JP2003286171A - Par inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a compound that has PAR2 inhibitory action and is useful as a therapeutic agent, a preventive agent or a disease progress inhibitor against the PAR2-participating diseases. <P>SOLUTION: The PAR2 inhibitor contains, as an active ingredient, the compound represented by formula (1) (wherein R<SP>1</SP>and R<SP>2</SP>are independently H, hydroxy, an alkoxy, nitrile, an aryl or an alkyl, or R<SP>1</SP>and R<SP>2</SP>are bound together with adjacent carbon atoms to form a heterocyclic cycloalkane having 1 or 2 N atoms, 0-1 O atom and 0-1 S atom; R<SP>3</SP>is H, an alkyl, a haloalkyl or an aryl; R<SP>4</SP>and R<SP>5</SP>are independently H, a halogen, an alkyl, an alkoxy, methylenedioxy or a haloalkyl) or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to PAR2 inhibitors, and PAR2-related allergic diseases, respiratory diseases, cardiovascular diseases, nervous system diseases, and inflammatory agents containing the PAR2 inhibitors as active ingredients. The present invention relates to a therapeutic agent, prophylactic agent, or antiprogressive agent for diseases, neuroinflammatory diseases, or arthritic diseases.

[0002]

BACKGROUND ART Protease receptor PAR (proteinase-ac)
tivated receptor) is a type of G protein-coupled 7-transmembrane receptor and is a family of receptors that mediate the cellular actions of serine proteases such as thrombin and trypsin.
To date, four PARs; PAR1, PAR2, PAR3, PAR4 have been cloned. The serine protease cleaves the extracellular N-terminal peptide chain of the PAR molecule at a specific site to expose a new N-terminus having a receptor activation sequence consisting of 5-6 amino acid residues. Newly exposed N
The activation of the receptor occurs by binding the end of the chain as a chain ligand to the active site of PAR itself. PAR2 has been shown to be activated by trypsin, tryptase, or blood coagulation factor VIIa or Xa. In addition, 5 to 6 synthesized based on the receptor activation sequence
It is known to be activated by a synthetic peptide consisting of 4 amino acids (Dery, O. et al. Am. J. Physi
ol., 274, C1429-52, 1998; Macfarlane, SR et al.,
Pharmacol Rev. 53, 245-82, 2001). PAR2 is a blood vessel,
It has been reported to be expressed in the prostate, small intestine, colon, liver, kidney, pancreas, stomach, lung, brain and skin. Also,
Phospholipase is an intracellular signal via PAR2.
Elevation of intracellular calcium concentration and production of inositol triphosphate with activation of C (Santulli, RJ et al. Proc.
Natl. Acad. Sci. USA, 92, 9151-5, 1995; Bohm, SK
et al. Biochem. J., 314, 1009-16, 1996), p38 MA
P-kinase activation and c-Jun N-terminal kinase activation are known (Kanke, T. et al., J. B.
iol. Chem., 276, 31657-66, 2001). PAR2 is a secretion of digestive juice (Kawabata, A. et al., Biochem. Biophys.
s. Commun., 270, 298-302, 2000; Kawabata, A. et a
l., J. Clin. Inv., 107, 1443-50, 2001), while it is known to be involved in neurogenic inflammation (Steinhof
f, M., et al., Nature Medicine, 6, 151-8, 2000),
Pain (Kawabata, A. et.al., Neuroreport 12, 715-9,
2001; Hoogerwerf, WA et al., J. Neurosci., 21, 90
36-42, 2001; Vergnolle, N., et al., Nature Medicin
e, 7, 821-6, 2001), inflammation (Nystedt, S., et al., J.
Biol. Chem., 271, 14910-5, 1996; Lindner, JR e
al., J. Immunol., 165, 6504-10, 2000), allergy (Sun, G. et al., J. Immunol., 167, 1014-21, 200)
1; Miike, S. et al., J. Immunol., 167, 6615-22, 20.
It is known to be an aggravating factor in various diseases such as 01). In addition, although a synthetic peptide derivative based on the receptor activation sequence has been reported as a PAR2 agonist,
From studies using the synthetic peptide derivatives, it has been suggested that PAR2 antagonists are useful as therapeutic agents for intestinal diseases, skin pigmentation inhibitors, allergic diseases, or cancer metastasis inhibitors. In addition, it has been suggested that PAR2 agonists are useful as therapeutic agents for bronchial diseases or agents for protecting digestive organs. However, a compound actually having PAR2 inhibitory activity has not been known at all. on the other hand,
A compound having a pyrazopyrimidine skeleton has a registry number: 334500-35- in Chemical Abstracts.
5, 304686-65-5, 312634-72-3, 312918-87-9, 312934-9
Compounds such as 8-6, 313987-33-6, or 313986-65-1 are known, and as pyrazopyrimidine compounds having an anti-inflammatory / analgesic action, JP-A-5-125079 and JP-A-1-25079.
The compounds described in 1-279178 and International Patent Publication No. 95/35298 are known, but no compounds suggesting a relationship with PAR2 inhibitory activity are known. Also,
Neither pyrazopyrimidine compound having a PGE2 production inhibitory action is known.

[0003]

At present, it is considered that PAR2 is involved in various diseases, but no compound that inhibits PAR2 has been obtained. The problem to be solved by the present invention is to find an inhibitor against PAR2 and to provide a therapeutic agent for a disease involving PAR2.

