examples of the substituent of the "alkoxy group having 1 to 3 carbon atoms which may have a substituent" include the above-mentioned substituents, and the number thereof is typically 1.

Among the above-mentioned compounds (A) to (C), the following compounds (A ') to (C') can be specifically exemplified.

(A') in the general formula (I),

X¹represents a carbonyl group;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms which may have a substituent (the substituent of the alkyl group is an alkoxy group having 1 to 6 carbon atoms, a di (C1-C6 alkyl) amino group, an acetamido group, a (C1-C6 alkoxy) carbonyl group, a carboxyl group, or a group having 1 or 1 carbon atom in the ring structureA saturated or unsaturated 5-or 6-membered heterocycle having 2 nitrogen atoms (the heterocycle may have 1 oxo group), a cycloalkyl group having 3 to 7 carbon atoms, or a phenyl group having 1 or 2 substituents of a halogen atom and an alkoxy group having 1 to 6 carbon atoms), an alkoxy group having 1 to 3 carbon atoms, a phenyl group, a morpholino group, an isoxazolyl group, an indolyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group, or a benzothiazolyl group, which may have 1 to 3 groups selected from the group consisting of a halogen atom, a cyano group, and an alkoxy group having 1 to 6 carbon atoms as substituents, or

(B') in the general formula (I),

X¹represents a carbonyl group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 3 carbon atoms which may have a substituent (the substituent of the alkyl group is an alkoxy group having 1 to 6 carbon atoms, a di (C1-C6 alkyl) amino group, an acetamido group, a (C1-C6 alkoxy) carbonyl group, a carboxyl group, a pyrrolidinyl group, a piperidyl group, a pyridyl group, a2, 3, 4, 5-tetrahydro-3-oxo-pyridazin-6-yl group, a cycloalkyl group having 3 to 7 carbon atoms, or an alkoxy group having a halogen atom and 1 to 6 carbon atomsOr 2 phenyl groups as substituents), an alkoxy group having 1 to 3 carbon atoms, or a phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom, a cyano group, and an alkoxy group having 1 to 3 carbon atoms as substituents, or

(C') in the general formula (I),

X¹represents a carbonyl group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other represents an alkyl group having 1 to 3 carbon atoms which may have a substituent (the substituent of the alkyl group is an alkoxy group having 1 to 6 carbon atoms, a di (C1-C6 alkyl) amino group, an acetamido group, (C1-C6 alkoxy) carbonyl group, a carboxyl group, a pyrrolidinyl group, a piperidyl group, a pyridyl group, a2, 3, 4, 5-tetrahydro-3-oxo-pyridazin-6-yl group, a cycloalkyl group having 3 to 7 carbon atoms, or a phenyl group having 1 or 2 of a halogen atom and an alkoxy group having 1 to 6 carbon atoms as substituents), or an alkoxy group having 1 to 3 carbon atoms, or

(D) Among the compounds represented by the above general formula (I), the following specific compounds are particularly exemplified. In addition, numerals in parentheses after the names of the following compounds indicate numbers of the compounds obtained in examples described later.

4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (2)

(4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethyl-2-furylcarbonyl) pyrrolidine (3),

N- (3, 4-methylenedioxyphenyl) methyl-4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (4),

2- (2-formyl-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (8),

2- (2-cyanovinyl-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (9),

4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid (10),

N-methyl-N- (2-dimethylaminoethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (11),

4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (12),

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (13),

N- (methoxy) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (14),

(N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (15),

N- (3-methoxypropyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (16),

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (17),

N- (2-acetamidoethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (18),

N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (19),

N- (1-methoxycarbonylmethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (20),

N- (2-carboxyethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (21),

N- (1-carboxymethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (22),

N- (2-pyrrolidin-1-yl-ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (23),

N- (2-piperidin-1-yl-ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (24),

N- (cyclohexylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (25),

N- (5-methylisoxazol-3-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (26),

N- (4-cyanophenyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (27),

N- (indol-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (28),

N- (3, 4-methylenedioxyphenyl-1-yl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (29),

N- (2, 3-dihydrobenzofuran-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (30),

N- (benzothiazol-6-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (31),

N- (3, 4-ethylenedioxyphenyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (32),

N- (2-pyridylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (33),

N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (34),

N- (3, 4-dichlorobenzyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (35),

N- (3, 4-dimethoxybenzyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (36),

N- (3, 4-methylenedioxyphenylmethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (37),

N- (2, 3, 4, 5-tetrahydro-3-oxo-pyridazin-6-yl-methyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (38),

((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) pyrrolidine (39),

((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) morpholine (40),

((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-phenylpiperazine (41),

((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) pyrazoline (42),

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-hydroxypiperidine (43),

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-ethoxycarbonylpiperidine (44),

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxylic acid (45),

N-dimethylaminoethyl-1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (46),

N-methyl-N- (2-dimethylaminoethyl) -1- ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (47),

N- (3-dimethylaminopropyl) -1- ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (48),

N- (3-methoxypropyl) -1- ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (49),

N-cyclohexylmethyl-1- ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (50),

(N, N-dimethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (64),

(N-hydroxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (65),

(N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (66),

(N-hydroxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (67),

4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid ethyl ester (68),

4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid (69),

((4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) -2-carbonyl) pyrrolidine (70),

((4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) -2-carbonyl) morpholine (71),

N- (2- (2-pyridyl) ethyl) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (72),

N- (methoxy) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (73),

(N-methoxy-N-methyl) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (74),

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-phenoxybenzimidazole (75),

4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (76),

Or a salt thereof.

(E) Among the compounds represented by the general formula (I), the following compounds are particularly preferable.

(4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethyl-2-furylcarbonyl) pyrrolidine,

4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid,

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole,

(N, N-dimethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide,

Or a salt thereof.

In the compound (I) of the present invention, there may be a tautomer formed by the benzimidazole ring, an optical isomer formed by a chiral carbon when the chiral carbon exists, and other isomers, and the present invention also includes all the compounds obtained by separating these isomers, or a mixture thereof.

The compound (I) of the present invention also includes pharmacologically acceptable prodrugs. The pharmacologically acceptable prodrug is a compound having a functional group that can be converted into a functional group such as an amino group, a hydroxyl group, a carboxyl group, or a carbonyl group of the compound (I) as an active ingredient of the pharmaceutical composition of the present invention under chemical conditions such as solvolysis or physiological conditions. Representative functional groups for forming prodrugs include those described in "development of pharmaceuticals" (guang Chuan bookstore, 1990) volume 7, 163-198.

In addition, the compound (I) of the present invention may form an acid addition salt or a salt with a base, and the salt, particularly a pharmaceutically acceptable salt, is also included in the present invention. Specifically, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, and glutamic acid; with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, etc., organic bases such as methylamine, ethylamine, meglumine, ethanolamine, etc., or salts of basic amino acids such as lysine, arginine, ornithine, etc.; or an ammonium salt.

In addition, the present invention also encompasses various hydrates, solvates and polymorphs of the compound (I) of the present invention and a salt thereof.

Process for producing the Compound of the present invention

The compound represented by the general formula (I) can be produced, for example, by the following method.

[ method 1]

Reaction scheme 1

In the above reaction scheme 1, R⁵Represents the aforementioned R¹、X²Represents the aforementioned X¹(the same applies below).

The production method is a method for producing a compound represented by the general formula (I) by subjecting a diaminobenzene derivative represented by the formula (1a) or a salt thereof and an aldehyde derivative represented by the formula (1b) to a cyclization reaction by a conventional method.

The reaction may be carried out in the presence of 0.5 to 10 moles, preferably 0.8 to 2 moles, of the aldehyde derivative represented by the formula (1b) with respect to 1 mole of the diaminobenzene derivative represented by the formula (1a), in the presence of 0.5 to 10 moles, preferably 0.8 to 3 moles of sodium hydrogen sulfite, potassium ferricyanide, iron chloride-oxygen and the like, usually in a solvent inert to the reaction such as ethyl acetate, butyl acetate and the like, water, methanol, ethanol, isopropanol and the like, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine and the like, at 0 to 180 ℃, preferably 50 to 150 ℃.

The reaction may be carried out in a solvent such as an alcohol, nitrobenzene, polyphosphoric acid, or the like, in the presence of 0.5 to 10 mol, preferably 1 to 5 mol, of an organic acid such as formic acid, acetic acid, or the like, or an inorganic acid such as hydrochloric acid, sulfuric acid, or the like, relative to 1 mol of the diaminobenzene derivative represented by formula (1a), at 0 to 200 ℃, preferably 50 to 180 ℃.

The diaminobenzene derivative represented by the above formula (1a) is known or can be produced by a known method. The aldehyde derivative represented by the above formula (1b) is known or can be produced by a known method.

[ method 2]

Reaction scheme 2

The production method is a method comprising a first step of amidating a diaminobenzene derivative represented by the formula (1a) or a salt thereof with a carboxylic acid derivative represented by the formula (2b) or a reactive derivative thereof by a conventional method to obtain an amidobenzene derivative represented by the formula (1d), and a second step of subjecting the amidobenzene derivative represented by the formula (1d) to a dehydration reaction to produce a compound represented by the general formula (I).

< first step >

In the first step, as the reactive derivative of the compound (2b), there may be mentioned a usual alkyl ester having 1 to 6 carbon atoms such as methyl ester, ethyl ester and t-butyl ester, an acid halide such as acid chloride and acid bromide, an acid azide, an active ester such as N-hydroxybenzotriazole, N-hydroxysuccinimide and p-nitrophenol, and a mixed acid anhydride such as a symmetrical acid anhydride, an alkyl carbonate and p-toluenesulfonic acid.

When the compound (2b) is reacted with a free acid or when the active ester or acid halide is reacted without separation, it is preferable to use a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, diphenyl phosphorazidate, diethyl phosphorazidate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, or 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium chloride.

The reaction may be carried out using 0.5 to 10 moles, preferably 0.8 to 2 moles, of the carboxylic acid derivative represented by the formula (2b) or a reactive derivative thereof per 1 mole of the diaminobenzene derivative represented by the formula (1a), and if the above-mentioned condensing agent is used, the amount thereof is 0.5 to 20 moles, preferably 0.8 to 3 moles per 1 mole of the diaminobenzene derivative represented by the formula (1a), and it is usually carried out in a solvent inert to the reaction, such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride and other halogenated hydrocarbons, benzene, toluene, xylene and other aromatic hydrocarbons, ether, tetrahydrofuran, dioxane and other ethers, ethyl acetate and other esters, methanol, ethanol, N-propanol, isopropanol and other alcohols, water, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, pyridine and the like, at-20 ℃ to 150 ℃, preferably 0 ℃ to 100 ℃.

The reaction can be carried out smoothly by carrying out the reaction in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, N-dimethylaniline, N-diethylaniline, 4- (N, N-dimethylamino) pyridine, picoline, lutidine or the like in an amount of 0.5 to 20 mol, preferably 0.8 to 5 mol, based on 1 mol of the diaminobenzene derivative represented by the formula (1 a).

< second step >

The dehydration reaction in the second step may be carried out at-20 to 200 ℃, preferably 20 to 180 ℃ in an organic solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, or in the absence of a solvent, using a catalyst in an amount up to the solvent. Examples of the acid used include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and the like.

The carboxylic acid derivative represented by the above formula (2b) is known or can be produced by a known method.

[ method 3]

Reaction scheme 3

The production method is a method comprising a first step, a second step and a third step, wherein the first step is a step of obtaining an amidonitrobenzene derivative represented by the formula (1c) by amidating an aminonitrobenzene derivative represented by the formula (2a) or a salt thereof with a carboxylic acid derivative represented by the formula (2b) or a reactive derivative thereof by a conventional method, the second step is a step of obtaining an amidobenzene derivative (1d) by subjecting the obtained amidonitrobenzene derivative represented by the formula (1c) to a reduction reaction, and the third step is a step of producing a compound represented by the general formula (I) by a dehydration reaction.

The amidation reaction of the first step may be performed according to the first step of method 2.

The reduction reaction of the second step may use any reaction conditions if it is a reaction of reducing a nitro group to convert it into an amino group, but the reaction conditions need to be selected in consideration of the nature of the other functional groups of the amidonitrobenzene derivative (1 c). Preferably, a method of reacting 0.01 to 5 moles, preferably 0.05 to 1 mole of a metal having reducibility, such as reduced iron, tin chloride, iron chloride, etc., in the presence of 1 to 30 moles, preferably 3 to 10 moles, of an ammonium salt such as ammonium chloride, etc., hydrazine hydrate, etc., relative to 1 mole of the acylaminonitrobenzene derivative represented by the formula (1c), or a mixed solvent thereof, at 0 to 150 ℃, preferably 20 to 120 ℃; or a method in which hydrogen gas is allowed to act under normal pressure or pressure in the presence of a reducing metal such as palladium, platinum oxide, raney nickel supported on carbon in an amount of 0.001 to 1 mol, preferably 0.01 to 0.3 mol, based on 1 mol of the acylaminonitrobenzene derivative represented by the formula (1c) in an alcohol, an ether, an ester such as ethyl acetate, butyl acetate, etc., an organic acid such as formic acid, acetic acid, etc., or a mixed solvent thereof at 0.001 to 1 mol, preferably 0.01 to 0.3 mol, at 0 to 120 ℃, preferably 20 to 100 ℃; or a method using formic acid, ammonium formate, cyclohexene or the like as a hydrogen source.

The dehydration reaction of the third step may be performed according to the second step of the method 2.

The aminonitrobenzene derivative represented by the above formula (2a) or a salt thereof is known or can be produced by a known method.

[ method 4]

Among the compounds of the present invention, compounds having a certain functional group can be converted to other compounds of the present invention by chemically modifying the functional group, as shown in the following reaction scheme 4.

Reaction scheme 4

In the above reaction scheme 4, Y¹Represents an oxygen atom or a nitrogen atom, R⁶Any protecting group for carboxylic acid, e.g. alkyl group having 1 to 6 carbon atoms, NR⁷R⁸Denotes the aforementioned NR³R⁴，X²Represents the aforementioned X¹(the same applies below).