[0004]

[Means for Solving the Problems] The present inventors believe that a PAR2 inhibitor is useful as a therapeutic agent for various diseases caused by the hyperfunction of PAR2, and therefore, using HEK293 cells, Fl
The PAR2 inhibitory activity of various test compounds was measured by measuring the change in intracellular calcium concentration using a method such as a uorometric Imaging Plate Reader (FLIPR). As a result, it was found that the pyrazopyrimidine compound exhibits PAR2 inhibitory activity. In addition, PAR2 is expressed in cultured cells of cartilage and synovium that form joints, and when PAR2 is activated by adding a synthetic peptide agonist or trypsin to the cultured cells, it is an arthritis exacerbating substance. It was found that the release of prostaglandin E2 (PGE2) occurs. It has been known that PGE2 is increased in tissues affected by arthritis such as rheumatoid arthritis, and is considered to be an aggravating factor for arthritis. Therefore, based on the above findings, PAR2 was considered to be an aggravating factor for arthritis. Furthermore,
It was found that the release of PGE2 in cultured cells was inhibited by the pyrazopyrimidine compound. Ie PA
The R2 inhibitor shows a PGE2 production inhibitory activity and is useful as a therapeutic agent for diseases associated with hyperfunction of PGE2. The present invention has been completed based on the above findings.

That is, the present invention is [1] General formula (1)

[Chemical 5] (In the formula, R¹And R^TwoEach independently represent a hydrogen atom
Or hydroxyl, alkoxy, nitrile, substituted or
An unsubstituted aryl group, or a substituted or unsubstituted hethe
Represents an alkyl group which may be substituted with a lower aryl group
Or R ¹And R^TwoTogether with adjacent carbon atoms
Bonded to an alkyl group, substituted or unsubstituted aryl
Carbonyl group, alkylcarbonyl group, alkoxycal
Bonyl group, substituted or unsubstituted aryl group, or
Substituted or unsubstituted with an arylalkyl group
1 to 2 nitrogen atoms, 0 to 1 oxygen atom,
And a heterocycloalkane containing 0 to 1 sulfur atom
Forming, R^ThreeIs a hydrogen atom, alkyl group, halo group
Represents a alkyl group or a substituted or unsubstituted aryl group.
And R^FourAnd R⁵Are independently hydrogen atom, halogen
Atom, alkyl group, alkoxy group, methylenedioxy
Represents a group or a haloalkyl group. A compound represented by
Or a pharmaceutically acceptable salt thereof as an active ingredient
PAR2 inhibitor. [2] R^ThreeIs represented by a haloalkyl group,
The PAR2 inhibitor according to [1]. [3] The haloalkyl group is a trifluoromethyl group
The PAR2 inhibitor according to [2], which is characterized in that [4] R¹And R^TwoBond with adjacent carbon atoms
, Alkyl group, alkylcarbonyl group, arylcarl
Bonyl group, alkoxycarbonyl group, phenyl group,
Is optionally substituted with a benzyl group, piperidine,
-Hydroazepine, morpholine, thiomorpholine,
Is characterized by forming piperazine, [1] ~
The PAR2 inhibitor according to any one of [3]. [5] R¹And R^TwoBond with adjacent carbon atoms
With an alkyl group or an alkoxycarbonyl group.
Optionally substituted piperidine, or perhydroa
[4], characterized in that it forms zepines
PAR2 inhibitor. [6] General formula (2)

[Chemical 6] [Wherein R ¹ is the following group:

[Chemical 7] Or

[Chemical 8] (In the formula, R ⁶ represents a hydrogen atom, an arylcarbonyl group or an alkylcarbonyl group, R ⁷ represents a hydrogen atom or an alkyl group, and R ⁸ and R ⁹ represent a hydrogen atom, an alkyl group or an alkoxycarbonyl group. Represents a group, R ¹⁰ represents an alkyl group, R ¹¹ represents a hydroxyl group, an alkoxy group, a nitrile group, a substituted or unsubstituted aryl group, or an alkyl group which may be substituted with a substituted or unsubstituted heteroaryl group. R ^{3 ′} represents a hydrogen atom, an alkyl group, a haloalkyl group, or a phenyl group, and R ^{4 ′} and R ^{4 ′
5 'independently} represent a hydrogen atom, a halogen atom, an alkyl group or a haloalkyl group. ] The PAR2 inhibitor containing the compound represented by these, or its pharmaceutically acceptable salt as an active ingredient. [7] A PGE2 production inhibitor containing a compound having PAR2 inhibitory activity as an active ingredient. [8] A compound having PAR2 inhibitory activity is [1] to
8. The PGE2 production inhibitor according to claim 7, which is the compound according to any one of [6] or a pharmaceutically acceptable salt thereof. [9] An anti-inflammatory agent containing a compound having PAR2 inhibitory activity as an active ingredient. [10] A compound having PAR2 inhibitory activity is [1] to
The anti-inflammatory agent according to [9], which is the compound according to any one of [6] or a pharmaceutically acceptable salt thereof. [11] An analgesic comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, PAR2 means
Represents a polypeptide that is a proteinase-activated receptor that is activated by proteases such as trypsin and tryptase that belong to the G protein-coupled 7-transmembrane receptor, and retains its binding activity with a known PAR2 agonist. Or as long as it retains PAR2 activity,
It also contains its homologues and derivatives. The amino acid sequence for humans is Bohm, SK et al. Biochem.l.
J., 314, 1009-16, 1996 (Genbank Ac. No. U34038). For homologues from other animal species, see Mouse: Nystedt S. et al., J. Biol. Chem., 270, 595.
0-55, 1995 (Genbank Ac. No. Z48043); Rat: Sa
ifeddine M. et al., Br. J. Pharmacol., 118, 521-3
0, 1996 (Genbank Ac. No. U61373). As the known PAR2 agonists, specifically, polypeptides synthesized based on the receptor activation sequence: SLIGKV, SLIGRL and its modified peptide trans-cinn
Amoyl-LIGRLO etc. are mentioned.