In the derivatives having a (C1-C6 alkoxy) carbonyl group represented by the formulae (I-1a, I-1b) (which can be produced by any of the methods of the aforementioned reaction schemes 1 to 3), the carboxylic acid derivative represented by the formulae (I-2a, I-2b) is obtained by deprotecting the ester group, and then condensed with the amine compound represented by the formula (5) by a conventional method, whereby the amide derivatives (I-3a, I-3b) can be obtained.

That is, in the first step, the derivative represented by the formula (I-1a, I-1b) is converted to the formula (I) by deprotecting the ester group of the derivativeCarboxylic acid derivatives represented by-2 a, I-2b), albeit with R⁶May be obtained by, for example, reacting an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group or the like in an appropriate solvent in the presence of 0.5 to 10 moles, preferably 1 to 5 moles, of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide based on 1 mole of the ester group of the derivative represented by (I-1a, I-1b) at-20 ℃ to 150 ℃, preferably 0 ℃ to 100 ℃. The suitable solvent is not particularly limited if it does not affect the reaction, and examples thereof include: water, methanol, ethanol, N-propanol, isopropanol, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like, and these solvents may be used alone or in a mixture.

In the second step, the amide compound represented by the general formula (I-3a, I-3b) can be obtained by condensing the amine derivative represented by the formula (5) or a salt thereof with the carboxylic acid derivative represented by the formula (I-2a, I-2b) or a reactive derivative thereof by a conventional method.

Examples of the reactive derivative of the compound (I-2a, I-2b) include acid halides such as acid chlorides and acid bromides, acid azides, active esters with N-hydroxybenzotriazole, N-hydroxysuccinimide, p-nitrophenol, and mixed acid anhydrides with symmetric acid anhydrides, alkyl carbonates, p-toluenesulfonic acid, and the like.

In addition, when the carboxylic acid derivatives represented by the formulae (I-2a, I-2b) or their reactive derivatives are reacted with a free acid or when the active ester or acid halide is not isolated, it is preferable to use a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, diphenyl phosphorazidate, diethyl phosphorazidate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, or 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium chloride.

The reaction may be carried out using 0.5 to 10 moles, preferably 0.8 to 5 moles, of the amine derivative represented by the formula (5) or a salt thereof per 1 mole of the carboxylic acid derivative represented by the formula (I-2a, I-2b) or the reactive derivative thereof, and when a condensing agent is used, the amount thereof is 0.5 to 20 moles, preferably 0.8 to 3 moles per 1 mole of the carboxylic acid derivative represented by the formula (I-2a, I-2b) or the reactive derivative thereof, and the reaction is usually carried out using a halogenated hydrocarbon such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride or the like, an aromatic hydrocarbon such as benzene, toluene, xylene or the like, an ether such as diethyl ether, tetrahydrofuran, dioxane or the like, an ester such as ethyl acetate or the like, an alcohol such as methanol, ethanol, N-propanol, isopropanol or the like, water, acetonitrile, N-dimethylformamide, isopropanol or the like, depending on the reactive derivative or the condensing agent used N, N-dimethylacetamide, dimethylsulfoxide, pyridine, etc., in a solvent inert to the reaction at-20 ℃ to 150 ℃, preferably 0 ℃ to 100 ℃.

The reaction can be carried out smoothly by carrying out the reaction in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, N-dimethylaniline, N-diethylaniline, 4- (N, N-dimethylamino) pyridine, picoline or lutidine in an amount of 0.5 to 20 mol, preferably 0.8 to 5 mol, based on 1 mol of the carboxylic acid derivative represented by the formula (I-2a, I-2b) or its reactive derivative.

The amine compound represented by the formula (5) is known or can be produced by a known method.

The production intermediate and the compound of the present invention thus obtained can be purified by a separation method usually used in synthetic chemistry, such as extraction, precipitation, suspension washing, recrystallization, distillation, column chromatography, and the like.

Pharmaceutical composition

The compound represented by the general formula (I) or a salt thereof is useful as a prostaglandin D synthase inhibitor, particularly an inhibitor of hematopoietic prostaglandin D synthase, because it can inhibit prostaglandin D synthase, particularly hematopoietic synthase.

Accordingly, the present invention provides a pharmaceutical composition comprising an effective amount of at least one compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof and a pharmaceutical carrier.

The present invention also provides the use of a compound represented by the general formula (I) or a salt thereof as a prostaglandin D synthase inhibitor, particularly, a hematopoietic prostaglandin D synthase inhibitor.

Thus, the compound represented by the general formula (I) or a salt thereof has a prostaglandin D synthase inhibitory action, and is therefore useful for preventing or ameliorating an undesirable symptom caused by prostaglandin D2 derived from the enzyme or a metabolite thereof. In particular, since the compound represented by the general formula (I) or a salt thereof has an inhibitory activity on hematopoietic synthase, a pharmaceutical composition containing the compound or a salt thereof is useful as a prophylactic and/or therapeutic agent for allergic diseases such as bronchial asthma, pollinosis, allergic rhinitis, paranasal inflammation, otitis media, allergic conjunctivitis, vernal conjunctivitis, atopic dermatitis, contact dermatitis, and food allergy in mammals, particularly humans.

The compound represented by the general formula (I) or a salt thereof is useful as a prophylactic and/or therapeutic agent for inflammatory diseases such as chronic obstructive pulmonary disease, interstitial pneumonia, allergic pneumonia, eosinophilic pneumonia, articular rheumatism, degenerative arthritis, inflammatory bowel disease, skin diseases (psoriasis, eczema, erythema, pruritus, pimple, and the like), myositis, muscular dystrophy, restenosis after PTCA, reperfusion injury, graft rejection, and the like, but is not limited thereto.

The compound represented by the general formula (I) or a salt thereof can also be expected to have an effect of preventing Alzheimer's disease or deterioration of brain injury and/or an effect of improving the prognosis of brain injury.

In addition, the compound represented by the general formula (I) or a salt thereof is useful for treating, preventing or improving mucus secretion disorders, reproductive disorders, blood coagulation disorders, pain, visual problems, obesity, and immune diseases and autoimmune diseases. In addition, since it can inhibit malignant transformation of cells and growth of metastases, it is useful for cancer treatment, and also useful for treatment and/or prevention of proliferation disorders mediated by prostaglandin D2 or its metabolites, which are found in fibroblast proliferation, diabetic retinopathy, tumor angiogenesis, and the like. In addition, since prostaglandin D2-induced smooth muscle contraction can be suppressed, it is also useful for the treatment and/or prevention of infertility, dysmenorrhea, premature labor, and eosinophil-related disorders.

When the compound of the present invention or a salt thereof is used for the treatment or prevention of the above-mentioned diseases in mammals including humans, the dose varies depending on the disease state or severity of the subject to be treated, the kind of the compound represented by the general formula (I) and the route of administration thereof, and the like. Further, it varies depending on the age, body weight, general health, sex, food intake, administration time, excretion rate, drug combination and response of each patient. Generally, there are oral and non-oral administrations. The amount to be administered is generally an amount effective for the treatment of the above-mentioned diseases, and for example, the amount is about 0.001 to about 100mg, preferably 0.01 to 50mg/kg per 1kg of body weight per day of mammals including humans. On the other hand, an amount outside the above range may be used in some cases.

The compound of the present invention or a salt thereof in an effective amount can be mixed with a pharmaceutically acceptable carrier to prepare a solid preparation such as a tablet, a capsule, a granule, or a powder, a liquid preparation such as a syrup or an injection, an external preparation such as an ointment, a lotion, a gel, or a cream, and the like, and the compound can be administered orally or parenterally (external administration, inhalation, subcutaneous injection, arterial/intravenous injection, intramuscular injection, intravesical injection, intracerebral injection, nasal drop, eye drop, or suppository).

As pharmaceutically acceptable carriers, various organic or inorganic carrier substances commonly used as pharmaceutical preparation materials can be used, and the pharmaceutical composition can be mixed as an excipient, a lubricant, a binder, or a disintegrating agent in a solid preparation, or as a solvent, a solubilizer, a suspending agent, an isotonic agent, a buffer, an analgesic, or the like in a liquid preparation. In addition, additives for pharmaceutical preparations such as preservatives, antioxidants, coloring agents, and sweeteners may be used as necessary.

Preferred examples of the excipient include: lactose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, etc. Preferred examples of the lubricant include: magnesium stearate, calcium stearate, talc, colloidal silicon dioxide, and the like. Preferred examples of the binder include: crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, etc. Preferred examples of the disintegrant include: starch, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, and the like. Preferred examples of the solvent include: water for injection, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, etc. Preferred examples of the solubilizer include: polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. As preferred examples of suspending agents there may be mentioned: examples of the surfactant include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glyceryl monostearate, and examples of the surfactant include hydrophilic high polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Preferred examples of the buffer include: phosphate, acetate, carbonate, citrate, and the like. Preferable examples of the analgesic agent include benzyl alcohol and the like. Preferred examples of the preservative include, for example: parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferred examples of the antioxidant include: sulfites, ascorbates, and the like.

Examples

The present invention will be described more specifically with reference to the following examples, which, however, do not limit the scope of the present invention.

In addition, the first and second substrates are,¹H-NMR spectrum was measured with TMS (tetramethylsilane) as an internal standard, and chemical shifts were expressed in terms of delta values (ppm). Regarding the chemical shifts, the parenthesis indicates the absorption form, coupling constant (J value), and number of protons.

In addition, the following notation is used for the absorption form: s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, dd ═ doublet, m ═ multiplet, br ═ broad singlet.

In addition, the structural formula of the compound uses the following symbols: me ═ methyl, Et ═ ethyl, Ph ═ phenyl.

Example 1

5-benzoyl-2- (2, 4-dimethylfuran-3-yl) -benzimidazole (1)

To a solution of 3, 4-diaminobenzophenone (43mg, 0.19mmol) in methanol (3ml) were added 2, 4-dimethylaminofuran-3-carboxylic acid (30mg, 0.21mmol) and 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium chloride (65mg, 0.23mmol), stirred overnight and the solvent was distilled off under reduced pressure. Chloroform/methanol (7: 1) and a saturated aqueous sodium carbonate solution were added to the residue and stirred for 30 minutes, followed by extraction with a chloroform/methanol solvent at the same ratio, washing of the organic layer with a saturated saline solution and drying with anhydrous magnesium sulfate.

The residue obtained by removing the solvent by distillation under reduced pressure was purified by medium-pressure silica gel flash column chromatography (chloroform: methanol 99: 1). The resulting condensate was dissolved in acetic acid (4ml) and stirred at 80 ℃ overnight, then allowed to cool to room temperature, and the solvent was distilled off. The resulting residue was purified by medium pressure flash column chromatography on silica gel (chloroform: methanol 99: 1) to give 5-benzoyl-2- (2, 4-dimethylfuran-3-yl) -benzimidazole (22mg, 35%) as a brown solid.

Melting point: 203 ℃ to 208 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.22(s，3H)、2.55(s，3H)、7.34-7.93(m，9H)、8.05(br，1H)。

Example 2

4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (2)

Example 2(1)

3, 5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (starting material for 2)

Ethyl 2, 4-dimethyl-5-formylfuran-3-carboxylate (1.78g, 9.1mmol), known from the literature, was dissolved in a mixture of acetic acid (32ml) and water (8ml), sulfamic acid (1.19g, 12.2mmol) was added, and the mixture was cooled to 0 ℃ with an ice bath. Sodium chlorite was added and stirred for 2 hours, then water was added to the system, and the precipitated solid was filtered to obtain 3, 5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (1.01g, 52%) as a white solid.

¹H-NMR(CDCl₃)：δ(ppm)1.38(t，J＝7.3Hz，3H)、2.56(s，3H)、2.64(s，3H)、4.33(q，J＝7.3Hz，2H)。

Example 2(2)

3, 5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide (starting material for 2)

To a solution of 3, 5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (250mg, 1.18mmol) obtained in example 2(1) in pyridine (4ml) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (248mg, 1.30mmol) and 1-hydroxybenzotriazole monohydrate (199mg, 1.30mmol), followed by 28% aqueous ammonia (0.19ml, 11.8mmol) and heating to 80 ℃ for 4 hours with stirring. After cooling to room temperature with stirring, water was added to the system and the precipitated solid was filtered to give 3, 5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide (176mg, 71%) as a white solid.

¹H-NMR(CDCl₃)：δ(ppm)1.37(t，J＝7.0Hz，3H)、2.56(s，3H)、2.59(s，3H)、4.32(q，J＝7.0Hz，2H)。

Example 2(3)

4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (2)

3, 5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide (176mg, 0.83mmol) obtained in example 2(2) was dissolved in ethanol (4ml), and 0.13ml of 4N aqueous sodium hydroxide solution was added, followed by stirring at 75 ℃ for 4 hours. The reaction mixture was neutralized with 1N hydrochloric acid at room temperature, and the solid (crude carboxylic acid) precipitated after removing the solvent by distillation was filtered and used as it is in the next reaction.

To a solution of 3, 4-diaminobenzophenone (43mg, 0.19mmol) in methanol (3ml) were added the above crude carboxylic acid (39mg, 0.21mmol) and 4- (4, 6-dimethoxy-1, 3, 5-triazin-2-yl) -4-methylmorpholinium chloride (65mg, 0.23mmol), stirred overnight and the solvent was distilled off under reduced pressure. Chloroform/methanol (7: 1) and a saturated aqueous sodium carbonate solution were added to the residue, and after stirring for 30 minutes, the mixture was extracted with a chloroform/methanol solvent at the same ratio, and the organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.

The residue obtained by removing the solvent by distillation under reduced pressure was purified by medium-pressure silica gel flash column chromatography (chloroform: methanol 99: 1). The resulting condensate was dissolved in acetic acid (4ml) and stirred at 80 ℃ overnight. After cooling to room temperature and stirring, the solvent was removed by distillation and purified by flash column chromatography on medium pressure silica gel (chloroform: methanol 99: 1) to give 4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (42mg, 62%) as a yellow solid.

Melting point: 143 ℃ C. and 146 ℃ C

¹H-NMR(CDCl₃)：δ(ppm)2.67(s，3H)、2.72(s，3H)、5.76-6.22(br，2H)、7.85-7.47(m，9H)。

Example 3

(4- (5-Benzoylbenzimidazol-2-yl) -3, 5-dimethyl-2-furanylcarbonyl) pyrrolidine (3)

Example 3(1)

(3, 5-dimethyl-4-ethoxycarbonyl-2-furylcarbonyl) pyrrolidine (starting material for 3)

According to example 2(2), by using pyrrolidine instead of 28% ammonia water, (3, 5-dimethyl-4-ethoxycarbonyl-2-furylcarbonyl) pyrrolidine (89%) was obtained as a white solid.

¹H-NMR(CDCl₃)：δ(ppm)1.37(t，J＝7.3Hz，3H)、1.92(br，4H)、2.49(s，3H)、2.57(s，3H)、3.62-3.73(m，4H)、4.31(q，J＝7.3Hz，2H)。

Example 3(2)

By using (3, 5-dimethyl-4-ethoxycarbonyl-2-furylcarbonyl) pyrrolidine instead of 3, 5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide according to example 2(3), the (4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethyl-2-furylcarbonyl) pyrrolidine was obtained (59%) as a light yellow solid.

Melting point: 112 ℃ and 114 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)1.85(br，4H)、2.44、2.46(s and s，total3H)、2.58、2.60(s and s，total 3H)、3.46(br，2H)、3.74(br，2H)、7.42-7.99(m，8H)、12.56、12.67(s and s，total 1H)。

Example 4

N- (3, 4-methylenedioxyphenyl) methyl-4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (4)

By using piperonylamine instead of pyrrolidine according to example 3, N- (3, 4-methylenedioxyphenyl) methyl-4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (87mg, 87%) was obtained as a light yellow solid.

Melting point: 122 ℃ to 125 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.51、2.53(s and s，total 3H)、2.58、2.61(s and s，total 3H)、4.28-4.32(m，2H)、5.97(s，2H)、6.75-6.89(m，3H)、7.42-7.99(m，8H)、8.71(brs，1H)、12.57、12.68(s and s，total 1H)。

Example 5

4- (5-Benzoylbenzimidazol-2-yl) pyrrole-2-carboxylic acid (5)

To ethyl pyrrole-2-carboxylate (3.0 g) were added ethanol (45ml), nitromethane (45ml), and aluminum chloride (7.2 g), and α, α -dichloromethyl ether (3.2 g) was slowly added dropwise under ice-cooling conditions, and allowed to stand at-20 ℃ overnight. After the disappearance of the starting material, ether and water were added for extraction, and the resulting organic layer was concentrated under reduced pressure and then heated to dryness under reduced pressure. The resulting solid was dissolved in N, N-dimethylformamide (20ml), and slowly added dropwise to a solution of 3, 4-diaminobenzophenone (4.6 g), sodium bisulfite (2.9 g) in N, N-dimethylformamide (30ml) heated to 130 ℃. After heating at bath temperature 130 ℃ for 5 hours, the reaction solution was cooled to room temperature and stirred with water, and the precipitated solid was filtered and dried by heating under reduced pressure.

The resulting solid was dissolved in tetrahydrofuran (10ml) and ethanol (10ml), a 4N aqueous solution of sodium hydroxide (15ml) was added and heated under reflux for 4 hours. After the disappearance of the starting material, the reaction solution was cooled to room temperature and then neutralized with an aqueous hydrochloric acid solution, and the precipitated solid was filtered and dried under reduced pressure with heating to give 4- (5-benzoylbenzoimidazol-2-yl) pyrrole-2-carboxylic acid (5.3 g, 75%) as a pale yellow solid.

Melting point: 239, 241 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)：7.40(d，J＝1.6Hz，1H)、7.55-7.77(m，8H)、7.87(s，1H)、12.3(br，1H)。

Example 6

((4- (5-benzoylbenzoimidazol-2-yl) pyrrol-2-yl) carbonyl) pyrrolidine (6)

4- (5-Benzoylbenzimidazol-2-yl) pyrrole-2-carboxylic acid (130mg) obtained in example 5 was dissolved in N, N-dimethylformamide (2ml) and pyridine (2ml), and pyrrolidine (56mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (112mg) and 1-hydroxybenzotriazole monohydrate (80mg) were added to stir at a bath temperature of 80 ℃ overnight with heating. After the disappearance of the starting material, the reaction mixture was cooled to room temperature, and the reaction mixture was dropped into water, and the precipitated solid was filtered and dried under reduced pressure by heating to give ((4- (5-benzoylbenzimidazol-2-yl) pyrrol-2-yl) carbonyl) pyrrolidine (118mg, 78%) as a red solid.

Melting point: 160 ℃ C. and 162 ℃ C

¹H-NMR(DMSO-d₆)：δ(ppm)1.86-2.04(m，4H)、3.48-3.92(m，4H)、7.28(s，1H)、7.55-7.77(m，9H)、12.0(br，1H)、12.8(br，1H)。

Example 7

2- (2, 4-dimethylpyrrol-3-yl) -5-benzoylbenzimidazole (7)

N, N-dimethylacetamide (5ml) was heated to 130 ℃, 3, 4-diaminobenzophenone (1.48 g) and sodium bisulfite (0.87 g) were added and stirred for 5 minutes, and then 2, 4-dimethyl-3-formyl-pyrrole (1.03 g) was added and stirred at 130 ℃ for 8 hours. After cooling to room temperature and stirring, water was added to the system and the precipitated solid was filtered, and dried under reduced pressure by heating to give 2- (2, 4-dimethylpyrrol-3-yl) -5-benzoylbenzimidazole (1.78g, 81%) as a brown solid.

Melting point: 207 ℃ 214 ℃

¹H-NMR(DMSO-d₆)：δ(ppm)2.22(s，3H)、2.37(s，3H)、5.79(s，1H)、7.55-7.88(m，8H)、11.15(s，1H)、12.97(s，1H)。

Example 8

2- (2-formyl-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (8)

Phosphorus oxychloride (2.43 g) was slowly added dropwise to N, N-dimethylformamide (15.9 g) at room temperature, and stirred at room temperature for 30 minutes. To this was slowly added dropwise a solution of 2- (2, 4-dimethylpyrrol-3-yl) -5-benzoylbenzimidazole (2.5 g) obtained in example 7 in N, N-dimethylformamide. After stirring for 2 hours, 1N aqueous sodium hydroxide solution was added, and 50ml was heated to 80 ℃ and stirred for 2 hours. After the disappearance of the starting material, the reaction solution was added dropwise to purified water and the precipitated solid was filtered and dried by heating under reduced pressure to give 2- (2-formyl-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (1.63 g, 60%) as a brown solid.

Melting point: 253 temperature 255 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.53(s，3H)、2.57(s，3H)、7.54-7.80(m，7H)、7.93(s，1H)、9.66(s，1H)、12.30(br，1H)。

Example 9

2- (2-cyanovinyl-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (9)

2- (2-formyl-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (105mg) obtained in example 8 was dissolved in tetrahydrofuran (2ml), and diethyl cyanomethylphosphonate (54mg) and sodium methoxide (33mg) were added to stir at room temperature for 1 hour. Diethyl cyanomethylphosphonate (54mg) was added thereto, the mixture was heated at a bath temperature of 60 ℃ for 4 hours, the reaction mixture was neutralized with 0.1N aqueous hydrochloric acid, chloroform (5ml) and water (2ml) were added, extraction and washing were carried out, the organic layer was concentrated, and the residue was purified by medium-pressure silica gel flash column chromatography (chloroform: ethyl acetate 1: 1) and dried under reduced pressure by heating to give 2- (2-cyanovinyl-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (61.6mg, 55%) as a pale yellow solid.

Melting point: 201 ℃ 203-

¹H-NMR(DMSO-d₆)：δ(ppm)2.36(s，3H)、2.54(s，3H)、5.79(d，J＝16.0Hz，1H)、7.48-7.98(m，10H)、11.85(s，1H)。

Example 10

4- (5-Benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid (10)

To a solution of 3, 4-diaminobenzophenone (1.6 g) in N, N-dimethylacetamide (20ml) were added sodium hydrogen sulfite (1.0 g) and ethyl 3, 5-dimethyl-4-formylpyrrole-2-carboxylate (1.5 g), and the mixture was heated to 120 ℃ and stirred for 10 hours. After cooling to room temperature, a 5% aqueous sodium carbonate solution (60 g) was added and stirred at room temperature, and the precipitated solid was filtered and washed with water. The resulting solid was dissolved in ethanol (15ml) and tetrahydrofuran (15ml), a 4N aqueous solution of sodium hydroxide (20ml) was added and heated under reflux for 12 hours. After the disappearance of the starting material, it was cooled to room temperature, neutralized with 1N aqueous hydrochloric acid solution, and the precipitated solid was filtered to give 4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid (2.3 g, 90%) as a pale yellow solid.

Melting point: 192 ℃ C

¹H-NMR(DMSO-d₆)：δ(ppm)2.49(s，3H)、2.55(s，3H)、7.49-8.01(m，8H)、11.63(brs，1H)、11.68-12.57(br，1H)。

Example 11

N-methyl-N- (2-dimethylaminoethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (11)

To a solution of 4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid (150mg, 0.42mmol) obtained in example 10 in pyridine (2ml) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (88mg, 0.46mmol) and 1-hydroxybenzotriazole monohydrate (70mg, 0.46mmol), followed by N, N, N' -trimethylethylenediamine (43mg, 0.42mmol) and heating. Stirred at an internal temperature of 60 ℃ for 5 hours, then allowed to cool to room temperature and stirred. After the solvent was distilled off, purification was performed by medium-pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol 98: 2) to give N-methyl-N- (2-dimethylaminoethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (112mg, 61%) as a pale yellow amorphous form.

¹H-NMR(DMSO-d₆)：δ(ppm)2.17(s，6H)、2.30(s，3H)、2.45、2.47(s and s，total 3H)、2.95-2.99(m，2H)、2.99(s，3H)、3.51(t，J＝4.3Hz，2H)、7.56-7.89(m，8H)、7.89(brs，1H)、12.00、12，14(brs and brs，total 1H)。

Example 12

4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (12)

According to example 11, using 7N methanolic ammonia solution instead of N, N' -trimethylethylenediamine, 4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (55%) was obtained as a tan solid.

Melting point: 188 ℃ plus 190 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.47(s，3H)、2.49(s，3H)、6.99(br，2H)、7.54-7.77(m，7H)、7.91(s，1H)、11.4(s，1H)、12.02-12.39(br 1H)。

Example 13

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (13)

Example 13(1)

5-cyano-2, 4-dimethylpyrrole-3-carbaldehyde

To N, N-dimethylformamide (8.04 g, 110mmol) was added phosphorus oxychloride (10.2ml, 110mmol) dropwise and stirred for 1 hour, then a solution of 2-cyano-3, 5-dimethylpyrrole (12.0g, 100mmol) known from the literature (Synthesis, 1999, 46) in N, N-dimethylformamide (25ml) was added dropwise over 30 minutes. After stirring for 3 hours, poured into ice water (ca 500g) and neutralized with solid sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was removed by distillation under the reduced pressure, and the resulting residue was purified by medium-pressure silica gel flash column chromatography (ethyl acetate: chloroform ═ 1: 20 to 1: 5) to give 5-cyano-2, 4-dimethylpyrrole-3-carbaldehyde (7.96g, 54%) as a pale yellow solid.

Melting point: 208 ℃ C. & lt 210 ℃ C. & gt

¹H-NMR(CDCl₃)：δ(ppm)2.46(s，3H)、2.57(s，3H)、9.10(brs，1H)、9.97(s，1H)。

Example 13(2)

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (13)

3, 4-Diaminobenzophenone (6.37g, 30mmol) was dissolved in N, N-dimethylacetamide (90ml), sodium hydrogen sulfite (3.43g, 33mmol) was added, and heated to 130 ℃ and a solution of 5-cyano-2, 4-dimethylpyrrole-3-carbaldehyde (4.89g, 33mmol) obtained in example 13(1) in N, N-dimethylacetamide (20ml) was added dropwise with stirring. The reaction solution was stirred at the same temperature for 12 hours, then the solvent was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution and water were added to the obtained residue, and the precipitated solid was filtered, washed with water, diethyl ether, and dried under reduced pressure. The resulting crude crystals were purified by medium pressure flash column chromatography on silica gel (methanol: chloroform ═ 1: 50 to 1: 15) to give 2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole (7.85g, 77%) as a pale yellow solid.

Melting point: 159 ℃ C. (163 ℃ C.)

¹H-NMR(DMSO-d₆)：δ(ppm)2.41(s，3H)、2.52(s，3H)、7.52-7.98(m，8H)、12.12-12.48(br，2H)。

Example 14

N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (14)

According to example 11, O-methylhydroxylamine hydrochloride was used instead of N, N' -trimethylethylenediamine to give N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (60%) as a tan solid.

Melting point: 203-

¹H-NMR(DMSO-d₆)：δ(ppm)2.45、2.45、2.47、2.48(s and s and sand s，total 6H)、3.71(s，3H)、7.56-7.95(m，8H)、10.75、10.77(s and s，total 1H)、11.46、11.50(s and s，total 1H)、12.14、12.28(s and s，total 1H)。

Example 15

(N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (15)

Example 15(1)

3, 5-dimethyl-4-formylpyrrole-2-carboxylic acid

Ethyl 3, 5-dimethyl-4-formylpyrrole-2-carboxylate (19.52g, 100mmol), which is known from the literature, was suspended in ethanol (100ml) and a 2N aqueous solution of sodium hydroxide (100ml, 200mmol), and stirred under reflux for 4 hours. After completion of the reaction, 200ml of water and 100ml of a 2N aqueous hydrochloric acid solution were added under ice-cooling, and the precipitated solid was filtered, washed with water and diethyl ether, and dried under reduced pressure to give 3, 5-dimethyl-4-formylpyrrole-2-carboxylic acid (16.8g, 97%) as a pale brown solid.