[0007] In the present specification, the PAR2 inhibitor is not limited as long as it is a compound that acts in the direction of inhibiting the activity of PAR2, and is a concept including a compound that decreases the expression level of PAR2, a PAR2 antagonist and the like. Is. Here, the "compound that decreases the expression level of PAR2" refers to a compound that decreases the expression level of mRNA encoding PAR2 or a compound that decreases the protein amount of PAR2. In the present specification, as a method for measuring the activity of PAR2, an increase in intracellular calcium concentration, an increase in intracellular inositol triphosphate production,
Examples include measurement of increase in intracellular protein phosphorylation by protein kinase C or MAP kinase, or increase in prostaglandin E2 (PGE2) release from cells. As a method for measuring intracellular calcium concentration increasing activity, human embryonic kidney-derived cell line HEK293 cells, human lung cancer-derived cell line A5
49, or a human fetal lung-derived cell line HFL1 or other cultured cell line is preloaded with a calcium-binding fluorescent probe, and PAR2 agonist (synthetic peptide such as NH2-SLIGRL-CONH2) or trypsin is added to activate PAR2. The intracellular calcium concentration that fluctuates as a result of changes to FLIPR (Molecular Devices) as a change in the fluorescence signal.
And a method of detecting with time. Also, Aequorin
It is also possible to measure the intracellular calcium concentration by quantifying the fluorescence intensity generated in proportion to the calcium concentration using a cell line that highly expresses a Ca-binding chromogenic protein such as. Specifically, the methods described in Examples of the present specification can be mentioned. The PAR2 inhibitors herein are preferably administered according to the Examples
In the method described in 16, the compound shows a PAR2 inhibitory activity of 30% or more at 10 μg / ml. The PAR2 inhibitor in the present specification is preferably a low molecular weight organic compound having a molecular weight of 300 to 2000, preferably a molecular weight of 300 to 800.

The PGE2 production inhibitor refers to a compound that inhibits the production amount of PGE2, and the PGE2 production inhibitory activity of the compound is
It can be measured by using a known method. Specifically, the PGE2 production inhibitory activity was measured by adding a test compound and a PAR2 agonist or a substance that activates PAR2 such as trypsin to the SW982 cell line for 1 hour to
After culturing for 24 hours, it can be calculated by measuring the amount of PGE2 produced in the culture supernatant. As a method for detecting PGE2, a method using a prostaglandin E2 antibody or the like can be mentioned.

In the present specification, the alkyl group represents an alkyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms.
And more preferably an alkyl group having 1 to 4 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a butyl group and the like. In the present specification, the alkoxy group has 1 to 1 carbon atoms.
It represents an alkoxy group having 0 carbon atoms, preferably an alkoxy group having 1 to 6 carbon atoms, and more preferably an alkoxy group having 1 to 4 carbon atoms. Specific examples include a methoxy group, an ethoxy group, a propoxy group, a 1-methylethoxy group, and a butoxy group. In the present specification, a halogen atom is
It represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom.
In the present specification, the haloalkyl group represents the same or different haloalkyl group having 1 to 3 carbon atoms and containing 1 to 3 halogen atoms, specifically, a trifluoromethyl group, a difluoromethyl group, 1, Examples thereof include a 1,1-trifluoroethyl group and a 2,2-difluoroethyl group. Preferred is a trifluoromethyl group. In the present specification, examples of the heterocycloalkane include pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide, perhydroazepine, perhydrodiazepine and the like. Preference is given to pyrrolidine, piperidine, piperazine or perhydroazepine. When the heterocycloalkane is substituted, examples of the substituent include an alkyl group, a substituted or unsubstituted arylcarbonyl group, an alkylcarbonyl group, an alkoxycarbonyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl group. An arylalkyl group may be mentioned. Preferably, when the substituent is substituted on the carbon atom, examples of the substituent include an alkyl group having 1 to 4 carbon atoms and an alkoxycarbonyl group having 2 to 4 carbon atoms. When the heterocycloalkane is substituted on the nitrogen atom, the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkylcarbonyl group having 1 to 4 carbon atoms. , A substituted or unsubstituted arylcarbonyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted arylalkyl group. The substituted or unsubstituted arylcarbonyl group, the substituted or unsubstituted aryl group, or the aryl in the substituted or unsubstituted arylalkyl group is phenyl, 1-naphthyl,
Alternatively, 2-naphthyl can be mentioned, and phenyl can be mentioned particularly preferably. Moreover, as the substituent in the substituted arylcarbonyl group, the substituted aryl group, or the substituted arylalkyl group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a methylenedioxy group, or the like. Is mentioned.

In the compound represented by the general formula (1),
R ¹ and R ² are preferably bonded together with adjacent carbon atoms and have 1 to 2 nitrogen atoms optionally substituted with an alkyl group, an arylcarbonyl group, an alkylcarbonyl group, or an alkoxycarbonyl group, 0 to A heterocycloalkane containing one oxygen atom and 0 to 1 sulfur atom is formed, and the heterocycloalkane is
Preferred is piperidine, piperazine, or perhydroazepine. Alternatively, in the compound represented by the general formula (1), R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents a hydroxyl group, an alkoxy group, a nitrile group, a substituted or unsubstituted aryl group, or a substituted group. Alternatively, it is also one of the preferable embodiments to represent an alkyl group which may be substituted with an unsubstituted heteroaryl group. Examples of the aryl group include a phenyl group. Moreover, a pyridyl group is mentioned as said heteroaryl group.
When the substituent of the alkyl group in R ² represents a substituted aryl group or a substituted heteroaryl group, the substituent of the aryl group or the heteroaryl group is a halogen atom, an alkyl group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms. And a haloalkyl group having 4 or an alkoxy group having 1 to 4 carbon atoms. In the compound represented by the general formula (1), examples of the aryl group for R ³ include a phenyl group, and when the aryl group is substituted, the substituent is a halogen atom or a C 1 to C 4 group. Alkyl group, carbon number 1-2
And a C 1-4 alkoxy group. R ³ preferably represents an alkyl group having 1 to 3 carbon atoms, a phenyl group, or a haloalkyl group having 1 to 2 carbon atoms. A particularly preferable example is a trifluoromethyl group. In the compound represented by the general formula (1), R ⁴ and R ⁵ are preferably the same or different and each represents a hydrogen atom or a halogen atom.