Melting point: 233-

¹H-NMR(DMSO-d₆)：δ(ppm)2.45(s，3H)、2.48(s，3H)、9.90(s，1H)、11.95(brs，1H)、12.58(br，1H)。

Example 15(2)

(N-methoxy-N-methyl) -3, 5-dimethyl-4-formylpyrrole-2-carboxamide

3, 5-dimethyl-4-formylpyrrole-2-carboxylic acid (10.0g, 60mmol) obtained in example 15(1) was suspended in N, N-dimethylformamide (120ml), and 1-hydroxybenzotriazole monohydrate (9.65g, 63mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (12.65g, 66mmol), N, O-dimethylhydroxylamine hydrochloride (7.02g, 72mmol) and triethylamine (12.6ml, 90mmol) were added under ice cooling, followed by stirring at room temperature for 16 hours. The resulting reaction solution was added with water, extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated brine, and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was removed by distillation under the reduced pressure, and the resulting residue was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform ═ 1: 10 to 1: 3) to give (N-methoxy-N-methyl) -3, 5-dimethyl-4-formylpyrrole-2-carboxamide (6.32g, 50%) as a pale yellow solid.

Melting point: 129 ℃ 131-

¹H-NMR(CDCl₃)：δ(ppm)2.55(s，3H)、2.57(s，3H)、3.34(s，3H)、3.70(s，3H)、9.43(brs，1H)、10.04(s，1H)。

Example 15(3)

3, 4-Diaminobenzophenone (5.31g, 25mmol) was dissolved in N, N-dimethylacetamide (70ml), sodium hydrogen sulfite (2.86g, 27.5mmol) was added, and the mixture was heated to 130 ℃ and a solution of (N-methoxy-N-methyl) -3, 5-dimethyl-4-formylpyrrole-2-carboxamide (5.78g, 27.5mmol) obtained in example 15(2) in N, N-dimethylacetamide (15ml) was added dropwise with stirring. The reaction solution was stirred at the same temperature for 16 hours, then a saturated aqueous sodium bicarbonate solution and water were added to the residue obtained by distilling off the solvent under reduced pressure, and the precipitated solid was filtered, washed with water, diethyl ether, and dried under reduced pressure. The resulting crude crystals were purified by medium pressure flash column chromatography on silica gel (methanol: chloroform ═ 1: 100 to 1: 20) to give (N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (7.25g, 72%) as a light yellow solid.

Melting point: 127 ℃ C

¹H-NMR(DMSO-d₆)：δ(ppm)2.43(s，3H)、2.50(s，3H)、3.26(s，3H)、3.63(s，3H)、7.50-8.00(m，8H)、11.31(brs，1H)、12.20(br，1H)。

Example 16

N- (3-methoxypropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (16)

According to example 11, using 3-methoxypropylamine instead of N, N' -trimethylethylenediamine, N- (3-methoxypropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (61%) was obtained as a white solid.

Melting point: 256-258 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)1.73-1.79(m，2H)、2.48(s，3H)、2.50(s，3H)、3.26(s，3H)、3.28-3.33(m，2H)、3.41(t，J＝6.5Hz，2H)、7.42(br，1H)、7.59-7.93(m，8H)、11.37(brs，1H)、12.09、12.24(brs and brs，total1H)。

Example 17

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (17)

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (51%) was obtained as a white solid using N, N-dimethyl-1, 3-propanediamine instead of N, N' -trimethylethylenediamine according to example 11.

Melting point: 238℃ and 248 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)1.63-1.69(m，2H)、2.16(s，6H)、2.31(t，J＝7.1Hz，2H)、2.45(s，3H)、2.47(s，3H)、3.27-3.32(m，2H)、7.54-7.93(m，9H)、11.38(s，1H)、12.10、12.24(s and s，total 1H)。

Example 18

N- (2-Acetylamidoethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (18)

N- (2-acetamidoethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide was obtained as a white solid according to example 11 using N-acetylethylenediamine instead of N, N' -trimethylethylenediamine (67%).

Melting point: 272 plus 273 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)1.82(s，3H)、2.45(s，3H)、2.50(s，3H)、3.20-3.23(m，2H)、3.29-3.32(m，2H)、7.46-7.98(m，10H)、11.35、11.39(brs and brs，total 1H)、12.10、12.25(s and s，total 1H)。

Example 19

N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (19)

Using beta-alanine ethyl ester hydrochloride instead of N, N' -trimethylethylenediamine according to example 11, N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (65%) was obtained as a purple solid.

Melting point: 135 ℃ 137 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)1.20(t，J＝7.3Hz，3H)、2.47(s，3H)、2.50(s，3H)、2.58(t，J＝6.8Hz，2H)、3.48-3.50(m，2H)、4.09(q，J＝7.0Hz，2H)、7.36-7.98(m，10H)、11.4(br，1H)。

Example 20

N- (1-Methoxycarbonylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (20)

According to example 11, glycine methyl ester hydrochloride was used instead of N, N' -trimethylethylenediamine to give N- (1-methoxycarbonylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (65%) as a purple solid.

Melting point: 149 ℃ C. -

¹H-NMR(DMSO-d₆)：δ(ppm)2.48(s，3H)、2.51(s，3H)、3.67(s，3H)、4.03(d，J＝5.9Hz，2H)、7.37-8.02(m，9H)、11.55(br，1H)。

Example 21

N- (2-carboxyethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (21)

N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide obtained in example 19 (300mg) was dissolved in tetrahydrofuran (5ml) and ethanol (5ml), and 4N aqueous sodium hydroxide solution (10ml) was added and stirred at room temperature for 1 hour. After the reaction solution was neutralized with 4N aqueous hydrochloric acid solution, the precipitated solid was filtered and dried under reduced pressure with heating to give N- (2-carboxyethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (211mg, 75%) as a purple solid.

Melting point: 256-258 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.40-2.50(m，2H)、2.47(s，3H)、2.50(s，3H)、3.38-3.53(m，2H)、7.54-7.95(m，10H)、11.60(br，1H)。

Example 22

N- (1-carboxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (22)

Using N- (1-methoxycarbonylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide instead of N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide according to example 21, N- (1-carboxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide was obtained (67%) as a purple solid.

Melting point: 274 ℃ and 276 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.47(s，3H)、2.54(s，3H)、3.79(brs，2H)、7.55-7.97(m，10H)、11.9(br，1H)。

Example 23

N- (2-pyrrolidin-1-yl-ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (23)

According to example 11, 1- (2-aminoethyl) pyrrolidine was used instead of N, N' -trimethylethylenediamine to give N- (2-pyrrolidin-1-yl-ethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (43%) as a light yellow amorphous.

¹H-NMR(CDCl₃)：δ(ppm)1.70(br，4H)、2.23(s，3H)、2.29(s，3H)、2.57(br，4H)、2.71(br，2H)、3.48(br，2H)、6.96(br，1H)、7.46-8.19(m，9H)、10.36(s，1H)。

Example 24

N- (2-piperidin-1-yl-ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (24)

According to example 11, 1- (2-aminoethyl) piperidine was used instead of N, N' -trimethylethylenediamine to give N- (2-piperidin-1-yl-ethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (71%) as a white solid.

Melting point: 230 ℃ 237-

¹H-NMR(DMSO-d₆)：δ(ppm)1.39(br，2H)、1.51(br，4H)、2.40-2.50(m，5H)、2.97-3.00(m，1H)、3.32-3.37(m，2H)、7.27(br，1H)、7.56-7.93(m，8H)、11.45(br，1H)、12.1、12.25(s and s，total 1H)。

Example 25

N- (cyclohexylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (25)

According to example 11, cyclohexylmethylamine was used instead of N, N' -trimethylethylenediamine to give N- (cyclohexylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (73%) as a white solid.

Melting point: 254 ℃ C. & lt 255 ℃ C

¹H-NMR(DMSO-d₆)：δ(ppm)0.91-0.97(m，2H)、1.17-1.22(m，3H)、1.51(br，1H)、1.63-1.75(m，5H)、2.46(s，3H)、2.49(s，3H)、3.10(t，J＝6.1Hz，2H)、7.38-7.41(m，1H)、7.55-7.90(m，9H)、11.36(s，1H)。

Example 26

N- (5-methylisoxazol-3-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (26)

According to example 11, 3-amino-5-methylisoxazole is used instead of N, N, N' -trimethylethylenediamine to give N- (5-methylisoxazol-3-yl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (45%) as a pale yellow solid.

Melting point: 271, 273 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.41(s，3H)、2.57(s，3H)、2.59(s，3H)、6.73(s，1H)、7.59-7.99(m，8H)、8.11(s，1H)、10.77(s，1H)、12.56(s，1H)。

Example 27

N- (4-cyanophenyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (27)

According to example 11, using 4-cyanoaniline instead of N, N' -trimethylethylenediamine, N- (4-cyanophenyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (38%) was obtained as a light yellow solid.

Melting point: 252 ℃ 254 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.51(s，3H)、2.58(s，3H)、7.58-8.07(m，12H)、10.6(br，1H)。

Example 28

N- (indol-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (28)

According to example 11, 5-aminoindole was used instead of N, N' -trimethylethylenediamine to give N- (indol-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (63%) as a light yellow solid.

Melting point: 167 deg.C and 169 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)2.53、2.55(s and s，3H)、2.58、2.59(s and s，3H)、6.40(t，J＝2.2Hz，1H)、7.29-7.38(m，3H)、7.56-7.95(m，9H)、9.30(d，J＝4.9Hz，1H)、11.00(brs，1H)、11.56、11.60(s and s，total1H)、12.14、12.29(s and s，total 1H)。

Example 29

N- (3, 4-methylenedioxyphenyl-1-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (29)

According to example 11, 3, 4-methylenedioxyaniline was used instead of N, N' -trimethylethylenediamine to give N- (3, 4-methylenedioxyphenyl-1-yl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (55%) as a light yellow solid.

Melting point: 160 ℃ C. and 162 ℃ C

¹H-NMR(DMSO-d₆)：δ(ppm)2.52(s，3H)、2.55(s，3H)、6.00(s，2H)、6.87(d，J＝8.3Hz，1H)、7.07(dd，J＝2.1，8.3Hz，1H)、7.39(d，J＝2.1Hz，1H)、7.55-7.77(m，8H)、7.91(brs，1H)、9.41(s，1H)。

Example 30

N- (2, 3-dihydrobenzofuran-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (30)

Using 2, 3-dihydro-5-aminobenzofuran instead of N, N' -trimethylethylenediamine according to example 11, N- (2, 3-dihydrobenzofuran-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (63%) was obtained as a light yellow solid.

Melting point: 170 ℃ and 172 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.50(s，3H)、2.55(s，3H)、3.19(t，J＝8.4Hz，2H)、4.52(t，J＝8.4Hz，2H)、6.73(d，J＝8.6Hz，1H)、7.30(s，1H)、7.31(d，J＝8.4Hz，1H)、7.55-7.91(m，9H)、11.56(br，1H)、12.14、12.28(s and s，total 1H)。

Example 31

N- (benzothiazol-6-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (31)

According to example 11, 6-aminobenzothiazole was used instead of N, N' -trimethylethylenediamine to give N- (benzothiazol-6-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (75%) as a light yellow solid.

Melting point: 155 ℃ to 157 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.55(s，3H)、2.56(s，3H)、7.55-8.08(m，11H)、8.62(s，1H)、9.27(s，1H)、9.79(s，1H)、11.71(s，1H)。

Example 32

N- (3, 4-ethylenedioxyphenyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (32)

According to example 11, 3, 4-ethylenedioxyaniline was used instead of N, N' -trimethylethylenediamine to give N- (3, 4-ethylenedioxyphenyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (63%) as a light yellow solid.

Melting point: 145-

¹H-NMR(DMSO-d₆)：δ(ppm)2.53(s，3H)、2.55(s，3H)、4.13-4.30(m，4H)、6.81(d，J＝9.0Hz，1H)、7.09(dd，J＝9.0，2.0Hz，1H)、7.32(d，J＝2.0Hz，1H)、7.55-7.98(m，8H)、9.32、9.34(s and s，total 1H)、11.55、11.59(s and s，total 1H)、12.14、12.29(s and s，total 1H)。

Example 33

N- (2-pyridylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (33)

According to example 11, using 2-aminomethylpyridine instead of N, N' -trimethylethylenediamine, N- (2-pyridylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (87%) was obtained as a light yellow amorphous.

¹H-NMR(DMSO-d₆)：δ(ppm)2.48、2.50(s and s，total 3H)、2.55、2.57(s and s，total 3H)、4.59(br，2H)、7.28-8.05(m，12H)、8.53(s，1H)、11.51(br，1H)、12.14、12.28(s and s，total 1H)。

Example 34

N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (34)

Using 2- (2-aminoethyl) pyridine instead of N, N' -trimethylethylenediamine according to example 11, N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (54%) was obtained as a white solid.

Melting point: 237.5-243.9 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)2.44(s，3H)、2.46(s，3H)、2.99-3.03(m，2H)、3.62-3.64(m，2H)、7.23-7.92(m，12H)、8.53(br，1H)、11.4(s，1H)、12.1(s，1H)。

Example 35

N- (3, 4-dichlorobenzyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (35)

Using 3, 4-dichlorobenzylamine instead of N, N' -trimethylethylenediamine according to example 11, N- (3, 4-dichlorobenzyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (63%) was obtained as a purple solid.