In the general formula (2), R ⁶ is preferably a hydrogen atom, an alkylcarbonyl group having 2 to 4 carbon atoms,
Alternatively, it represents a benzoyl group. In the general formula (2), R
⁷ is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a hydrogen atom or a methyl group. In the general formula (2), R ⁸ is preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or 2 to 4 carbon atoms.
And more preferably a hydrogen atom, a methyl group, a methoxycarbonyl group, or an ethoxycarbonyl group. When R ⁸ represents an alkoxycarbonyl group, R ⁷ preferably represents a hydrogen atom. In the general formula (2), R ⁹ is preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or 2 to 4 carbon atoms.
Of the above, and more preferably a hydrogen atom, a methoxycarbonyl group, or an ethoxycarbonyl group. In formula (2), R ¹⁰ preferably represents a methyl group or an ethyl group, and R ¹¹ represents
It preferably represents a hydroxyl group, or an ethyl group which may be substituted with a pyridyl group, or a propyl group.

Many of the compounds represented by the formula (1) are known and can be obtained as commercial products. It can also be manufactured by the following method. Manufacturing method:

[Chemical 9] [In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ have the same meanings as described above. The hydrazone of the formula (1-2) is a known compound of the formula (1
-1) compound and hydrazine monohydrate, under acidic conditions
It can be produced by reacting at 0 to 100 ° C. Examples of the solvent include alcohol solvents such as methanol and ethanol, halogen solvents such as chloroform and dichloromethane, dimethylformamide, dimethyl sulfoxide,
Acetone, acetonitrile, an ether solvent such as dioxane or tetrahydrofuran, water, a mixed solvent thereof or the like is used. Alcohol solvents such as methanol and ethanol are more preferable. As the acid, acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid or the like can be used. In this reaction, the compound of formula (1-3) can be produced by a method such as using sulfuric acid as an acid in chloroform without isolating the compound of formula (1-2). The compound of formula (1-2) can be obtained by adding a base and heating the compound of formula (1-2) in an alcohol solvent such as methanol or ethanol. As the base, an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium hydrogen carbonate, or an organic base such as triethylamine or pyridine is used. Preferably, potassium carbonate or sodium carbonate can be used.
The compound of the formula (1-5) is obtained by reacting the compound of the formula (1-3) and the 1,3-diketone of the formula (1-4) at room temperature in the presence or absence of a base or an acid. It can be produced by reacting at 100 ° C. Examples of the solvent include alcohol solvents such as methanol and ethanol, halogen solvents such as chloroform and dichloromethane, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, ether solvents such as dioxane and tetrahydrofuran, water, or a mixed solvent thereof. Etc. are used. Of these, alcohol solvents such as methanol and ethanol are more preferable. Acids include acetic acid, hydrochloric acid,
Alternatively, a Lewis acid such as zinc chloride can be used. As the base, an organic base such as pyrrolidine or piperidine can be used. As the compound of the formula (1-4), a known compound can be used, or it can be produced by the method described in Examples of the present specification. In addition, the compound of formula (1-5) can also be produced from the compound of formula (1-2) without isolation of the compound of formula (1-3). The compound of formula (1-6) can be produced by hydrolyzing the compound of formula (1-5) to give a carboxylic acid, and then condensing it with a commercially available amine compound according to a known method. Examples of the condensation method include a method using a water-soluble carbodiimide (WSCI) described in the present specification, a mixed acid anhydride method, and a method using an acid halide. For the condensation method, refer to “Comprehensive Organic Transformation
(Larock, RC, VCH Publishers, Inc. 1989) "and the like.

Particularly preferred compounds represented by the general formula (1) include compounds represented by the following formulas 51 to 64.

[Chemical 10]

The compound represented by the general formula (1), or a pharmaceutically acceptable salt thereof, is useful as a therapeutic agent, preventive agent, or antiprogressive agent for diseases associated with PAR2 hyperactivity. Specifically as the disease, arthritis (degenerative arthritis,
Osteoarthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, including juvenile arthritis and rheumatoid arthritis), fever (rheumatic fever and influenza and other viral infection-related fever), common cold, menstruation Difficult,
Menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reaction, allergic contact hypersensitivity, Cancer (eg, solid tumor cancers including colon cancer, breast cancer, lung cancer and prostate cancer; hematopoietic malignancies including leukemia and lymphoma; Hodgkin's disease; aplastic anemia, skin cancer and familial adenoma polyposis),
Tissue ulcer, peptic ulcer, gastritis, localized enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia,
Synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants,
Atherosclerosis (atherosclerotic platelet destruction),
Aortic aneurysm (abdominal aortic aneurysm and cerebral aortic aneurysm), nodular periarteritis, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head injury, spinal cord injury, neuralgia, neurodegenerative disease (acute and chronic), self Immune diseases, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (lower back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic
pic) or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscular or joint sprain or tension, tendonitis, skin disease (Eg, psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, burns, diabetes (type I and II diabetes, diabetic retinopathy), tumor invasion, Tumor growth, tumor metastasis, corneal scars, scleritis, immunodeficiency diseases (eg human AIDS, feline FL)
V, FIV), sepsis, preterm birth, hypoprothrombinemia,
Examples include hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease and the like. Preferably,
Arthritis (including osteoarthritis, spondyloarthropathy, gouty arthritis, systemic lupus erythematosus, juvenile arthritis and rheumatoid arthritis), dermatitis, fever, asthma, bone resorption, cardiovascular disease, dysmenorrhea, preterm birth , Nephritis, nephrosis, atherosclerosis, hypotension, shock, pain, neurogenic inflammation derived from painful nerve tissue, cancer, and Alzheimer's disease. In addition, the present inventors
As can be seen from Example 19, PAR2 is expressed in cultured cells of cartilage and synovium that compose a joint, and as can be seen from Example 20, PAR2 is activated in cells of cartilage and synovium. It was discovered for the first time that the release of prostaglandin E2 (PGE2), which is an arthritis exacerbating substance, occurs when activated. Furthermore, it was found that the PAR2 inhibitor of the present invention actually suppresses the release of PGE2 in the cells of cartilage and synovium described above. That is, a PGE2 production inhibitor containing a compound having PAR2 inhibitory activity as an active ingredient is also one aspect of the present invention.

The dosage and administration form of the therapeutic, prophylactic or antiprogressive agent for the above diseases containing the PAR2 inhibitor of the present invention as an active ingredient will be described below. The PAR2 inhibitor of the present invention can be administered orally or parenterally, preferably orally,
It is used in humans and non-human animals in various dosage forms suitable for oral or parenteral administration as drugs. For example, when it is orally administered, it can be administered in a commonly used administration form such as tablets, capsules, syrups and suspensions. In the case of parenteral administration, solutions such as solutions, emulsions and suspensions can be administered as injections, and can be rectally administered in the form of suppositories. Such a dosage form can be produced according to a general method by mixing an active ingredient with an auxiliary agent such as a usual carrier, excipient, binder and stabilizer. When used in an injection form, a buffering agent, a solubilizing agent, an isotonicity agent, etc. may be added. The dose and the number of doses vary depending on the disease to be treated, the symptoms of the patient, age, body weight, etc., and the administration form, but when orally administered, the active ingredient is usually about 1 to 1000 mg per day for an adult. The range, preferably the range of about 10 to 500 mg, can be administered once or in several divided doses. When administered as an injection, the active ingredient is in the range of about 0.1 to about 500 mg, preferably about 3 to.
The range of about 100 mg can be administered once or in several divided doses.

[0016]

[Example] Example 1 Ethyl (2E) -3-cyano-2-hydrazonopropanoate

[Chemical 11] Ethyl cyanopyruvate sodium enolate
cyanopyruvate sodium-enolate (7.8g) with acetic acid (40m
l) and ethanol (40 ml), and add hydrazine 1 at 0 ℃.
The hydrate was added. After 30 minutes, the mixture was brought to room temperature and stirred overnight. The reaction solution was concentrated, water and chloroform were added, and the layers were separated and extracted. The organic layer was dried and concentrated to obtain the desired product (5.0 g). ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.34-1.41 (m, 3H), 3.
46 (s), 3.63 (s), 4.26-4.38 (m, 2H), 6.52 (brs), 8.50
(br)

Example 2 Ethyl 5-phenyl-7- (trifluoromethyl) pyrazolo
[1,5-a] pyrimidine-2-carboxylate

[Chemical 12] The compound (5.0 g) of Example 1 was dissolved in ethanol (50 ml), potassium carbonate (1.0 g) was added, and the mixture was heated under reflux. 3
After 4 hours, 4,4,4-trifluoro-1-phenyl-1,3-butanedione (10.5 g) was added, and the mixture was heated under reflux. The generated crystals were filtered and dried to obtain the desired product (4.0 g). ¹ H-NMR (400MHz, DMSO-d ₆ ) δppm: 1.37 (t, 3H, J = 7.1H
z), 4.42 (q, 2H, J = 7.1Hz), 7.44 (s, 1H), 7.57-7.65
(m, 3H), 8.31-8.38 (m, 3H)

Example 3 Potassium 5-phenyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine-2-carboxylate

[Chemical 13] The compound of Example 2 (4.6 g), ethanol (50 ml) and a 1N aqueous potassium hydroxide solution (15 ml) were mixed and heated to reflux. After 30 minutes, it was cooled to room temperature. The generated crystals were filtered and dried to obtain the desired product (4.2 g). ¹ H-NMR (400MHz, DMSO-d ₆ ) δppm: 6.87 (s, 1H), 7.53-
7.59 (m, 3H), 8.02 (s, 1H), 8.24-8.31 (m, 2H)

Example 4 5-Phenyl-2- (piperidin-1-ylcarbonyl) -7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine

[Chemical 14] The compound (3.0 g) obtained in Example 3 was dissolved in DMF to give N-hydroxybenzotriazole (2.35 g) and piperidine (0.95 m).
l) and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (1.84 g) were added, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction solution, and the layers were separated and extracted. The organic layer was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over sodium sulfate, and concentrated.
The residue is washed with diisopropyl ether, filtered, dried,
The desired product (2.8 g) was obtained. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.62-1.78 (m, 6H),
3.75-3.83 (m, 4H), 7.17 (s, 1H), 7.54-7.59 (m, 3H),
7.68 (s, 1H), 8.09-8.16 (m, 2H)

Example 5 2-[(2-Methylpiperidin-1-yl) carbonyl] -5-phenyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine

[Chemical 15] The target product (1.8 g) was obtained from the compound obtained in Example 3 and 2-methylpiperidine by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.30-1.40 (m, 3H),
1.49-1.90 (m, 6H), 2.90-3.30 (m, 1H), 4.20-4.74 (m, 1
H), 4.55-5.14 (m, 1H), 7.15 (s, 1H), 7.54-7.59 (m, 3
H), 7.67 (s, 1H), 8.09-8.15 (m, 2H)

Example 6 2- (azepan-1-ylcarbonyl) -5-phenyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine

[Chemical 16] The target product (1.7 g) was obtained from the compound obtained in Example 3 and hexamethyleneimine by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.60-1.73 (m, 4H),
1.81-1.93 (m, 4H), 3.73-3.85 (m, 4H), 7.23 (s, 1H),
7.54-7.59 (m, 3H), 7.68 (s, 1H), 8.09-8.15 (m, 2H)

Example 7 2-[(4-benzoylpiperazin-1-yl) carbonyl] -5-phenyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine

[Chemical 17] The target product (1.6 g) was obtained from the compound obtained in Example 3 and 1-benzoylpiperazine hydrochloride by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 3.50-4.25 (m, 8H),
7.28 (s, 1H), 7.55-7.60 (m, 3H), 7.72 (brs, 1H), 8.10
-8.15 (m, 2H)