Melting point: 141 ℃ 143-

¹H-NMR(DMSO-d₆)：δ(ppm)2.48(s，3H)、2.53(s，3H)、4.46(d，J＝5.4Hz，2H)、7.27-8.15(m，12H)、11.51(s，1H)。

Example 36

N- (3, 4-dimethoxybenzyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (36)

According to example 11, 3, 4-dimethoxybenzylamine was used instead of N, N' -trimethylethylenediamine to give N- (3, 4-dimethoxybenzyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (68%) as a purple solid.

Melting point: 120 ℃ C. & 122 ℃ C

¹H-NMR(DMSO-d₆)：δ(ppm)2.47(s，3H)、2.54(s，3H)、3.73(s，3H)、3.75(s，3H)、4.41(d，J＝5.4Hz，2H)、6.85-6.98(m，3H)、7.55-7.95(m，8H)、11.44(brs，1H)。

Example 37

N- (3, 4-methylenedioxyphenylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (37)

According to example 11, piperonylamine was used instead of N, N' -trimethylethylenediamine to give N- (3, 4-methylenedioxyphenylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (56%) as a light yellow solid.

Melting point: 165-

¹H-NMR(DMSO-d₆)：δ(ppm)2.47(s，3H)、2.50(s，3H)、4.38(d，J＝5.6Hz，2H)、5.99(s，2H)、6.81-6.93(m，3H)、7.55-7.77(m，7H)、7.90(brs，1H)。

Example 38

N- (2, 3, 4, 5-tetrahydro-3-oxopyridazin-6-yl-methyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (38)

According to example 11, 6-aminomethyl-4, 5-dihydropyridazin-3 (2H) -one was used instead of N, N, N' -trimethylethylenediamine to give N- (2, 3, 4, 5-tetrahydro-3-oxopyridazin-6-ylmethyl) -4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (14%) as a pale red solid.

Melting point: 287 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)2.29-2.33(m，2H)、2.46-2.50(m，2H)、2.50(s，6H)、4.10(s，2H)、7.56-7.93(m，8H)、10.60(s，1H)、11.48(br，1H)、12.13、12.28(s and s，total 1H)。

Example 39

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) pyrrolidine (39)

Using pyrrolidine instead of N, N' -trimethylethylenediamine according to example 11, ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) pyrrolidine (73%) was obtained as a light yellow solid.

Melting point: 155 ℃ to 157 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)1.85(br，4H)、2.48(s，3H)、2.50(s，3H)、3.48(br，4H)、7.55-7.77(m，8H)、7.89(s，1H)、11.3(s，1H)。

Example 40

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) morpholine (40)

According to example 11, morpholine was used instead of N, N' -trimethylethylenediamine to give ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) morpholine (65%) as a light yellow solid.

Melting point: 201 ℃ 203-

¹H-NMR(DMSO-d₆)：δ(ppm)2.30(s，3H)、2.48(s，3H)、3.54(brs，4H)、3.61(brs，4H)、7.55-7.76(m，8H)、7.91(s，1H)、11.51(brs，1H)。

EXAMPLE 41

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-phenylpiperazine (41)

According to example 11, 1-phenylpiperazine was used instead of N, N' -trimethylethylenediamine to give ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-phenylpiperazine (70%) as an off-white solid.

Melting point: 145-

¹H-NMR(DMSO-d₆)：δ(ppm)2.33(s，3H)、2.23-2.57(m，2H)、2.50(s，3H)、3.01-3.54(m，4H)、3.70(br，2H)、6.82(t，J＝7.3Hz，1H)、6.98(d，J＝8.1Hz，2H)、7.15-7.28(m，2H)、7.55-8.08(m，8H)、11.43(brs，1H)。

Example 42

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) pyrazoline (42)

According to example 11, pyrazoline was used instead of N, N' -trimethylethylenediamine to give ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) pyrazoline (73%) as a light yellow solid.

Melting point: 148 deg.C and 150 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)2.47(s，3H)、2.49(s，3H)、2.85-3.00(m，2H)、3.79-3.93(m，2H)、7.29(s，1H)、7.54-7.80(m，7H)、7.91(s，1H)、11.20(s，1H)、12.23(br，1H)。

Example 43

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-hydroxypiperidine (43)

According to example 11, using 4-hydroxypiperidine instead of N, N' -trimethylethylenediamine, ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-hydroxypiperidine (55%) was obtained as a light yellow solid.

Melting point: 288, 290 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)1.27-1.48(m，2H)、1.69-1.87(m，2H)、2.28(s，3H)、2.47(s，3H)、3.14-3.35(m，2H)、3.65-3.97(m，3H)、4.78(s，1H)、7.52-7.96(m，8H)、11.43(s，1H)、11.85-12.33(br，1H)。

Example 44

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-ethoxycarbonylpiperidine (44)

According to example 11, using ethylpiperidinoate instead of N, N' -trimethylethylenediamine, ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-ethoxycarbonylpiperidine (72%) was obtained as a brown solid.

Melting point: 272 sub-274 deg.C

¹H-NMR(CDCl₃)：δ(ppm)1.27(t，J＝7.1Hz，3H)、1.74(br，2H)、1.97(br，2H)、2.35(brs，3H)、2.54(br，3H)、2.58-2.59(m，1H)、3.06-3.11(br，2H)、4.15(q，J＝7.1Hz，2H)、4.22(br，2H)、7.47-8.15(m，8H)、10.52(br，1H)、11.53、11.60(s and s，total 1H)。

Example 45

((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxylic acid (45)

To a solution of ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) -4-ethoxycarbonylpiperidine (4.19g, 10.8mmol) obtained in example 44 in ethanol (15ml) was added 1N aqueous sodium hydroxide solution (16.2ml, 16.2mmol), and the mixture was stirred at 100 ℃ for 4 hours. After cooling to room temperature and stirring, the mixture was neutralized with 6N hydrochloric acid (12ml, 16.2 mmol). The precipitated solid was filtered and dried under reduced pressure to give ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxylic acid (3.02g, 78%) as white crystals.

Melting point: 267-271 deg.C

¹H-NMR(CDCl₃)：δ(ppm)1.74(m，2H)、1.98(d，J＝10Hz，2H)、2.35(s，3H)、2.53(s，3H)、2.58-2.59(m，1H)、3.14(dd，J＝10，10Hz，2H)、4.20(d，J＝10Hz，2H)、7.49-8.11(m，8H)、10.39(br，1H)、11.50(br，1H)。

Example 46

N-dimethylaminoethyl-1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (46)

To a solution of ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxylic acid (70mg, 0.15mmol) obtained in example 45 in pyridine (4ml) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (31mg, 0.16mmol) and 1-hydroxybenzotriazole monohydrate (25mg, 0.16mmol), followed by N, N-dimethylethylenediamine (13mg, 0.15mmol) and heating. Stirred at an internal temperature of 60 ℃ for 10 hours, then allowed to cool to room temperature and stirred. The solvent was removed by distillation and purified by flash column chromatography on medium pressure silica gel (NH silica gel; chloroform: methanol 98: 2) to give N-dimethylaminoethyl-1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (44mg, 55%) as white crystals.

Melting point: 258 ℃ and 260 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)1.48-1.72(m，4H)、2.13(s，6H)、2.26(brs，3H)、2.42、2.46(brs and brs，total 3H)、2.94-3.18(m，3H)、3.32(br4H)、4.09(br，2H)、7.55-7.90(m，8H)、11.42、11.46(s and s，total 1H)、12.02、12.17(s and s，total 1H)。

Example 47

N-methyl-N- (2-dimethylaminoethyl) -1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (47)

N-methyl-N- (2-dimethylaminoethyl) -1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (68%) was obtained as white crystals using N, N' -trimethylethylenediamine instead of N, N-dimethylethylenediamine according to example 46.

Melting point: 264-266 deg.C

¹H-NMR(CDCl₃)：δ(ppm)1.75(br，4H)、2.22(s，3H)、2.27(s，3H)、2.32、2.34(s and s，total 3H)、2.40(t，J＝4.6Hz，1H)、2.47(t，J＝4.6Hz，1H)、2.52、2.54(s and s，total 3H)、2.85(br，1H)、2.98-3.08(m，2H)、3.11(s，3H)、3.42-3.44(m，2H)、4.30(m，2H)、7.51-8.07(m，8H)、11.14(s，1H)、11.80(s，1H)。

Example 48

N- (3-dimethylaminopropyl) -1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (48)

According to example 46, N-dimethyl-1, 3-propanediamine was used instead of N, N-dimethylethylenediamine to give N- (3-dimethylaminopropyl) -1- ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (41%) as a white solid.

Melting point: 247 deg.C 251 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)1.49-1.73(m，6H)、2.10(s，6H)、2.18(t，J＝7.3Hz，2H)、2.27、2.28(s and s，total 3H)、2.39、2.50(s and s，total3H)、2.95-3.12(m，5H)、4.11(br，2H)、7.56-7.91(m，8H)、11.42、11.46(brs and brs，total 1H)、12.02、12.17(s and s，total 1H)。

Example 49

N- (3-methoxypropyl) -1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (49)

According to example 46, using 3-methoxypropylamine instead of N, N-dimethylethylenediamine, N- (3-methoxypropyl) -1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (98%) was obtained as a white solid.

Melting point: 289 Ampelopsis Grossdentata 291 deg.C

¹H-NMR(CDCl₃)：δ(ppm)1.72-1.87(m，6H)、2.34、2.36(s and s，total 3H)、2.37(m，1H)、2.53、2.55(s and s，total 3H)、3.03(dd，J＝12.7，12.7Hz，2H)、3.25-3.38(m，2H)、3.34(s，3H)、3.46(t，J＝5.7Hz，2H)、4.32(d，J＝12.7Hz，2H)、6.82(brs，1H)、7.48-7.82(m，7H)、8.00、8.16(sand s，total 1H)、10.41、10.46(brs and brs，total 1H)、11.50、11.56(brs andbrs，total 1H)。

Example 50

N-cyclohexylmethyl-1- ((4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (50)

According to example 46, cyclohexylmethylamine was used instead of N, N-dimethylethylenediamine to give N-cyclohexylmethyl-1- ((4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) carbonyl) piperidine-4-carboxamide (64%) as a white solid.

Melting point: 274 ℃ and 276 DEG C

¹H-NMR(CDCl₃)：δ(ppm)1.71-1.86(m，4H)、1.95(br，5H)、2.33、2.34(s and s，total 3H)、2.53、2.54(s and s，total 3H)、2.59(br，2H)、2.99(br，5H)、3.30(br，4H)、4.29(d，J＝12.0Hz，2H)、7.47-7.80(m，8H)、7.98、8.12(s and s，total 1H)、10.78、10.82(brs and brs，total 1H)、11.67、11.75(br and br，total 1H)。

Example 51

5-benzoyl-2- (pyrrol-2-yl) benzimidazole (51)

N, N-Dimethylacetamide (5ml) was heated to 130 ℃ and 3, 4-diaminobenzophenone (150mg, 0.71mmol) and sodium bisulfite (89mg, 0.85mmol) were added and stirred for 5 minutes, then 2-formylpyrrole (81mg, 0.85mmol) was added and stirred at 130 ℃ for 1.5 hours. After cooling to room temperature and stirring, water was added to the system, and the precipitated crystal was filtered to give 5-benzoyl-2- (pyrrol-2-yl) benzimidazole (129mg, 63%) as a pale yellow solid.

Melting point: 133 ℃ of 128-

¹H-NMR(DMSO-d₆)：δ(ppm)6.26(s，1H)、6.96(s，1H)、7.04(s，1H)、7.55-7.77(m，8H)、7.89(s，1H)、11.92(s，1H)。

Example 52

5-benzoyl-2- (3, 5-dimethylpyrrol-2-yl) benzimidazole (52)

To a solution of 3, 4-diaminobenzophenone (150mg, 0.71mmol) in pyridine (3ml) was added 3, 5-dimethylpyrrole-2-carboxylic acid (99mg, 0.71mmol), and further 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (149mg, 0.78mmol) and 1-hydroxybenzotriazole monohydrate (119mg, 0.78mmol), heated to 70 ℃ and stirred overnight. After cooling to room temperature and stirring, the solvent was distilled off, purification was carried out directly using medium-pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol 98: 2), and the resulting oily substance was dissolved in acetic acid (3ml) and stirred with heating at 100 ℃ for 8 hours. After cooling to room temperature and stirring, the solvent was distilled off and purified by flash column chromatography on medium pressure silica gel (NH silica gel; chloroform: methanol 98: 2) to give 5-benzoyl-2- (3, 5-dimethylpyrrol-2-yl) benzimidazole (34mg, 15%/2 steps) as a yellow solid.

Melting point: 225 ℃ C. -

¹H-NMR(DMSO-d₆)：δ(ppm)2.23(s，3H)、2.37(s，3H)、5.79(s，1H)、7.55-7.88(m，8H)、11.09、11.21(s and s，total 1H)、11.90、12.06(sand s，total 1H)。

Example 53

5- (5-Benzoylbenzimidazol-2-yl) -2, 4-dimethylpyrrole-3-carboxylic acid ethyl ester (53)

Example 53(1)

5-formyl-2, 4-dimethylpyrrole-3-carboxylic acid ethyl ester (starting material for 53)

2.4-Diethoxycarbonyl-3, 5-dimethylpyrrole (2.0g) was dissolved in ethanol (20ml), and a 1N aqueous solution (20ml) of sodium hydroxide was added thereto, followed by heating and stirring at a bath temperature of 80 ℃ overnight. After cooling to room temperature, the reaction solution was neutralized with hydrochloric acid, and the precipitated solid was filtered and dried by heating under reduced pressure. The obtained solid was dissolved in trifluoroacetic acid (20ml), and the mixture was heated and stirred at a bath temperature of 40 ℃ for 1 hour, and then triethyl orthoformate (2.5ml) was slowly added dropwise under ice cooling, and the mixture was stirred for 2 hours after warming to room temperature. After the solvent was evaporated by concentration under reduced pressure, the residue was added to a saturated aqueous sodium hydrogencarbonate solution and stirred, and the precipitated solid was filtered. The resulting solid was purified by medium pressure silica gel flash column chromatography (hexane: ethyl acetate 5: 1 to 1: 1) and dried under reduced pressure with heating to give ethyl 5-formyl-2, 4-dimethylpyrrole-3-carboxylate (1.21g, 74%) as a pale yellow solid.