Example 8 Ethyl 1-{[5-phenyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-2-yl] carbonyl} piperidine-2
-Carboxylate

[Chemical 18] The target product (0.1 g) was obtained from the compound obtained in Example 3 and ethyl pipecolic acid hydrochloride by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.26-1.35 (m, 3H),
1.40-1.90 (m, 5H), 2.28-2.43 (m, 1H), 3.00-3.40 (m, 1
H), 4.20-4.32 (m, 2H), 4.45-4.80 (m, 1H), 5.45-5.60
(m, 1H), 7.21-7.28 (m, 1H), 7.53-7.60 (m, 3H), 7.67-
7.71 (m, 1H), 8.10-8.06 (m, 2H)

Example 9 Ethyl 1-{[5-phenyl-7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-2-yl] carbonyl} piperidine-4
-Carboxylate From the compound obtained in Example 3 and ethyl isonipecotate,
The target product (0.2 g) was obtained by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.28 (t, 3H, J = 7.1H
z), 1.80-2.12 (m, 4H), 2.64 (m, 1H), 3.13 (m, 1H), 3.3
7 (m, 1H), 4.18 (q, 1H, J = 7.1Hz), 4.46-4.62 (m, 2H),
7.21 (s, 1H), 7.54-7.60 (m, 3H), 7.69 (s, 1H), 8.10-
8.16 (m, 2H) Example 10 1- (4-chlorophenyl) -4,4,4-trifluorobutane-1,3-
Zeon

[Chemical 19] 4-Chloroacetophenone (4.6 ml) was dissolved in tetrahydrofuran (50 ml), cooled to 0 ° C., and sodium hydride (1.55 g; 60%) was added. After 15 minutes, it was brought to room temperature and stirred for 30 minutes. The reaction solution was cooled to 0 ° C., and ethyl trifluoroacetate was added. After 2 hours, the temperature was raised to room temperature and the mixture was further stirred for 1.5 hours. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to obtain the desired product (10.6 g). ¹ H-NMR (400MHz, DMSO-d ₆ ) δppm: 7.02 (s, 1H), 7.6
6 (d, 2H, J = 8.7Hz), 8.14 (d, 2H, J = 8.7Hz)

Example 11 Ethyl 5- (4-chlorophenyl) -7- (trifluoromethyl)
Pyrazolo [1,5-a] pyrimidine-2-carboxylate

[Chemical 20] Using the compound obtained in Example 1 and the compound obtained in Example 10, the target product (4.3 g) was obtained in the same manner as in Example 2. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.47 (t, 3H, J = 7.1
Hz), 4.51 (q, 2H, J = 7.1Hz), 7.38 (s, 1H), 7.52-7.57
(m, 2H), 7.71 (s, 1H), 8.07-8.12 (m, 2H)

Example 12 Potassium 5- (4-chlorophenyl) -7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine-2-carboxylate

[Chemical 21] The target product (3.5 g) was obtained from the compound obtained in Example 11 by the same method as in Example 3.

Example 13 5- (4-chlorophenyl) -2- (piperidin-1-ylcarbonyl) -7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidine

[Chemical formula 22] The target product (0.1 g) was obtained from the compound obtained in Example 12 and piperidine by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.61-1.77 (m, 6H),
3.76-3.83 (m, 2H), 7.18 (s, 1H), 7.51-7.56 (m, 2H),
7.63 (s, 1H), 8.06-8.11 (m, 2H)

Example 14 5- (4-chlorophenyl) -2-[(2-methylpiperidin-1-yl) carbonyl] -7- (trifluoromethyl) pyrazolo [1,5-
a] pyrimidine

[Chemical formula 23] The target product (0.1 g) was obtained from the compound obtained in Example 12 and 2-methylpiperidine by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.31-1.40 (m, 3H),
1.50-1.90 (m, 6H), 2.90-3.30 (m, 1H), 4.20-4.73 (m, 1
H), 4.53-5.15 (m, 1H), 7.14 (s, 1H), 7.51-7.56 (m, 2
H), 7.63 (s, 1H), 8.06-8.11 (m, 2H)

Example 15 2- (azepan-1-ylcarbonyl) -5- (4-chlorophenyl)
-7- (Trifluoromethyl) pyrazolo [1,5-a] pyrimidine

[Chemical formula 24] The target product (0.1 g) was obtained from the compound obtained in Example 12 and hexamethyleneimine by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.60-1.71 (m, 4H),
1.80-1.92 (m, 4H), 3.73-3.84 (m, 4H), 7.23 (s, 1H),
7.51-7.56 (m, 2H), 7.63 (s, 1H), 8.06-8.11 (m, 2H)

Example 16 Ethyl 1-{[5- (4-chlorophenyl) -7- (trifluoromethyl) pyrazolo [1,5-a] pyrimidin-2-yl] carbonyl}
Piperidine-2-carboxylate

[Chemical 25] The target product (1.6 g) was obtained from the compound obtained in Example 12 and ethyl pipecolic acid hydrochloride by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 1.26-1.35 (m, 3H),
1.36-1.90 (m, 5H), 2.27-2.42 (m, 1H), 3.00-3.40 (m,
1H), 4.20-4.33 (m, 2H), 4.50-4.80 (m, 1H), 5.50-5.58
(m, 1H), 7.22-7.26 (m, 1H), 7.50-7.56 (m, 2H), 7.62-
7.66 (m, 1H), 8.06-8.12 (m, 2H) Example 17 5- (4-chlorophenyl) -N- (2-hydroxyethyl) -N-methyl-7- (trifluoromethyl) pyrazolo [1, 5-a] pyrimidine
-2-carboxamide The target product (1.8 g) was obtained from the compound obtained in Example 12 and 2- (methylamino) ethanol by the same method as in Example 4. ¹ H-NMR (400MHz, CDCl ₃ ) δppm: 3.05-3.24 (m, 1H),
3.24-3.47 (m, 3H), 3.78-4.00 (m, 4H), 7.27-7.33 (m, 1
H), 7.51-7.58 (m, 2H), 7.65-7.70 (m, 1H), 8.06-8.12
(m, 2H)