Example 53(2)

To a solution of 3, 4-diaminobenzophenone (160mg) in N, N-dimethylacetamide (5ml) were added sodium hydrogen sulfite (101mg) and ethyl 5-formyl-2, 4-dimethylpyrrole-3-carboxylate (146mg) obtained in example 53(1), and the mixture was heated to 120 ℃ and stirred for 10 hours. After cooling to room temperature, a 5% aqueous solution of sodium carbonate (6ml) was added and stirred at room temperature. The precipitated solid was filtered to give ethyl 5- (5-benzoylbenzoimidazol-2-yl) -2, 4-dimethylpyrrole-3-carboxylate (248mg, 85%) as a pale yellow solid.

Melting point: 185 ℃ C., 187 ℃ C

¹H-NMR(DMSO-d₆)：δ(ppm)1.32(t，J＝7.2Hz，3H)、2.50(s，3H)、2.52(s，3H)、4.29(q，J＝7.2Hz，2H)、7.55-7.77(m，7H)、7.95(s，1H)、11.8(brs，1H)。

Example 54

5- (5-Benzoylbenzimidazol-2-yl) -2, 4-dimethylpyrrole-3-carboxylic acid (54)

Ethyl 5- (5-benzoylbenzoimidazol-2-yl) -2, 4-dimethylpyrrole-3-carboxylate (200mg) obtained in example 53(2) was dissolved in ethanol (5ml) and tetrahydrofuran (5ml), and a 4N aqueous sodium hydroxide solution (10ml) was added and heated under reflux for 12 hours. After the disappearance of the starting material, it was cooled to room temperature, neutralized with a 1N aqueous hydrochloric acid solution, and the precipitated solid was filtered to give 5- (5-benzoylbenzimidazol-2-yl) -2, 4-dimethylpyrrole-3-carboxylic acid (139mg, 75%) as a pale yellow solid.

Melting point: more than 300 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.50(s，3H)、2.63(s，3H)、7.55-7.77(m，8H)、7.90(s，1H)、12.20(br，1H)。

Example 55

2- (5-pyrrolidin-1-yl-methylfuran-2-yl) -5-benzoylbenzimidazole (55)

Example 55(1)

5-pyrrolidin-1-yl-methylfuran-2-carboxylic acid ethyl ester (55 as starting material)

To a solution of ethyl 5-chloromethylfuran-2-carboxylate (1.0g, 5.3mmol) in N, N-dimethylacetamide (15ml) was added pyrrolidine (0.75g, 10.6mmol), and the mixture was stirred at room temperature for 24 hours. After removal of the solvent by distillation, purification was performed by medium-pressure silica gel flash column chromatography (NH silica; chloroform: methanol 98: 2) to give 5-pyrrolidin-1-yl-methylfuran-2-carboxylic acid ethyl ester (793mg, 67%).

¹H-NMR(DMSO-d₆)：δ(ppm)1.70(br，3H)、2.54(br，4H)、3.17(br，4H)、3.70(s，2H)、4.29(br，2H)、6.59(s，1H)、6.75(br，1H)。

Example 55(2)

5-pyrrolidin-1-yl-methylfuran-2-carboxylic acid (55 as starting material)

Ethyl 5-pyrrolidin-1-yl-methylfuran-2-carboxylate (770mg, 3.45mmol) obtained in example 55(1) was dissolved in ethanol (4ml), and a 1N aqueous sodium hydroxide solution (5.17ml) was added dropwise and stirred overnight. After neutralization with 1N aqueous hydrochloric acid (5.17ml), ethanol was distilled off, and dried to give 5-pyrrolidin-1-yl-methylfuran-2-carboxylic acid (1.08g, containing 38% by weight of sodium chloride, quant.) mixed with sodium chloride as a white solid.

Example 55(3)

2- (5-pyrrolidin-1-yl-methylfuran-2-yl) -5-benzoylbenzimidazole (55)

To a solution of 3, 4-diaminobenzophenone (150mg, 0.71mmol) in pyridine (3ml) was added 5-pyrrolidin-1-yl-methylfuran-2-carboxylic acid (purity 62%, 223mg, 0.71mmol), and further 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (149mg, 0.78mmol) and 1-hydroxybenzotriazole monohydrate (119mg, 0.78mmol), heated to 70 ℃ and stirred overnight. After cooling to room temperature and stirring, the solvent was distilled off, purified directly by medium-pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol 98: 2), and the resulting oily substance was dissolved in acetic acid (3ml) and stirred with heating at 100 ℃ for 8 hours. After cooling to room temperature and stirring, the solvent was distilled off and purified by flash column chromatography on medium pressure silica gel (NH silica gel; chloroform: methanol 98: 2) to give 2- (5-pyrrolidin-1-yl-methylfuran-2-yl) -5-benzoylbenzimidazole (143mg, 55%/2 steps) as a yellow oil.

¹H-NMR(CDCl₃)：δ(ppm)1.90(br，4H)、2.81(br，4H)、3.88(s，2H)、6.45(d，J＝3.5Hz，1H)、7.19(d，J＝3.5Hz，1H)、7.44-7.84(m，8H)、8.10(s，1H)。

Example 56

2- (5-Dimethylaminomethylfuran-2-yl) -5-benzoylbenzimidazole (56)

According to example 55, dimethylamine was used instead of pyrrolidine to give 2- (5-dimethylaminomethylfuran-2-yl) -5-benzoylbenzimidazole (203mg, 83%) as a pale yellow amorphous form.

¹H-NMR(DMSO-d₆)：δ(ppm)2.21(s，6H)、3.59(s，2H)、6.56(d，J＝3.2Hz，1H)、7.22(d，J＝3.2Hz，1H)、7.54-7.92(m，8H)、13.23(br，1H)。

Example 57

5- (5-Benzoylbenzimidazol-2-yl) furan-2-carboxylic acid (57)

N, N-Dimethylacetamide (5ml) was heated to 130 ℃ and 3, 4-diaminobenzophenone (63mg, 0.30mmol) and sodium bisulfite (37mg, 0.36mmol) were added and stirred for 5 minutes, then 5-formylfuran-2-carboxylic acid (50mg, 0.36mmol) was added and stirred for 1.5 hours at 130 ℃. After cooling to room temperature and stirring, water was added to the system, and the precipitated solid was filtered to give 5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxylic acid (63mg, 64%) as a pale yellow solid.

Melting point: 170 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)7.39-8.01(m，10H)、13.61(s，1H)。

Example 58

2- (5-Bromofuran-2-yl) -5-benzoylbenzimidazole (58)

Using 5-bromofuran-2-carboxylic acid instead of 2, 4-dimethylfuran-3-carboxylic acid according to example 1, 2- (5-bromofuran-2-yl) -5-benzoylbenzimidazole (92%) was obtained as a yellow solid.

Melting point: 167 ℃ plus 172 DEG C

¹H-NMR(CDCl₃)：δ(ppm)6.59(d，J＝3.4Hz，1H)、7.23(d，J＝3.4Hz，1H)、7.41-7.81(m，8H)、8.06(s，1H)。

Example 59

(4- (5-Benzoylbenzimidazol-2-yl) -2-furanylcarbonyl) pyrrolidine (59)

To a solution of 5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxylic acid (100mg, 0.30mmol) obtained in example 57 and pyridine (4ml) were added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (63mg, 0.33mmol) and 1-hydroxybenzotriazole monohydrate (51mg, 0.33mmol), followed by pyrrolidine (21mg, 0.30mmol) and heating. Stirred at 70 ℃ for 6 hours, then allowed to cool to room temperature and stirred. The solvent was removed by distillation and purified by flash column chromatography on medium pressure silica gel (NH silica gel; chloroform: methanol 98: 2) to give (4- (5-benzoylbenzoimidazol-2-yl) -2-furylcarbonyl) pyrrolidine (102mg, 88%) as a brown oil.

¹H-NMR(CDCl₃)：δ(ppm)1.95-2.10(m，4H)、3.68(t，J＝6.8Hz，2H)、3.82(t，J＝6.8Hz，2H)、7.04(d，J＝3.7Hz，1H)、7.32(d，J＝3.7Hz，1H)、7.45-7.83(m，8H)、8.12(s，1H)。

Example 60

5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxamide (60)

According to example 59, using 28% aqueous ammonia instead of pyrrolidine, 5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxamide (96%) was obtained as a brown oily substance.

¹H-NMR(CDCl₃)：δ(ppm)6.58-8.19(m，12H)、12.76(s，1H)。

Example 61

N- (2-dimethylaminoethyl) -5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxamide (61)

According to example 59, N-dimethylethylenediamine was used instead of pyrrolidine to give N- (2-dimethylaminoethyl) -5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxamide (64%) as a brown oily substance.

¹H-NMR(CDCl₃)：δ(ppm)2.32(s，6H)、3.22(br，2H)、3.56(br，2H)、5.51(br，1H)、7.19-8.09(m，11H)。

Example 62

N- (3, 4-methylenedioxyphenylmethyl) -5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxamide (62)

According to example 59, piperonylamine was used instead of pyrrolidine to give N- (3, 4-methylenedioxyphenylmethyl) -5- (5-benzoylbenzoimidazol-2-yl) furan-2-carboxamide (77%) as a brown oily substance.

¹H-NMR(CDCl₃)：δ(ppm)4.42(s，2H)、5.85(s，2H)、6.63-7.96(m，15H)。

Example 63

(4- (5-Benzoylbenzimidazol-2-yl) -2-furylcarbonyl) thiazolidine (63)

According to example 59, (4- (5-benzoylbenzoimidazol-2-yl) -2-furylcarbonyl) thiazolidine (64%) was obtained as a brown oily substance using thiazolidine instead of pyrrolidine.

¹H-NMR(CDCl₃)：δ(ppm)2.25(s，2H)、3.12-3.26(m，4H)、7.28(d，J＝3.6Hz，1H)、7.34(d，J＝3.6Hz，1H)、7.48-7.82(m，8H)、8.08(s，1H)。

Example 64

(N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3.5-dimethylpyrrole-2-carboxamide (64)

According to example 11, using 40% aqueous dimethylamine solution instead of N, N' -trimethylethylenediamine, (N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (95%) was obtained as a light yellow solid.

Melting point: 165- "170 deg.C

¹H-NMR(DMSO-d₆)：δ(ppm)2.28，2.30(s and s，total 3H)，2.50，2.51(s and s，total 3H)，3.01(s，6H)，7.53-7.98(m，8H)，11.38，11.42(brsand brs，total 1H)，12.03，12.17(brs and brs，total 1H)。

Example 65

(N-hydroxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3.5-dimethylpyrrole-2-carboxamide (65)

Using N-methyl hydroxylamine hydrochloride instead of N, N' -trimethylethylenediamine according to example 11, (N-hydroxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (41%) was obtained as a light yellow solid.

Melting point: 227 + 229 deg.C (decomposition)

¹H-NMR(DMSO-d₆)：δ(ppm)2.38-2.57(m，6H)，3.30(s，3H)，7.54-8.00(m，8H)，9.92(s，1H)，11.19，11.23(brs and brs，total 1H)，12.11，12.25(s and s，total 1H)。

Example 66

(N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3.5-dimethylpyrrole-2-carboxamide (66)

According to example 11, using 40% aqueous methylamine instead of N, N' -trimethylethylenediamine, (N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (81%) was obtained as a light yellow solid.

Melting point: 188 ℃ plus 190 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.41-2.53(m，6H)，2.78，2.79(s and s，total 3H)，7.33-7.47(br，1H)，7.52-7.99(m，8H)，11.36，11.40(brs and brs，total 1H)，12.11，12.26(s and s，total 1H)。

Example 67

(N-hydroxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3.5-dimethylpyrrole-2-carboxamide (67)

To a solution of 4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (358mg, 1.0mmol) obtained in example 12 in dimethylsulfoxide (3ml) were added 37% aqueous formaldehyde (0.17ml) and 1N aqueous sodium hydroxide (0.02ml), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, and the precipitated solid was filtered, washed with water, and dried under reduced pressure. The resulting crude crystals were purified by medium pressure flash column chromatography on silica gel (methanol: chloroform ═ 1: 15 to 1: 10) to give (N-hydroxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (76%) as a light yellow solid.

Melting point: 196 ℃ C. & lt 210 ℃ C. & gt

¹H-NMR(DMSO-d₆)：δ(ppm)2.48(s，3H)，2.53(s，3H)，4.72(dd，J＝6.6，6.6Hz，2H)，5.59(t，J＝6.6Hz，1H)，7.53-7.78(m，7H)，7.91(s，1H)，8.03(t，J＝6.3Hz，1H)，11.44(brs，1H)，12.10-12.18(br，1H)。

Example 68

4- (5-Phenoxybenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid ethyl ester (68)

To a solution of 4-phenoxy-1, 2-phenylenediamine (1.60g, 8.0mmol) known in the literature in N, N-dimethylacetamide (25ml) were added sodium bisulfite (0.87g, 8.4mmol) and ethyl 3, 5-dimethyl-4-formylpyrrole-2-carboxylate (1.64g, 8.4mmol), heated to 110 ℃ and stirred for 18 hours. The resulting reaction solution was cooled to room temperature, and a 5% sodium carbonate aqueous solution was added thereto, followed by extraction with ethyl acetate, washing with water and saturated brine, and drying over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by medium-pressure silica gel flash column chromatography (methanol: chloroform ═ 1: 100 to 1: 30) to give ethyl 4- (5-phenoxybenzimidazol-2-yl) -3.5-dimethylpyrrole-2-carboxylate (2.27g, 76%) as a pale yellow solid.