Example 18: Fluorometric Imaging Plate
Measurement of intracellular calcium concentration using Reader (FLIPR) [Materials and methods] Human embryonic kidney-derived cell line HEK293 cells cultured in DMEM culture medium (Invitrogen) supplemented with 10% fetal bovine serum (10% FBS) were 2.5. 96-well black plate (clear bottom) prepared with X10 ⁵ cells / ml and coated with poly-D-lysine
(Falcon) was seeded at 80 μl / well and cultured overnight in a carbon dioxide gas culture device. Hanks-20mM Hepes buffer (pH7.4)
FLIPR Calcium Assay Kit (Molecular Devic
es) was added to the cells at 80 μl / well, and the cells were cultured for 1 hour in a carbon dioxide incubator. Hanks-20 mM Hepes buffer (pH 7.
Trypsin (SIGMA T8642) adjusted to 0.0005% in 4)
Was added to a 96-well V-bottom polypropylene plate (Nunc Co., Ltd.) to prepare a reagent plate. FLIPR (Molecular Devices
Immediately before measuring with Hanks-20 mM Hepes buffer (pH 7.
The test compound prepared in 4) was added to the cells at 40 μl / well, and the mixture was stirred with a plate shaker. Set the cell plate and reagent plate to which the test compound was added to FLIPR,
Changes in intracellular calcium concentration were detected with a CCD camera. The measurement was performed at room temperature for 70 seconds, and the addition of the reagent from the reagent plate to the cell plate (50 μl / well) was performed by a 96-well automatic pipetting machine built in the FLIPR main body. [Results] Table 1 shows the intracellular calcium elevation inhibitory rate (%) of the test compounds.

[Table 1]   Compound Compound concentration Suppression rate (%) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Compound of Example 4 10 μg / ml 90.5 Compound of Example 5 10 μg / ml 52.1 Compound of Example 6 10 μg / ml 52.8 Compound of Example 7 10 μg / ml 51.4 Example 8 compound 10 μg / ml 79.6 Example 13 compound 10 μg / ml 63.7 Example 14 compound 10 μg / ml 47.6 Compound of Example 15 10 μg / ml 67.5 Compound of Example 17 10 μg / ml 40.5 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−

Example 19: Western blotting using PAR2 antibody Human synovial cell line SW982, human chondroid cell line SW1353, human lung cancer-derived cell line A549, human fetal lung-derived cell line HFL1,
Human embryonic kidney-derived cell line HEK293 was suspended in DMEM culture solution containing FBS 10% (Invitrogen) or F12K culture solution containing FBS 10% (Invitrogen) so as to have 2.5 × 10 ⁵ cells / ml, and 12-well plate ( Asahi Techno Glass Co., Ltd.)
Each cell was seeded at 1 ml / well. After culturing in a carbon dioxide incubator for two nights, RIPA buffer (1xPBS, 1% NP
40, 0.5% sodium deoxycholate, 0.1% SDS, 1mM PMSF,
1 μg / ml trypsin inhibitor, 1 μg / ml leupeptin) 3
0 μl / well was added to lyse and suspend the cells. 25 μl of 2X Sample buffer was added to 25 μl of the lysate and heat-treated at 100 ° C. for 5 minutes, then 10 μl was collected and electrophoresed on a 10% polyacrylamide gel. After the migration, the sample was transferred onto an Immobilon-PVDF membrane (Millipore) under the condition of 50V for 2 hours using a blotting cell (Bio-Rad). The membrane was blocked with 3% skim milk-0.1% Tween-PBS solution overnight at 4 ° C, and then diluted with 500-fold human PAR2 antibody (Santa Cruz # sc-8205 [C-17]) at room temperature. The reaction was carried out for 3 hours. After the reaction, the membrane was washed and reacted with a secondary antibody (Amersham Pharmacia) diluted 5000 times at room temperature for 1 hour. Then, the signal was detected according to the ECL western blotting detection system protocol (Amersham Pharmacia). The results are shown in Fig. 1. As shown in FIG. 1, PAR2 is also expressed in human synovium-like cell line SW982 and human chondroid-like cell line SW1353, similar to the cell lines such as A549, HFL1 and HEK293 which have been reported to date. It became clear.

Example 20: Measurement of PGE2 amount using human synovial cell line SW982 SW982 cells were diluted with each medium to 2.5 × 10 ⁵ cells / ml, and 100 μl / well cells were added to a 96-well plate. I sown.
After preculturing overnight in a carbon dioxide incubator, the medium was removed, and 5 μg / ml compound-containing medium was added at 80 μl / well (0.1% for control group, control peptide group, agonist peptide alone group, IL-1β group). % DMSO containing medium was added). To the wells containing the compound, 20 μl / well of a medium containing 500 uM agonist peptide was added (final concentration: 4 μg / ml compound / 100 uM agonist peptite). Control medium wells 20 ul / well, control peptide group wells 500 μM control peptide medium 20 μl / well (final concentration 100 μM), agonist peptide alone group wells 500 uM agonist peptide medium 20 μl / well (final concentration 100 μM), IL-
20 μl / w of medium containing 50 ng / ml IL-1β was added to the wells of 1β group.
ell (final concentration 10 ng / ml) was added. 24 hours later (N
= 3) Each supernatant was collected and stored at -80 ° C until measurement. The amount of PGE2 in each supernatant was measured by prostaglandin E2 EIA.
(Cayman chemical 514010). The PGE2 level of the control peptide is 100%, and the PGE2 level of the agonist peptide is 0%.
The production inhibition rate was calculated. Table 2 shows the amount of PGE2 produced (pg / ml) by each stimulation of the human synovial cell line SW982.