Melting point: 239, 242 ℃ and

¹H-NMR(CDCl₃)：δ(ppm)1.39(t，J＝7.1Hz，3H)，2.57(s，6H)，4.35(q，J＝7.1Hz，2H)，6.96-7.82(m，8H)，8.94(brs，1H)，9.17(br，1H)。

example 69

4- (5-Phenoxybenzoimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid (69)

Ethyl 4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylate (1.88g, 5.0mmol) obtained in example 68 was dissolved in ethanol (10ml) and tetrahydrofuran (5ml), and a 4N aqueous solution (6ml, 24mmol) of sodium hydroxide was added thereto, followed by stirring at 80 ℃ for 6 hours. The obtained reaction solution was cooled to 0 ℃, neutralized with a 1N aqueous hydrochloric acid solution, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid (1.70g, 98%) as a pale yellow solid.

Melting point: 167-

¹H-NMR(DMSO-d₆)：δ(ppm)2.42(s，3H)，2.47(s，3H)，6.85-7.16(m，5H)，7.30-7.38(m，2H)，7.54(d，J＝8.6Hz，1H)，11.44(brs，1H)，11.50-12.38(br，3H)。

Example 70

((4- (5-phenoxybenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) -2-carbonyl) pyrrolidine (70)

To a solution of 4- (5-phenoxybenzimidazol-2-yl) -3.5-dimethylpyrrole-2-carboxylic acid (174mg, 0.5mmol) obtained in example 69 in N, N-dimethylformamide (3ml) were added 1-hydroxybenzotriazole monohydrate (84mg, 0.55mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (115mg, 0.6mmol) and pyrrolidine (0.06ml, 0.75mmol), and the mixture was stirred at 60 ℃ for 19 hours. The resulting reaction solution was allowed to cool to room temperature, water and a saturated aqueous solution of sodium hydrogencarbonate were added, and the precipitated solid was filtered. The resulting crude crystals were purified by medium pressure flash column chromatography on silica gel (methanol: chloroform ═ 1: 20 to 1: 10) to give ((4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) -2-carbonyl) pyrrolidine (116mg, 58%) as a pale yellow solid.

Melting point: 251 deg.C 254 deg.C

¹H-NMR(CDCl₃)：δ(ppm)1.90(br，4H)，2.25(s，3H)，2.28(s，3H)，3.55(br，4H)，6.91-7.72(m，8H)，9.44(s，1H)，10.30(brs，1H)。

Example 71

((4- (5-phenoxybenzoimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) -2-carbonyl) morpholine (71)

According to example 70, using morpholine instead of pyrrolidine, ((4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrol-2-yl) -2-carbonyl) morpholine was obtained (67%) as a light yellow solid.

Melting point: 268 ℃ C. and 270 ℃ C

¹H-NMR(CDCl₃)：δ(ppm)2.24(s，3H)，2.28(s，3H)，3.38-3.82(m，8H)，6.91-7.12(m，4H)，7.21-7.73(m，4H)，9.43(s，1H)，10.00(brs，1H)。

Example 72

N- (2- (2-pyridyl) ethyl) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (72)

Using 2- (2-aminoethyl) pyridine instead of pyrrolidine, according to example 70, N- (2- (2-pyridyl) ethyl) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (76%) was obtained as a light yellow solid.

Melting point: 290 ℃ and 293 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.42(s，3H)，2.43(s，3H)，3.01(t，J＝7.1Hz，2H)，3.64(dt，J＝12.5，7.1Hz，2H)，6.83-7.84(m，12H)，8.43-8.65(m，1H)，11.31(s，1H)，11.81，11.92(s and s，total 1H)。

Example 73

N- (methoxy) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (73)

Using O-methyl hydroxylamine hydrochloride instead of pyrrolidine according to example 70, N- (methoxy) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (71%) was obtained as a light yellow solid.

Melting point: 166 ℃ 168-

¹H-NMR(CDCl₃)：δ(ppm)2.43(s，6H)，3.71(s，3H)，6.83-7.64(m，8H)，10.71(s，1H)，11.38(s，1H)，11.83，11.94(s and s，total 1H)。

Example 74

(N-methoxy-N-methyl) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (74)

According to example 15(3), 4-phenoxy-1, 2-phenylenediamine was used instead of 3, 4-diaminobenzophenone to give (N-methoxy-N-methyl) -4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (74%) as a light yellow solid.

Melting point: 130 ℃ and 134 DEG C

¹H-NMR(CDCl₃)：δ(ppm)2.57(s，6H)，3.35(s，3H)，3.72(s，3H)，6.92-7.85(m，8H)，9.14-9.43(br，2H).

Example 75

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-phenoxybenzimidazole (75)

According to example 13(2), 4-phenoxy-1, 2-phenylenediamine was used instead of 3, 4-diaminobenzophenone to give 2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-phenoxybenzimidazole (77%) as a light yellow solid.

Melting point: 278 heat 280 deg.C

¹H-NMR(CDCl₃)：δ(ppm)2.42(s，3H)，2.48(s，3H)，6.90-7.77(m，8H)，10.61(brs，1H)，11.31(s，1H)。

Example 76

4- (5-Phenoxybenzoimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (76)

According to example 2(3), 4-phenoxy-1, 2-phenylenediamine was used instead of 3, 4-diaminobenzophenone to give 4- (5-phenoxybenzimidazol-2-yl) -3, 5-dimethylfuran-2-carboxamide (59%) as a light yellow solid.

Melting point: 248, 251 DEG C

¹H-NMR(DMSO-d₆)：δ(ppm)2.49(s，3H)，2.57(s，3H)，6.89-7.86(m，10H)，12.27(brs，1H)。

Comparative example 1

4- (5- (4-pyridylthio) -6-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid ethyl ester

To 2.75g (8.10mmol) of 4-phenoxy-2-nitro-5- (4-pyridylthio) aniline synthesized according to the method described in the publication (Japanese patent application laid-open No. 2000-026430) was added 2.0g (35.8mmol) of iron powder to obtain a mixture, 10ml (10.0mmol) of 1N aqueous ammonium chloride solution was added and the mixture was stirred at 85 ℃ for 3 hours. Then, the reaction solution was allowed to return to room temperature, and 60ml of ethyl acetate was added thereto, and insoluble matter was removed by filtration using celite. The obtained filtrate was separated, and the ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and then dried under reduced pressure to obtain crude diamine (2.0 g).

1.0g (3.23mmol) of the resulting crude diamine was dissolved in 15ml of N, N-dimethylacetamide, and 0.37g (3.55mmol) of sodium hydrogen sulfite and 0.69g (3.53mmol) of ethyl 3, 5-dimethyl-4-formylpyrrole-2-carboxylate were added, followed by heating to 130 ℃ and stirring for 16 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, a 5% aqueous sodium hydrogencarbonate solution was added to the resulting residue, and the precipitated solid was filtered, washed with water, and dried under reduced pressure. The obtained crude crystals were purified by medium pressure flash column chromatography on silica gel (methanol: chloroform: 1: 50 to 1: 10) to give ethyl 4- (5- (4-pyridylthio) -6-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylate (0.75g, 48%) as an amorphous form.

¹H-NMR(DMSO-d₆)δ(ppm)：1.35(t，J＝7.2Hz，3H)，2.46(s，3H)，2.55(s，3H)，4.29(q，J＝7.2Hz)，7.10-7.80(m，9H)，8.23-8.36(m，2H)，11.61(br，1H)，12.20(br，1H)。

Comparative example 2

(N, N-dimethyl) -4- (5- (4-pyridylthio) -6-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide

To 0.48g (1.0mmol) of ethyl 4- (5- (4-pyridylthio) -6-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylate obtained in comparative example 1 were added 5ml of ethanol and 3.5ml (3.5mmol) of a 1N aqueous solution of sodium hydroxide, and the mixture was stirred at 60 ℃ for 17 hours. After cooling, the reaction mixture was concentrated, water was added and insoluble matter was filtered off. The filtrate was neutralized with a 2N aqueous hydrochloric acid solution, and the precipitated solid was filtered, washed with water and dried under reduced pressure to give a crude carboxylic acid (0.22 g). 0.2g (0.4mmol) of the crude carboxylic acid was dissolved in 3ml of N, N-dimethylformamide, and 92mg (0.5mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 0.25ml (2.2mmol) of a 40% aqueous solution of dimethylamine were added thereto, and the mixture was stirred at 60 ℃ for 18 hours. The reaction solution was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure flash column chromatography on silica gel (methanol: chloroform ═ 1: 100 to 1: 10) to give (N, N-dimethyl) -4- (5- (4-pyridylthio) -6-phenoxybenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxamide (83mg, 43%) as an amorphous form.

¹H-NMR(DMSO-d₆)δ(ppm)：2.44-2.55(m，6H)，3.02(s，6H)，7.08-7.81(m，9H)，8.33-8.47(m，2H)，11.56(br，1H)，12.18(br，1H)。

Comparative example 3

Comparative example 3(1)

2-Furfural-5-phosphoric acid diethyl ester

A solution of 2-furaldehyde furfural diethylacetal (13.6g, 80mmol) in tetrahydrofuran (30ml) was cooled to-78 deg.C, a 1.6M n-butyllithium-hexane solution (50ml, 80mmol) was added dropwise, and stirred at the same temperature for 1 hour. Diethyl chlorophosphate (12.7ml, 88mmol) was added dropwise to the resulting reaction solution, and stirred at the same temperature for 30 minutes, followed by addition of a saturated aqueous ammonium chloride solution. The precipitated solid was removed by filtration, the filtrate was distilled under reduced pressure to remove the solvent, and water was added to the obtained residue, followed by extraction with ethyl acetate, washing with water and saturated brine, and drying over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure, and 80% acetic acid (100ml) was added to the obtained residue, followed by stirring at 90 ℃ for 4 hours. The reaction mixture was cooled to room temperature, the solvent was then distilled off under reduced pressure, and the obtained residue was added with water, extracted with ethyl acetate, washed with water, a saturated aqueous sodium bicarbonate solution, water, and a saturated brine, and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by medium-pressure silica gel flash column chromatography (ethyl acetate: hexane ═ 1: 1 to 5: 1) to obtain diethyl 2-furfural-5-phosphate (1.65g, 9%) as a pale yellow oil.

¹H-NMR(CDCl₃)：δ(ppm)1.30-1.50(m，6H)，4.02-4.35(m，4H)，7.18-7.32(m，2H)，9.80(s，1H)。

Comparative examples 3 and 2

5-benzophenone-2- (2-diethylphosphono-5-furyl) benzimidazole

To a solution of 3, 4-diaminobenzophenone (0.85g, 4.0mmol) in N, N-dimethylformamide (10ml) was added sodium bisulfite (0.46g, 4.4mmol) and heated to 100 ℃. N, N-dimethylformamide (5ml) was added dropwise to the diethyl 2-furfural-5-phosphate (1.16g, 5.0mmol) obtained in comparative example 3(1), and the mixture was stirred at the same temperature for 3 hours. The resulting reaction solution was cooled to room temperature, and then a 5% aqueous solution of sodium carbonate was added, followed by extraction with ethyl acetate, washing with water and saturated brine, and drying over anhydrous sodium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure, and the obtained residue was purified by medium-pressure silica gel flash column chromatography (ethyl acetate: chloroform ═ 1: 5 to 1: 1) to give 5-benzophenone-2- (2-diethylphosphono-5-furyl) benzimidazole (1.05g, 62%) as a pale yellow oil.

¹H-NMR(CDCl₃)：δ(ppm)1.38(t，J＝7.1Hz，6H)，4.13-4.35(m，4H)，7.20-8.28(m，10H)，10.65-11.38(br，1H)。

Comparative examples 3(3)

5-benzophenone-2- (2-phosphono-5-furanyl) benzimidazole dihydrate

To 5-benzophenone-2- (2-diethylphosphono-5-furyl) benzimidazole (424mg, 1.0mmol) obtained in comparative example 3(2) were added 47% hydrobromic acid (6.0ml) and water (4.0ml), and the mixture was stirred at 100 ℃ for 8 hours. The obtained reaction liquid was cooled to room temperature, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the precipitated solid was filtered, washed with water and dried under reduced pressure to obtain 5-benzophenone-2- (2-phosphono-5-furanyl) benzimidazole dihydrate (359mg, 89%) as a pale yellow solid.

Melting point: 224 ℃ 229 DEG C

C₁₈H₁₃N₂O₅P+2H₂Elemental analysis of O: calculated value C: 53.47 percent; h: 4.24 percent; n: 6.93 percent; found value C: 53.74 percent; h: 4.19 percent; n: 6.92 percent.

¹H-NMR(DMSO-d₆)：δ(ppm)7.08-7.17(m，1H)，7.31-7.39(m，1H)，7.53-7.87(m，9H)，7.97(s，1H)。

Experimental example 1: inhibition of hematopoietic synthase

According to the method of Urade, Y, et al (J.biol.chem.262, 3820-3825 (1987)). Namely, the reaction solution (49. mu.L); 100mM Tris-HCl (pH8.0), 1mM reduced glutathione, 0.1mg/mL gamma-globulin, human hematopoietic synthetic enzyme (appropriate amount) and test compound (final concentration: 0.01 to 100. mu.M) were preincubated at 25 ℃ for 5 minutes. In addition, a DMSO solution having a final concentration of 1% was added to the solvent Control group (Control group). Then, add [ 2]¹⁴C]Prostaglandin H2 (final concentration: 10. mu.M) 1. mu.L was used to initiate the reaction. 1 minute after the start of the reaction, a reaction stop solution (diethyl ether/methanol/1M citric acid (30/4/1) 250. mu.L) at-20 ℃ was added to stop the reaction.

50. mu.L of the upper layer (organic solvent phase) after the reaction was stopped was spotted on a TLC plate and developed at-20 ℃ for 45 minutes (developing solvent: diethyl ether/methanol/acetic acid (capacity ratio: 90/2/1)). After drying the plates, they were exposed to light for 1 hour to one day on an imaging plate and the radioactivity corresponding to prostaglandin D2 was analyzed using an image analyzer (fuji film). The ratio (%) of the prostaglandin D2 band in each lane was calculated, and the 50% inhibitory concentration (IC50 value) of the test compound against the hematopoietic synthase was calculated from the inhibitory rate of the Control group set in each experiment. The results are shown in tables 1 to 3.