[Table 2] Stimulator PGE2 production (pg / ml) −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 900 SLIGRL (Agonist peptide) 2000 LSIGRL (Control peptide) 900 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− PGE2 of the test compound The production inhibition rate (%) is shown in Table 3.

Table 3 0.25 μg / ml 1 μg / ml −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Compound of Example 4 84 119 Compound of Example 6 58 115 Compound of Example 17 71 111 Compound of Example 13 97 75 Compound of Example 8 21 135 Compound of Example 14 56 192 Compound of Example 15 91 119 Compound of Example 9 55 91 Compound of Example 16 98 131 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− From the results of Table 2 and Table 3, When PAR2 of synovial cells is activated, the release of PGE2, which is an inflammation / pain exacerbating factor, occurs, and the PAR2 inhibitor found by the present invention is an inhibitor of PGE2 that occurs with activation of these PAR2. It turns out that production can be inhibited.

[0034]

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a PAR2 inhibitor useful as a therapeutic agent, preventive agent, or antiprogressive agent for PAR2-related diseases.

[0035]

[Brief description of drawings]

FIG. 1 (left) shows an SDS-PAGE stained image of each cell suspension. An amount corresponding to cells growing in 0.6 cm ² of each sample was electrophoresed. (Right) Shows the results of Western blotting using anti-human PAR2 antibody. Since PAR2 undergoes glycosylation, multiple bands are detected. It can be seen that PAR2 is expressed in all cells. SW982: human synovial cell line; SW1353: human chondroid cell line; A549: human lung cancer-derived cell line; HFL1: human fetal lung-derived cell line; HEK293: human fetal kidney-derived cell line.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/10 103 A61P 9/10 103 11/00 11/00 19/00 19/00 21/04 21/04 25 / 00 25/00 25/16 25/16 25/28 25/28 29/00 29/00 101 101 31/04 31/04 31/18 31/18 35/00 35/00 37/08 37/08 43 / 00 111 43/00 111 C07D 487/04 142 C07D 487/04 142 (72) Inventor Shinshi Ogawa 1-46, Nigamine, Taketoyo-cho, Chita-gun, Aichi 5C room F term (reference) 4C050 AA01 BB05 CC08 EE03 FF05 GG01 HH01 HH04 4C086 AA01 AA02 CB06 MA01 MA04 NA14 ZA01 ZA02 ZA16 ZA36 ZA40 ZA45 ZA59 ZA68 ZA94 ZA96 ZB11 ZB13 ZB15 ZB26 ZB35 ZC20 ZC35 ZC55

Claims (8)

[Claims] 1. The general formula (1) [Chemical 1] (In the formula, R¹And R^TwoEach independently represent a hydrogen atom
Or hydroxyl, alkoxy, nitrile, substituted or
An unsubstituted aryl group, or a substituted or unsubstituted hethe
Represents an alkyl group which may be substituted with a lower aryl group
Or R ¹And R^TwoTogether with adjacent carbon atoms
Bonded to an alkyl group, substituted or unsubstituted aryl
Carbonyl group, alkylcarbonyl group, alkoxycal
Bonyl group, substituted or unsubstituted aryl group, or
Substituted or unsubstituted with an arylalkyl group
1 to 2 nitrogen atoms, 0 to 1 oxygen atom,
And a heterocycloalkane containing 0 to 1 sulfur atom
Forming, R^ThreeIs a hydrogen atom, alkyl group, halo group
Represents a alkyl group or a substituted or unsubstituted aryl group.
And R^FourAnd R⁵Are independently hydrogen atom, halogen
Atom, alkyl group, alkoxy group, methylenedioxy
Represents a group or a haloalkyl group. ) Compound
Substance or a pharmaceutically acceptable salt thereof as an active ingredient.
PAR2 inhibitor having. 2. The PAR2 inhibitor according to claim 1, wherein R ³ is represented by a haloalkyl group. 3. The PAR2 inhibitor according to claim 2, wherein the haloalkyl group represented by R ³ is a trifluoromethyl group. 4. A piperidine, wherein R ¹ and R ² are bonded together with adjacent carbon atoms and may be substituted with an alkyl group, an alkylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl group, a phenyl group, or a benzyl group. PAR2 inhibitor according to any one of claims 1 to 3, which forms perhydroazepine, morpholine, thiomorpholine, or piperazine. 5. R ¹ and R ² are bonded together with adjacent carbon atoms to form piperidine or perhydroazepine, which may be substituted with an alkyl group or an alkoxycarbonyl group. The PAR2 inhibitor according to claim 4, which is 6. A compound represented by the general formula (2): [Wherein R ^{1 ′} is in the following group: Or, (In the formula, R ⁶ represents a hydrogen atom, an arylcarbonyl group or an alkylcarbonyl group, R ⁷ represents a hydrogen atom or an alkyl group, and R ⁸ and R ⁹ represent a hydrogen atom, an alkyl group or an alkoxycarbonyl group. Represents a group, R ¹⁰ represents an alkyl group, R ¹¹ represents a hydroxyl group, an alkoxy group, a nitrile group, a substituted or unsubstituted aryl group, or an alkyl group which may be substituted with a substituted or unsubstituted heteroaryl group. R ^{3 ′} represents a hydrogen atom, an alkyl group, a haloalkyl group, or a phenyl group, and R ^{4 ′} and R ^{5 ′.}
Are independently a hydrogen atom, a halogen atom, an alkyl group,
Alternatively, it represents a haloalkyl group. ] Or a pharmaceutically acceptable salt thereof is contained as an active ingredient.
PAR2 inhibitor. 7. A PGE2 production inhibitor containing a compound having PAR2 inhibitory activity as an active ingredient. 8. The inhibitor of PGE2 production according to claim 7, wherein the compound having PAR2 inhibitory activity is the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.