TABLE 1

Compound numbering	The concentration of drug (μ M) that inhibits the hematopoietic group enzyme by 50%
Compound numbering		1	0.796
2	0.274	1	0.796
2	0.274	3	0.178
4	0.278	3	0.178
4	0.278	5	1.45
6	1.74	5	1.45
6	1.74	7	0.588
9	0.110	7	0.588
9	0.110	10	0.436
11	0.269	10	0.436
11	0.269	12	0.100
13	0.540	12	0.100
13	0.540	14	0.355
15	0.256	14	0.355
15	0.256	16	2.28
17	0.124	16	2.28
17	0.124	18	0.080
19	0.874	18	0.080
19	0.874	20	0.871
21	0.304	20	0.871
21	0.304	22	0.829
23	0.223	22	0.829
23	0.223	24	0.496
25	0.286	24	0.496
25	0.286	26	0.149
27	0.309	26	0.149
27	0.309	28	0.073
29	0.053	28	0.073
29	0.053	30	0.113

TABLE 2

Compound numbering	The concentration of drug (μ M) that inhibits the hematopoietic group enzyme by 50%
Compound numbering		31	0.090
32	0.124	31	0.090
32	0.124	34	0.072
35	0.746	34	0.072
35	0.746	36	0.195
37	0.213	36	0.195
37	0.213	38	0.136
39	0.351	38	0.136
39	0.351	40	0.592
41	1.45	40	0.592
41	1.45	42	0.063
43	0.791	42	0.063
43	0.791	44	1.67
45	0.643	44	1.67
45	0.643	46	0.758
47	0.269	46	0.758
47	0.269	48	0.124
49	0.649	48	0.124
49	0.649	50	0.843
52	4.80	50	0.843
52	4.80	53	3.08
56	4.78	53	3.08
56	4.78	57	4.13
58	2.37	57	4.13
58	2.37	59	3.56
60	4.36	59	3.56
60	4.36	62	2.43
63	1.25	62	2.43

TABLE 3

Compound numbering	The concentration of drug (μ M) that inhibits the hematopoietic group enzyme by 50%
Compound numbering		64	0.377
65	0.124	64	0.377
65	0.124	66	0.077
67	0.109	66	0.077
67	0.109	68	0.210
69	0.491	68	0.210
69	0.491	70	0.614
71	0.870	70	0.614
71	0.870	72	0.209
73	0.240	72	0.209
73	0.240	74	0.263
75	0.218	74	0.263
75	0.218	76	0.109
HQL-79	24.4	76	0.109
HQL-79	24.4	Comparative example 1	＞30μM
Comparative example 2	＞30μM	Comparative example 1	＞30μM
Comparative example 2	＞30μM	Comparative example 3	29.3

From the above results, it can be seen that the compound of the present invention has more excellent hematopoietic synthase inhibitory activity as an inhibitor of hematopoietic synthase than the known HQL-79.

Experimental example 2: inhibition of prostaglandin D2 production in rat alveolar lavage fluid

Male Brawn Norway rats of 7 weeks old were subcutaneously injected on the back with 1 mL/mouse of a physiological saline solution containing 1mg of ovalbumin and 4mg of alum, and further, were self-sensitized by intraperitoneal administration of 0.06mg of a pertussis toxin dead bacteria. After 14 days of sensitization, 2% ovalbumin was inhaled for 10 minutes, and alveolar lavage fluid was recovered 1 hour after inhalation. The amount of PGD2 in alveolar lavage fluid was determined using the EIA kit. Test compound (10mg/kg) was administered orally 2 hours prior to antigen inhalation. The results are shown in Table 4.

TABLE 4

Compound (I)	Inhibition rate (%) of PGD2 amount in alveolar lavage fluid
Compound (I)	Inhibition rate (%) of PGD2 amount in alveolar lavage fluid	3	36
13	48	3	36
13	48	15	＞72
40	65	15	＞72
40	65	42	88

From the above results, it can be seen that the compound of the present invention strongly inhibits the amount of PGD2 in alveolar lavage fluid by oral administration at 10 mg/kg.

Experimental example 3: antigen-induced nasal obstruction improvement in guinea pigs

A5-week-old male Std, Hartley guinea pig was subjected to autoactivation (primary sensitization) by subcutaneously injecting 1 mL/1 mg/mL of an ovalbumin physiological saline solution into the back of the guinea pig. After 1 week and 2 weeks of the initial sensitization, a 10mg/mL physiological saline solution of ovalbumin was administered into each of the two nasal cavities at 20. mu.L each time using a micropipette (nasal drip sensitization). After 3 weeks of initial sensitization, 20mg/mL of an ovalbumin physiological saline solution was administered into both nasal cavities 10. mu.L at a time using a micropipette, causing a rhinitis reaction.

Nasal airway resistance (nRaw) was measured 100 breaths before dropping nose with ovalbumin, 10 minutes after dropping nose, 2, 3, 4, 5, 6, and 7 hours using an integrated respiratory function measurement system (Pulmos-I, m.i.p.s. co.), and the average value thereof was used as nRaw for each measurement time. The calculation of the rate of increase in nPaw is shown below.

Increase (%) of nRaw at each measurement time

(nRaw-nPaw before Induction)/(nRaw before Induction X100 at each measurement time

Nasal congestion was assessed by calculating the area under the curve (AUC) of the rate of increase of nRaw after induction of 3 to 7 hours_{3 to 7 hours}) The process is carried out. In addition, I_{3 to 7 hours}The increase rate of nRaw after 3 to 7 hours of induction is shown.

AUC_{3 to 7 hours}＝1/2(I_{3 hours}+2×I_{4 hours}+2×I_{5 hours}+2×I_{6 hours}+I_{7 hours})

In order to confirm the nasal congestion effect by PDG2 production inhibition, compound 15 was selected as a representative compound, and oral administration was repeated once a day for 15 days from nasal drop sensitization one week after the initial sensitization to an induction target 3 weeks after the initial sensitization. In addition, the nasal drip sensitization day (1 week and 2 weeks after the initial sensitization) and the induction day were orally administered 1 hour before the intranasal administration of ovalbumin.

As positive control substances, a leukotriene antagonist Pranlukast and a thromboxane antagonist ramatoban having a strong nasal obstruction-improving effect were used. The results are shown in Table 5 below.

TABLE 5

Compound (I)	Dosage (mg/kg)	AUC_{3 to 7 hours}(%, hour)	Inhibition ratio (%)
Compound (I)	Dosage (mg/kg)	AUC_{3 to 7 hours}(%, hour)	Inhibition ratio (%)	Normal group	-	27.0±15.9	-
Control group	-	564.8±103.4^**	0	Normal group	-	27.0±15.9	-
Control group	-	564.8±103.4^**	0	15	3	237.9±69.1^##	60.8
10	153.5±27.1^##	76.5			3	237.9±69.1^##	60.8
10	153.5±27.1^##	76.5	30		65.7±28.9^##	92.8
Pranlukast	30	126.3±41.7^$$	30		65.7±28.9^##	92.8	81.5
Pranlukast	30	126.3±41.7^$$	Ramatroban	30	183.4±29.3^$$	70.9	81.5

Repeated oral administration of 3, 1O, 30mg/kg of Compound 15 dose-dependently inhibited antigen-induced nasal congestion (rise in nasal airway resistance: AUC)_{3 to 7 hours}) The inhibition rates were 60.8%, 76.5% and 92.8%, respectively. The nasal congestion-improving effect of compound 15 at 10mg/kg was equivalent to that of Pranlukast or Ramatroban at 30mg/kg, and showed a stronger improving effect than those of the positive control substances at the same administration amount of 30 mg/kg.

Examples of formulations containing the compound of the present invention as an active ingredient are shown below.

Formulation example 1: tablet formulation

Example 15 Compound 50mg

Corn starch 50mg

Microcrystalline cellulose 50mg

Hydroxypropyl cellulose 15mg

Lactose 47mg

Talc 2mg

Magnesium stearate 2mg

Ethyl cellulose 30mg

Unsaturated glyceride 2mg

Titanium dioxide 2mg

Tablets of 250mg per 1 tablet were prepared according to a conventional method at the above mixing ratio.

Preparation example 2: granules

Example 19 Compound 300mg

Lactose 540mg

Corn starch 100mg

Hydroxypropyl cellulose 50mg

Talc 10mg

Granules each containing 1000mg of the above were prepared in the above mixing ratio according to a conventional method.

Preparation example 3: capsule preparation

Example 20 Compound 100mg

Lactose 30mg

Corn starch 50mg

Microcrystalline cellulose 10mg

Magnesium stearate 3mg

193mg of each capsule was prepared according to a conventional method in the above-mentioned mixing ratio.

Preparation example 4: injection preparation

Example 21 Compound 100mg

Sodium chloride 3.5mg

Proper amount of distilled water for injection

(2ml per ampoule)

The injection is prepared according to the conventional method at the mixing ratio.

Preparation example 5: syrup preparation

Example 27 Compound 200mg

Refined white sugar 60g

Ethyl p-hydroxybenzoate 5mg

P-hydroxybenzoic acid butyl ester 5mg

Proper amount of perfume

Proper amount of coloring material

Proper amount of purified water

Syrups were prepared according to the usual methods with the above mixing ratios.

Preparation example 6: suppository

Example 35 Compound 300mg

Witepsol W-35 1400mg

(registered trade name, a mixture of mono-, di-and triglycerides of saturated fatty acids ranging from lauric acid to stearic acid, manufactured by Dynamite Nobel)

The suppository is prepared according to the conventional method by the mixing ratio.

Industrial applicability

The present invention provides a benzimidazole compound represented by the general formula (I) or a salt thereof, which is useful as a prostaglandin D synthase inhibitor.

The benzimidazole compound or a salt thereof of the present invention has an excellent prostaglandin D synthase inhibitory activity.

Therefore, the benzimidazole compound or a salt thereof of the present invention is useful as a prophylactic and/or therapeutic agent for diseases in which prostaglandin D2 or a metabolite thereof is involved, for example, allergic diseases or inflammatory diseases, and an inhibitor of the deterioration of alzheimer's disease and brain injury, based on its excellent prostaglandin D synthase inhibitory activity, and is expected to have other useful pharmaceutical effects.

Claims

1. A benzimidazole compound represented by the following general formula (I) or a salt thereof,

in the formula, X¹Represents an oxygen atom or a carbonyl group, R¹Represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents; provided that the substituent is not a phosphoric acid group or a phosphate groupA compound (I) is provided.

2. The benzimidazole compound or a salt thereof according to claim 1, wherein X¹Is a carbonyl group.

3. The benzimidazole compound or a salt thereof according to claim 1, wherein X¹Represents an oxygen atom or a carbonyl group;

4. The benzimidazole compound or a salt thereof according to claim 1, wherein X¹Represents a carbonyl group, and represents a carbonyl group,

R¹indicating toolA furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents;

R³And R⁴A saturated or unsaturated cyclic amino group which may form a ring structure together with an adjacent nitrogen atom and may have one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom, the cyclic amino group may have a group selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, a formyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, an aryl group having 6 to 14 carbon atoms which may have a substituent, and a cyclic amino group which may have a group selected from the group consisting of a halogen atom, a hydroxyl group, aA substituted (C1-C6 alkoxy) carbonyl group and a mono-or di (C1-C6 alkyl) aminocarbonyl group which may have a substituent, as a substituent.

5. The benzimidazole compound or a salt thereof according to claim 1, wherein X¹Represents a carbonyl group;

R³And R⁴May form, together with an adjacent nitrogen atom, a saturated or unsaturated cyclic amino group having one hetero atom selected from a nitrogen atom and an oxygen atom in the ring structure in addition to the adjacent nitrogen atom.

6. The benzimidazole compound or a salt thereof according to claim 1, wherein X¹Represents a carbonyl group;

7. The benzimidazole compound or a salt thereof according to claim 1, wherein X¹Represents a carbonyl group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

R³and R⁴One of them is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other is a hydrogen atom or a hydroxyl groupAn alkyl group having 1 to 3 carbon atoms which may have a substituent, an alkoxy group having 1 to 3 carbon atoms which may have a substituent, or a phenyl group which may have 1 to 3 groups selected from the group consisting of a halogen atom, a cyano group, and an alkoxy group having 1 to 3 carbon atoms as substituents, or

8. The benzimidazole compound or a salt thereof according to claim 1, wherein X¹Represents a carbonyl group;

R²represents a hydroxyl group, an ethoxy group, or-NR³R⁴A group;

-NR³R⁴The group represents a pyrrolidinyl group or a morpholino group.

9. The benzimidazole compound or a salt thereof according to claim 1, which is:

(4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethyl-2-furylcarbonyl) pyrrolidine,

4- (5-benzoylbenzimidazol-2-yl) -3, 5-dimethylpyrrole-2-carboxylic acid,

2- (2-cyano-3, 5-dimethylpyrrol-4-yl) -5-benzoylbenzimidazole,

10. A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A prostaglandin D synthase inhibitor comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A prophylactic and/or therapeutic agent for a disease in which prostaglandin D2 or a metabolite thereof is involved, which comprises an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. The prophylactic and/or therapeutic agent according to claim 12, wherein the disease in which prostaglandin D2 or a metabolite thereof is involved is any one of an allergic disease, an inflammatory disease, Alzheimer's disease, and brain injury.

14. A prophylactic and/or therapeutic agent for allergic diseases, which comprises an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. A prophylactic and/or therapeutic agent for inflammatory diseases, which comprises an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A prophylactic and/or therapeutic agent for alzheimer's disease or brain injury, which comprises an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method for preventing or treating a disease in which prostaglandin D2 or a metabolite thereof is involved, which comprises administering to a patient an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a prostaglandin D synthase inhibitor.